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  • 151. Lotta, Luca A.
    et al.
    Sharp, Stephen J.
    Burgess, Stephen
    Perry, John R. B.
    Stewart, Isobel D.
    Willems, Sara M.
    Luan, Jian'an
    Ardanaz, Eva
    Arriola, Larraitz
    Balkau, Beverley
    Boeing, Heiner
    Deloukas, Panos
    Forouhi, Nita G.
    Franks, Paul W.
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Medicin. Skane University Hospital, Malmö, Sweden.
    Grioni, Sara
    Kaaks, Rudolf
    Key, Timothy J.
    Navarro, Carmen
    Nilsson, Peter M.
    Overvad, Kim
    Palli, Domenico
    Panico, Salvatore
    Quiros, Jose-Ramon
    Riboli, Elio
    Rolandsson, Olov
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Allmänmedicin.
    Sacerdote, Carlotta
    Salamanca-Fernandez, Elena
    Slimani, Nadia
    Spijkerman, Annemieke M. W.
    Tjonneland, Anne
    Tumino, Rosario
    van der A, Daphne L.
    van der Schouw, Yvonne T.
    McCarthy, Mark I.
    Barroso, Ines
    O'Rahilly, Stephen
    Savage, David B.
    Sattar, Naveed
    Langenberg, Claudia
    Scott, Robert A.
    Wareham, Nicholas J.
    Association Between Low-Density Lipoprotein Cholesterol-Lowering Genetic Variants and Risk of Type 2 Diabetes A Meta-analysis2016Ingår i: Journal of the American Medical Association (JAMA), ISSN 0098-7484, E-ISSN 1538-3598, Vol. 316, nr 13, s. 1383-1391Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Importance  Low-density lipoprotein cholesterol (LDL-C)–lowering alleles in or near NPC1L1 or HMGCR, encoding the respective molecular targets of ezetimibe and statins, have previously been used as proxies to study the efficacy of these lipid-lowering drugs. Alleles near HMGCR are associated with a higher risk of type 2 diabetes, similar to the increased incidence of new-onset diabetes associated with statin treatment in randomized clinical trials. It is unknown whether alleles near NPC1L1 are associated with the risk of type 2 diabetes.

    Objective  To investigate whether LDL-C-lowering alleles in or near NPC1L1 and other genes encoding current or prospective molecular targets of lipid-lowering therapy (ie, HMGCR, PCSK9, ABCG5/G8, LDLR) are associated with the risk of type 2 diabetes.

    Design, Setting, and Participants  The associations with type 2 diabetes and coronary artery disease of LDL-C-lowering genetic variants were investigated in meta-analyses of genetic association studies. Meta-analyses included 50 775 individuals with type 2 diabetes and 270 269 controls and 60 801 individuals with coronary artery disease and 123 504 controls. Data collection took place in Europe and the United States between 1991 and 2016.

    Exposures  Low-density lipoprotein cholesterol–lowering alleles in or near NPC1L1, HMGCR, PCSK9, ABCG5/G8, and LDLR.

    Main Outcomes and Measures  Odds ratios (ORs) for type 2 diabetes and coronary artery disease.

    Results  Low-density lipoprotein cholesterol–lowering genetic variants at NPC1L1 were inversely associated with coronary artery disease (OR for a genetically predicted 1-mmol/L [38.7-mg/dL] reduction in LDL-C of 0.61 [95% CI, 0.42-0.88]; P = .008) and directly associated with type 2 diabetes (OR for a genetically predicted 1-mmol/L reduction in LDL-C of 2.42 [95% CI, 1.70-3.43]; P < .001). For PCSK9 genetic variants, the OR for type 2 diabetes per 1-mmol/L genetically predicted reduction in LDL-C was 1.19 (95% CI, 1.02-1.38; P = .03). For a given reduction in LDL-C, genetic variants were associated with a similar reduction in coronary artery disease risk (I2 = 0% for heterogeneity in genetic associations; P = .93). However, associations with type 2 diabetes were heterogeneous (I2 = 77.2%; P = .002), indicating gene-specific associations with metabolic risk of LDL-C-lowering alleles.

    Conclusions and Relevance  In this meta-analysis, exposure to LDL-C-lowering genetic variants in or near NPC1L1 and other genes was associated with a higher risk of type 2 diabetes. These data provide insights into potential adverse effects of LDL-C-lowering therapy.

  • 152. Lunetta, Kathryn L.
    et al.
    Day, Felix R.
    Sulem, Patrick
    Ruth, Katherine S.
    Tung, Joyce Y.
    Hinds, David A.
    Esko, Tonu
    Elks, Cathy E.
    Altmaier, Elisabeth
    He, Chunyan
    Huffman, Jennifer E.
    Mihailov, Evelin
    Porcu, Eleonora
    Robino, Antonietta
    Rose, Lynda M.
    Schick, Ursula M.
    Stolk, Lisette
    Teumer, Alexander
    Thompson, Deborah J.
    Traglia, Michela
    Wang, Carol A.
    Yerges-Armstrong, Laura M.
    Antoniou, Antonis C.
    Barbieri, Caterina
    Coviello, Andrea D.
    Cucca, Francesco
    Demerath, Ellen W.
    Dunning, Alison M.
    Gandin, Ilaria
    Grove, Megan L.
    Gudbjartsson, Daniel F.
    Hocking, Lynne J.
    Hofman, Albert
    Huang, Jinyan
    Jackson, Rebecca D.
    Karasik, David
    Kriebel, Jennifer
    Lange, Ethan M.
    Lange, Leslie A.
    Langenberg, Claudia
    Li, Xin
    Luan, Jian'an
    Maegi, Reedik
    Morrison, Alanna C.
    Padmanabhan, Sandosh
    Pirie, Ailith
    Polasek, Ozren
    Porteous, David
    Reiner, Alex P.
    Rivadeneira, Fernando
    Rudan, Igor
    Sala, Cinzia F.
    Schlessinger, David
    Scott, Robert A.
    Stoeckl, Doris
    Visser, Jenny A.
    Voelker, Uwe
    Vozzi, Diego
    Wilson, James G.
    Zygmunt, Marek
    Boerwinkle, Eric
    Buring, Julie E.
    Crisponi, Laura
    Easton, Douglas F.
    Hayward, Caroline
    Hu, Frank B.
    Liu, Simin
    Metspalu, Andres
    Pennell, Craig E.
    Ridker, Paul M.
    Strauch, Konstantin
    Streeten, Elizabeth A.
    Toniolo, Daniela
    Uitterlinden, Andre G.
    Ulivi, Sheila
    Voelzke, Henry
    Wareham, Nicholas J.
    Wellons, Melissa
    Franceschini, Nora
    Chasman, Daniel I.
    Thorsteinsdottir, Unnur
    Murray, Anna
    Stefansson, Kari
    Murabito, Joanne M.
    Ong, Ken K.
    Perry, John R. B.
    Forouhi, Nita G.
    Kerrison, Nicola D.
    Sharp, Stephen J.
    Sims, Matt
    Barroso, Ines
    Deloukas, Panos
    McCarthy, Mark I.
    Arriola, Larraitz
    Balkau, Beverley
    Barricarte, Aurelio
    Boeing, Heiner
    Franks, Paul W.
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Medicin.
    Gonzalez, Carlos
    Grioni, Sara
    Kaaks, Rudolf
    Key, Timothy J.
    Navarro, Carmen
    Nilsson, Peter M.
    Overvad, Kim
    Palli, Domenico
    Panico, Salvatore
    Ramon Quiros, J.
    Rolandsson, Olov
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Allmänmedicin.
    Sacerdote, Carlotta
    Sanchez, Maria-Jose
    Slimani, Nadia
    Tjonneland, Anne
    Tumino, Rosario
    van der A, Daphne L.
    van der Schouw, Yvonne T.
    Riboli, Elio
    Smith, Blair H.
    Campbell, Archie
    Deary, Ian J.
    McIntosh, Andrew M.
    Rare coding variants and X-linked loci associated with age at menarche2015Ingår i: Nature Communications, ISSN 2041-1723, E-ISSN 2041-1723, Vol. 6, artikel-id 7756Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    More than 100 loci have been identified for age at menarche by genome-wide association studies; however, collectively these explain only similar to 3% of the trait variance. Here we test two overlooked sources of variation in 192,974 European ancestry women: low-frequency proteincoding variants and X-chromosome variants. Five missense/nonsense variants (in ALMS1/LAMB2/TNRC6A/TACR3/PRKAG1) are associated with age at menarche (minor allele frequencies 0.08-4.6%; effect sizes 0.08-1.25 years per allele; P<5 x 10(-8)). In addition, we identify common X-chromosome loci at IGSF1 (rs762080, P = 9.4 x 10(-13)) and FAAH2 (rs5914101, P = 4.9 x 10(-10)). Highlighted genes implicate cellular energy homeostasis, post-transcriptional gene silencing and fatty-acid amide signalling. A frequently reported mutation in TACR3 for idiopathic hypogonatrophic hypogonadism (p.W275X) is associated with 1.25-year-later menarche (P = 2.8 x 10(-11)), illustrating the utility of population studies to estimate the penetrance of reportedly pathogenic mutations. Collectively, these novel variants explain similar to 0.5% variance, indicating that these overlooked sources of variation do not substantially explain the 'missing heritability' of this complex trait.

  • 153. Ma, Lijun
    et al.
    Hanson, Robert L
    Que, Lorem N
    Mack, Janel L
    Franks, Paul W
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Medicin.
    Infante, Aniello M
    Kobes, Sayuko
    Bogardus, Clifton
    Baier, Leslie J
    Association analysis of Krüppel-like factor 11 variants with type 2 diabetes in Pima Indians2008Ingår i: Journal of Clinical Endocrinology and Metabolism, ISSN 0021-972X, E-ISSN 1945-7197, Vol. 93, nr 9, s. 3644-3649Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    CONTEXT: Krüppel-like factor 11 (KLF11) is a transcription factor of the zinc finger domain family that has been shown to regulate expression of the insulin gene. An initial study reported that a KLF11 variant predicting a Q62R was associated with type 2 diabetes (T2D) in French Caucasians; however, subsequent studies have failed to identify an association between this variant and T2D in subjects from a similar Northern-European ancestry. OBJECTIVE: We sought to determine whether the Q62R or other variants within KLF11 were associated with T2D in Pima Indians, a population with an extremely high prevalence of this disease.

    DESIGN, SETTING, AND SUBJECTS: KLF11 was sequenced in 24 Pima Indians to identify potentially novel variants. There were 18 variants genotyped in a family-based sample of 1337 Pima Indians to analyze the linkage disequilibrium pattern of this gene and identify representative variants. Four representative variants were further genotyped in a population-based sample of 3501 full-heritage Pima Indians for association analyses. Among these subjects, 413 had undergone metabolic studies when they were nondiabetic to measure traits that predict T2D.

    RESULTS: Neither the Q62R nor any other common variant in KLF11 was associated with T2D in the Pima population. In addition, no variant was associated with insulin secretion or insulin-stimulated glucose disposal rate.

    CONCLUSIONS: Common variation in KLF11 variation does not appear to influence the population-based risk for developing T2D among full-heritage Pima Indians. Thus, KLF11 is unlikely to play a major role in the etiology of T2D among this Native American population.

  • 154. Ma, Lijun
    et al.
    Hanson, Robert L
    Traurig, Michael T
    Muller, Yunhua L
    Kaur, Bakhshish P
    Perez, Jessica M
    Meyre, David
    Fu, Mao
    Körner, Antje
    Franks, Paul W
    Clinical Research Center, Malmö General Hospital, Lund University, Malmö, Sweden.
    Kiess, Wieland
    Kobes, Sayuko
    Knowler, William C
    Kovacs, Peter
    Froguel, Philippe
    Shuldiner, Alan R
    Bogardus, Clifton
    Baier, Leslie J
    Evaluation of A2BP1 as an obesity gene2010Ingår i: Diabetes, ISSN 0012-1797, E-ISSN 1939-327X, Vol. 59, nr 11, s. 2837-2845Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Association analysis suggests that variation in A2BP1 influences obesity, and functional studies suggest that A2BP1 could potentially affect adiposity via the hypothalamic MC4R pathway.

  • 155. Mahajan, Anubha
    et al.
    Wessel, Jennifer
    Willems, Sara M.
    Zhao, Wei
    Robertson, Neil R.
    Chu, Audrey Y.
    Gan, Wei
    Kitajima, Hidetoshi
    Taliun, Daniel
    Rayner, N. William
    Guo, Xiuqing
    Lu, Yingchang
    Li, Man
    Jensen, Richard A.
    Hu, Yao
    Huo, Shaofeng
    Lohman, Kurt K.
    Zhang, Weihua
    Cook, James P.
    Prins, Bram Peter
    Flannick, Jason
    Grarup, Niels
    Trubetskoy, Vassily Vladimirovich
    Kravic, Jasmina
    Kim, Young Jin
    Rybin, Denis V.
    Yaghootkar, Hanieh
    Mueller-Nurasyid, Martina
    Meidtner, Karina
    Li-Gao, Ruifang
    Varga, Tibor V.
    Marten, Jonathan
    Li, Jin
    Smith, Albert Vernon
    An, Ping
    Ligthart, Symen
    Gustafsson, Stefan
    Malerba, Giovanni
    Demirkan, Ayse
    Tajes, Juan Fernandez
    Steinthorsdottir, Valgerdur
    Wuttke, Matthias
    Lecoeur, Cecile
    Preuss, Michael
    Bielak, Lawrence F.
    Graff, Marielisa
    Highland, Heather M.
    Justice, Anne E.
    Liu, Dajiang J.
    Marouli, Eirini
    Peloso, Gina Marie
    Warren, Helen R.
    Afaq, Saima
    Afzal, Shoaib
    Ahlqvist, Emma
    Almgren, Peter
    Amin, Najaf
    Bang, Lia B.
    Bertoni, Alain G.
    Bombieri, Cristina
    Bork-Jensen, Jette
    Brandslund, Ivan
    Brody, Jennifer A.
    Burtt, Noel P.
    Canouil, Mickael
    Chen, Yii-Der Ida
    Cho, Yoon Shin
    Christensen, Cramer
    Eastwood, Sophie V.
    Eckardt, Kai-Uwe
    Fischer, Krista
    Gambaro, Giovanni
    Giedraitis, Vilmantas
    Grove, Megan L.
    de Haan, Hugoline G.
    Hackinger, Sophie
    Hai, Yang
    Han, Sohee
    Tybjaerg-Hansen, Anne
    Hivert, Marie-France
    Isomaa, Bo
    Jager, Susanne
    Jorgensen, Marit E.
    Jorgensen, Torben
    Karajamaki, Annemari
    Kim, Bong-Jo
    Kim, Sung Soo
    Koistinen, Heikki A.
    Kovacs, Peter
    Kriebel, Jennifer
    Kronenberg, Florian
    Lall, Kristi
    Lange, Leslie A.
    Lee, Jung-Jin
    Lehne, Benjamin
    Li, Huaixing
    Lin, Keng-Hung
    Linneberg, Allan
    Liu, Ching-Ti
    Liu, Jun
    Loh, Marie
    Magi, Reedik
    Mamakou, Vasiliki
    McKean-Cowdin, Roberta
    Nadkarni, Girish
    Neville, Matt
    Nielsen, Sune F.
    Ntalla, Ioanna
    Peyser, Patricia A.
    Rathmann, Wolfgang
    Rice, Kenneth
    Rich, Stephen S.
    Rode, Line
    Rolandsson, Olov
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Allmänmedicin.
    Schonherr, Sebastian
    Selvin, Elizabeth
    Small, Kerrin S.
    Stancakova, Alena
    Surendran, Praveen
    Taylor, Kent D.
    Teslovich, Tanya M.
    Thorand, Barbara
    Thorleifsson, Gudmar
    Tin, Adrienne
    Tonjes, Anke
    Varbo, Anette
    Witte, Daniel R.
    Wood, Andrew R.
    Yajnik, Pranav
    Yao, Jie
    Yengo, Loic
    Young, Robin
    Amouyel, Philippe
    Boeing, Heiner
    Boerwinkle, Eric
    Bottinger, Erwin P.
    Chowdhury, Rajiv
    Collins, Francis S.
    Dedoussis, George
    Dehghan, Abbas
    Deloukas, Panos
    Ferrario, Marco M.
    Ferrieres, Jean
    Florez, Jose C.
    Frossard, Philippe
    Gudnason, Vilmundur
    Harris, Tamara B.
    Heckbert, Susan R.
    Howson, Joanna M. M.
    Ingelsson, Martin
    Kathiresan, Sekar
    Kee, Frank
    Kuusisto, Johanna
    Langenberg, Claudia
    Launer, Lenore J.
    Lindgren, Cecilia M.
    Mannisto, Satu
    Meitinger, Thomas
    Melander, Olle
    Mohlke, Karen L.
    Moitry, Marie
    Morris, Andrew D.
    Murray, Alison D.
    de Mutsert, Renee
    Orho-Melander, Marju
    Owen, Katharine R.
    Perola, Markus
    Peters, Annette
    Province, Michael A.
    Rasheed, Asif
    Ridker, Paul M.
    Rivadineira, Fernando
    Rosendaal, Frits R.
    Rosengren, Anders H.
    Salomaa, Veikko
    Sheu, Wayne H. -H.
    Sladek, Rob
    Smith, Blair H.
    Strauch, Konstantin
    Uitterlinden, Andre G.
    Varma, Rohit
    Willer, Cristen J.
    Bluher, Matthias
    Butterworth, Adam S.
    Chambers, John Campbell
    Chasman, Daniel I.
    Danesh, John
    van Duijn, Cornelia
    Dupuis, Josee
    Franco, Oscar H.
    Franks, Paul W.
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Avdelningen för medicin.
    Froguel, Philippe
    Grallert, Harald
    Groop, Leif
    Han, Bok-Ghee
    Hansen, Torben
    Hattersley, Andrew T.
    Hayward, Caroline
    Ingelsson, Erik
    Kardia, Sharon L. R.
    Karpe, Fredrik
    Kooner, Jaspal Singh
    Kottgen, Anna
    Kuulasmaa, Kari
    Laakso, Markku
    Lin, Xu
    Lind, Lars
    Liu, Yongmei
    Loos, Ruth J. F.
    Marchini, Jonathan
    Metspalu, Andres
    Mook-Kanamori, Dennis
    Nordestgaard, Borge G.
    Palmer, Colin N. A.
    Pankow, James S.
    Pedersen, Oluf
    Psaty, Bruce M.
    Rauramaa, Rainer
    Sattar, Naveed
    Schulze, Matthias B.
    Soranzo, Nicole
    Spector, Timothy D.
    Stefansson, Kari
    Stumvoll, Michael
    Thorsteinsdottir, Unnur
    Tuomi, Tiinamaija
    Tuomilehto, Jaakko
    Wareham, Nicholas J.
    Wilson, James G.
    Zeggini, Eleftheria
    Scott, Robert A.
    Barroso, Ines
    Frayling, Timothy M.
    Goodarzi, Mark O.
    Meigs, James B.
    Boehnke, Michael
    Saleheen, Danish
    Morris, Andrew P.
    Rotter, Jerome I.
    McCarthy, Mark I.
    Refining the accuracy of validated target identification through coding variant fine-mapping in type 2 diabetes2018Ingår i: Nature Genetics, ISSN 1061-4036, E-ISSN 1546-1718, Vol. 50, nr 4, s. 559-571Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    We aggregated coding variant data for 81,412 type 2 diabetes cases and 370,832 controls of diverse ancestry, identifying 40 coding variant association signals (P < 2.2 × 10−7); of these, 16 map outside known risk-associated loci. We make two important observations. First, only five of these signals are driven by low-frequency variants: even for these, effect sizes are modest (odds ratio ≤1.29). Second, when we used large-scale genome-wide association data to fine-map the associated variants in their regional context, accounting for the global enrichment of complex trait associations in coding sequence, compelling evidence for coding variant causality was obtained for only 16 signals. At 13 others, the associated coding variants clearly represent ‘false leads’ with potential to generate erroneous mechanistic inference. Coding variant associations offer a direct route to biological insight for complex diseases and identification of validated therapeutic targets; however, appropriate mechanistic inference requires careful specification of their causal contribution to disease predisposition.

  • 156. Manning, Alisa
    et al.
    Highland, Heather M.
    Gasser, Jessica
    Sim, Xueling
    Tukiainen, Taru
    Fontanillas, Pierre
    Grarup, Niels
    Rivas, Manuel A.
    Mahajan, Anubha
    Locke, Adam E.
    Cingolani, Pablo
    Pers, Tune H.
    Vinuela, Ana
    Brown, Andrew A.
    Wu, Ying
    Flannick, Jason
    Fuchsberger, Christian
    Gamazon, Eric R.
    Gaulton, Kyle J.
    Im, Hae Kyung
    Teslovich, Tanya M.
    Blackwell, Thomas W.
    Bork-Jensen, Jette
    Burtt, Noel P.
    Chen, Yuhui
    Green, Todd
    Hartl, Christopher
    Kang, Hyun Min
    Kumar, Ashish
    Ladenvall, Claes
    Ma, Clement
    Moutsianas, Loukas
    Pearson, Richard D.
    Perry, John R. B.
    Rayner, N. William
    Robertson, Neil R.
    Scott, Laura J.
    van de Bunt, Martijn
    Eriksson, Johan G.
    Jula, Antti
    Koskinen, Seppo
    Lehtimaki, Terho
    Palotie, Aarno
    Raitakari, Olli T.
    Jacobs, Suzanne B. R.
    Wessel, Jennifer
    Chu, Audrey Y.
    Scott, Robert A.
    Goodarzi, Mark O.
    Blancher, Christine
    Buck, Gemma
    Buck, David
    Chines, Peter S.
    Gabriel, Stacey
    Gjesing, Anette P.
    Groves, Christopher J.
    Hollensted, Mette
    Huyghe, Jeroen R.
    Jackson, Anne U.
    Jun, Goo
    Justesen, Johanne Marie
    Mangino, Massimo
    Murphy, Jacquelyn
    Neville, Matt
    Onofrio, Robert
    Small, Kerrin S.
    Stringham, Heather M.
    Trakalo, Joseph
    Banks, Eric
    Carey, Jason
    Carneiro, Mauricio O.
    DePristo, Mark
    Farjoun, Yossi
    Fennell, Timothy
    Goldstein, Jacqueline I.
    Grant, George
    de Angelis, Martin Hrabe
    Maguire, Jared
    Neale, Benjamin M.
    Poplin, Ryan
    Purcell, Shaun
    Schwarzmayr, Thomas
    Shakir, Khalid
    Smith, Joshua D.
    Strom, Tim M.
    Wieland, Thomas
    Lindstrom, Jaana
    Brandslund, Ivan
    Christensen, Cramer
    Surdulescu, Gabriela L.
    Lakka, Timo A.
    Doney, Alex S. F.
    Nilsson, Peter
    Wareham, Nicholas J.
    Langenberg, Claudia
    Varga, Tibor V.
    Franks, Paul W.
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Medicin. Department of Clinical Sciences, Lund University Diabetes Centre, and Genetic and Molecular Epidemiology Unit, Lund University, Malmö, Sweden; Department of Nutrition, Harvard School of Public Health, Boston, MA.
    Rolandsson, Olov
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Allmänmedicin.
    Rosengren, Anders H.
    Farook, Vidya S.
    Thameem, Farook
    Puppala, Sobha
    Kumar, Satish
    Lehman, Donna M.
    Jenkinson, Christopher P.
    Curran, Joanne E.
    Hale, Daniel Esten
    Fowler, Sharon P.
    Arya, Rector
    DeFronzo, Ralph A.
    Abboud, Hanna E.
    Syvanen, Ann-Christine
    Hicks, Pamela J.
    Palmer, Nicholette D.
    Ng, Maggie C. Y.
    Bowden, Donald W.
    Freedman, Barry I.
    Esko, Tonu
    Magi, Reedik
    Milani, Lili
    Mihailov, Evelin
    Metspalu, Andres
    Narisu, Narisu
    Kinnunen, Leena
    Bonnycastle, Lori L.
    Swift, Amy
    Pasko, Dorota
    Wood, Andrew R.
    Fadista, Joao
    Pollin, Toni I.
    Barzilai, Nir
    Atzmon, Gil
    Glaser, Benjamin
    Thorand, Barbara
    Strauch, Konstantin
    Peters, Annette
    Roden, Michael
    Mueller-Nurasyid, Martina
    Liang, Liming
    Kriebel, Jennifer
    Illig, Thomas
    Grallert, Harald
    Gieger, Christian
    Meisinger, Christa
    Lannfelt, Lars
    Musani, Solomon K.
    Griswold, Michael
    Taylor, Herman A., Jr.
    Wilson, Gregory, Sr.
    Correa, Adolfo
    Oksa, Heikki
    Scott, William R.
    Afzal, Uzma
    Tan, Sian-Tsung
    Loh, Marie
    Chambers, John C.
    Sehmi, Jobanpreet
    Kooner, Jaspal Singh
    Lehne, Benjamin
    Cho, Yoon Shin
    Lee, Jong-Young
    Han, Bok-Ghee
    Karajamaki, Annemari
    Qi, Qibin
    Qi, Lu
    Huang, Jinyan
    Hu, Frank B.
    Melander, Olle
    Orho-Melander, Marju
    Below, Jennifer E.
    Aguilar, David
    Wong, Tien Yin
    Liu, Jianjun
    Khor, Chiea-Chuen
    Chia, Kee Seng
    Lim, Wei Yen
    Cheng, Ching-Yu
    Chan, Edmund
    Tai, E. Shyong
    Aung, Tin
    Linneberg, Allan
    Isomaa, Bo
    Meitinger, Thomas
    Tuomi, Tiinamaija
    Hakaste, Liisa
    Kravic, Jasmina
    Jorgensen, Marit E.
    Lauritzen, Torsten
    Deloukas, Panos
    Stirrups, Kathleen E.
    Owen, Katharine R.
    Farmer, Andrew J.
    Frayling, Timothy M.
    O'Rahilly, Stephen P.
    Walker, Mark
    Levy, Jonathan C.
    Hodgkiss, Dylan
    Hattersley, Andrew T.
    Kuulasmaa, Teemu
    Stancakova, Alena
    Barroso, Ines
    Bharadwaj, Dwaipayan
    Chan, Juliana
    Chandak, Giriraj R.
    Daly, Mark J.
    Donnelly, Peter J.
    Ebrahim, Shah B.
    Elliott, Paul
    Fingerlin, Tasha
    Froguel, Philippe
    Hu, Cheng
    Jia, Weiping
    Ma, Ronald C. W.
    McVean, Gilean
    Park, Taesung
    Prabhakaran, Dorairaj
    Sandhu, Manjinder
    Scott, James
    Sladek, Rob
    Tandon, Nikhil
    Teo, Yik Ying
    Zeggini, Eleftheria
    Watanabe, Richard M.
    Koistinen, Heikki A.
    Kesaniemi, Y. Antero
    Uusitupa, Matti
    Spector, Timothy D.
    Salomaa, Veikko
    Rauramaa, Rainer
    Palmer, Colin N. A.
    Prokopenko, Inga
    Morris, Andrew D.
    Bergman, Richard N.
    Collins, Francis S.
    Lind, Lars
    Ingelsson, Erik
    Tuomilehto, Jaakko
    Karpe, Fredrik
    Groop, Leif
    Jorgensen, Torben
    Hansen, Torben
    Pedersen, Oluf
    Kuusisto, Johanna
    Abecasis, GonOalo
    Bell, Graeme I.
    Blangero, John
    Cox, Nancy J.
    Duggirala, Ravindranath
    Seielstad, Mark
    Wilson, James G.
    Dupuis, Josee
    Ripatti, Samuli
    Hanis, Craig L.
    Florez, Jose C.
    Mohlke, Karen L.
    Meigs, James B.
    Laakso, Markku
    Morris, Andrew P.
    Boehnke, Michael
    Altshuler, David
    McCarthy, Mark I.
    Gloyn, Anna L.
    Lindgren, Cecilia M.
    A Low-Frequency Inactivating AKT2 Variant Enriched in the Finnish Population Is Associated With Fasting Insulin Levels and Type 2 Diabetes Risk2017Ingår i: Diabetes, ISSN 0012-1797, E-ISSN 1939-327X, Vol. 66, nr 7, s. 2019-2032Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    To identify novel coding association signals and facilitate characterization of mechanisms influencing glycemic traits and type 2 diabetes risk, we analyzed 109,215 variants derived from exome array genotyping together with an additional 390,225 variants from exome sequence in up to 39,339 normoglycemic individuals from five ancestry groups. We identified a novel association between the coding variant (p.Pro50Thr) in AKT2 and fasting plasma insulin (FI), a gene in which rare fully penetrant mutations are causal for monogenic glycemic disorders. The low-frequency allele is associated with a 12% increase in FI levels. This variant is present at 1.1% frequency in Finns but virtually absent in individuals from other ancestries. Carriers of the FI-increasing allele had increased 2-h insulin values, decreased insulin sensitivity, and increased risk of type 2 diabetes (odds ratio 1.05). In cellular studies, the AKT2-Thr50 protein exhibited a partial loss of function. We extend the allelic spectrum for coding variants in AKT2 associated with disorders of glucose homeostasis and demonstrate bidirectional effects of variants within the pleckstrin homology domain of AKT2.

  • 157. Manning, Alisa K.
    et al.
    Hivert, Marie-France
    Scott, Robert A.
    Grimsby, Jonna L.
    Bouatia-Naji, Nabila
    Chen, Han
    Rybin, Denis
    Liu, Ching-Ti
    Bielak, Lawrence F.
    Prokopenko, Inga
    Amin, Najaf
    Barnes, Daniel
    Cadby, Gemma
    Hottenga, Jouke-Jan
    Ingelsson, Erik
    Jackson, Anne U.
    Johnson, Toby
    Kanoni, Stavroula
    Ladenvall, Claes
    Lagou, Vasiliki
    Lahti, Jari
    Lecoeur, Cecile
    Liu, Yongmei
    Martinez-Larrad, Maria Teresa
    Montasser, May E.
    Navarro, Pau
    Perry, John R. B.
    Rasmussen-Torvik, Laura J.
    Salo, Perttu
    Sattar, Naveed
    Shungin, Dmitry
    Umeå universitet, Medicinska fakulteten, Institutionen för odontologi. Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Medicin.
    Strawbridge, Rona J.
    Tanaka, Toshiko
    van Duijn, Cornelia M.
    An, Ping
    de Andrade, Mariza
    Andrews, Jeanette S.
    Aspelund, Thor
    Atalay, Mustafa
    Aulchenko, Yurii
    Balkau, Beverley
    Bandinelli, Stefania
    Beckmann, Jacques S.
    Beilby, John P.
    Bellis, Claire
    Bergman, Richard N.
    Blangero, John
    Boban, Mladen
    Boehnke, Michael
    Boerwinkle, Eric
    Bonnycastle, Lori L.
    Boomsma, Dorret I.
    Borecki, Ingrid B.
    Boettcher, Yvonne
    Bouchard, Claude
    Brunner, Eric
    Budimir, Danijela
    Campbell, Harry
    Carlson, Olga
    Chines, Peter S.
    Clarke, Robert
    Collins, Francis S.
    Corbaton-Anchuelo, Arturo
    Couper, David
    de Faire, Ulf
    Dedoussis, George V.
    Deloukas, Panos
    Dimitriou, Maria
    Egan, Josephine M.
    Eiriksdottir, Gudny
    Erdos, Michael R.
    Eriksson, Johan G.
    Eury, Elodie
    Ferrucci, Luigi
    Ford, Ian
    Forouhi, Nita G.
    Fox, Caroline S.
    Franzosi, Maria Grazia
    Franks, Paul W.
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Medicin.
    Frayling, Timothy M.
    Froguel, Philippe
    Galan, Pilar
    de Geus, Eco
    Gigante, Bruna
    Glazer, Nicole L.
    Goel, Anuj
    Groop, Leif
    Gudnason, Vilmundur
    Hallmans, Göran
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Näringsforskning.
    Hamsten, Anders
    Hansson, Ola
    Harris, Tamara B.
    Hayward, Caroline
    Heath, Simon
    Hercberg, Serge
    Hicks, Andrew A.
    Hingorani, Aroon
    Hofman, Albert
    Hui, Jennie
    Hung, Joseph
    Jarvelin, Marjo-Riitta
    Jhun, Min A.
    Johnson, Paul C. D.
    Jukema, J. Wouter
    Jula, Antti
    Kao, W. H.
    Kaprio, Jaakko
    Kardia, Sharon L. R.
    Keinanen-Kiukaanniemi, Sirkka
    Kivimaki, Mika
    Kolcic, Ivana
    Kovacs, Peter
    Kumari, Meena
    Kuusisto, Johanna
    Kyvik, Kirsten Ohm
    Laakso, Markku
    Lakka, Timo
    Lannfelt, Lars
    Lathrop, G. Mark
    Launer, Lenore J.
    Leander, Karin
    Li, Guo
    Lind, Lars
    Lindstrom, Jaana
    Lobbens, Stephane
    Loos, Ruth J. F.
    Luan, Jian'an
    Lyssenko, Valeriya
    Magi, Reedik
    Magnusson, Patrik K. E.
    Marmot, Michael
    Meneton, Pierre
    Mohlke, Karen L.
    Mooser, Vincent
    Morken, Mario A.
    Miljkovic, Iva
    Narisu, Narisu
    O'Connell, Jeff
    Ong, Ken K.
    Oostra, Ben A.
    Palmer, Lyle J.
    Palotie, Aarno
    Pankow, James S.
    Peden, John F.
    Pedersen, Nancy L.
    Pehlic, Marina
    Peltonen, Leena
    Penninx, Brenda
    Pericic, Marijana
    Perola, Markus
    Perusse, Louis
    Peyser, Patricia A.
    Polasek, Ozren
    Pramstaller, Peter P.
    Province, Michael A.
    Raikkonen, Katri
    Rauramaa, Rainer
    Rehnberg, Emil
    Rice, Ken
    Rotter, Jerome I.
    Rudan, Igor
    Ruokonen, Aimo
    Saaristo, Timo
    Sabater-Lleal, Maria
    Salomaa, Veikko
    Savage, David B.
    Saxena, Richa
    Schwarz, Peter
    Seedorf, Udo
    Sennblad, Bengt
    Serrano-Rios, Manuel
    Shuldiner, Alan R.
    Sijbrands, Eric J. G.
    Siscovick, David S.
    Smit, Johannes H.
    Small, Kerrin S.
    Smith, Nicholas L.
    Smith, Albert Vernon
    Stancakova, Alena
    Stirrups, Kathleen
    Stumvoll, Michael
    Sun, Yan V.
    Swift, Amy J.
    Toenjes, Anke
    Tuomilehto, Jaakko
    Trompet, Stella
    Uitterlinden, Andre G.
    Uusitupa, Matti
    Vikstrom, Max
    Vitart, Veronique
    Vohl, Marie-Claude
    Voight, Benjamin F.
    Vollenweider, Peter
    Waeber, Gerard
    Waterworth, Dawn M.
    Watkins, Hugh
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Näringsforskning.
    Wheeler, Eleanor
    Widen, Elisabeth
    Wild, Sarah H.
    Willems, Sara M.
    Willemsen, Gonneke
    Wilson, James F.
    Witteman, Jacqueline C. M.
    Wright, Alan F.
    Yaghootkar, Hanieh
    Zelenika, Diana
    Zemunik, Tatijana
    Zgaga, Lina
    Wareham, Nicholas J.
    McCarthy, Mark I.
    Barroso, Ines
    Watanabe, Richard M.
    Florez, Jose C.
    Dupuis, Josee
    Meigs, James B.
    Langenberg, Claudia
    A genome-wide approach accounting for body mass index identifies genetic variants influencing fasting glycemic traits and insulin resistance2012Ingår i: Nature Genetics, ISSN 1061-4036, E-ISSN 1546-1718, Vol. 44, nr 6, s. 659-669Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Recent genome-wide association studies have described many loci implicated in type 2 diabetes (T2D) pathophysiology and beta-cell dysfunction but have contributed little to the understanding of the genetic basis of insulin resistance. We hypothesized that genes implicated in insulin resistance pathways might be uncovered by accounting for differences in body mass index (BMI) and potential interactions between BMI and genetic variants. We applied a joint meta-analysis approach to test associations with fasting insulin and glucose on a genome-wide scale. We present six previously unknown loci associated with fasting insulin at P < 5 x 10(-8) in combined discovery and follow-up analyses of 52 studies comprising up to 96,496 non-diabetic individuals. Risk variants were associated with higher triglyceride and lower high-density lipoprotein (HDL) cholesterol levels, suggesting a role for these loci in insulin resistance pathways. The discovery of these loci will aid further characterization of the role of insulin resistance in T2D pathophysiology.

  • 158. Marouli, Eirini
    et al.
    Graff, Mariaelisa
    Medina-Gomez, Carolina
    Lo, Ken Sin
    Wood, Andrew R.
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    Lu, Yingchang
    Schurmann, Claudia
    Highland, Heather M.
    Rueger, Sina
    Thorleifsson, Gudmar
    Justice, Anne E.
    Lamparter, David
    Stirrups, Kathleen E.
    Turcot, Valerie
    Young, Kristin L.
    Winkler, Thomas W.
    Esko, Tonu
    Karaderi, Tugce
    Locke, Adam E.
    Masca, Nicholas G. D.
    Ng, Maggie C. Y.
    Mudgal, Poorva
    Rivas, Manuel A.
    Vedantam, Sailaja
    Mahajan, Anubha
    Guo, Xiuqing
    Abecasis, Goncalo
    Aben, Katja K.
    Adair, Linda S.
    Alam, Dewan S.
    Albrecht, Eva
    Allin, Kristine H.
    Allison, Matthew
    Amouyel, Philippe
    Appel, Emil V.
    Arveiler, Dominique
    Asselbergs, Folkert W.
    Auer, Paul L.
    Balkau, Beverley
    Banas, Bernhard
    Bang, Lia E.
    Benn, Marianne
    Bergmann, Sven
    Bielak, Lawrence F.
    Blueher, Matthias
    Boeing, Heiner
    Boerwinkle, Eric
    Boeger, Carsten A.
    Bonnycastle, Lori L.
    Bork-Jensen, Jette
    Bots, Michiel L.
    Bottinger, Erwin P.
    Bowden, Donald W.
    Brandslund, Ivan
    Breen, Gerome
    Brilliant, Murray H.
    Broer, Linda
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    Butterworth, Adam S.
    Carey, David J.
    Caulfield, Mark J.
    Chambers, John C.
    Chasman, Daniel I.
    Chen, Yii-Der Ida
    Chowdhury, Rajiv
    Christensen, Cramer
    Chu, Audrey Y.
    Cocca, Massimiliano
    Collins, Francis S.
    Cook, James P.
    Corley, Janie
    Galbany, Jordi Corominas
    Cox, Amanda J.
    Cuellar-Partida, Gabriel
    Danesh, John
    Davies, Gail
    de Bakker, Paul I. W.
    de Borst, Gert J.
    de Denus, Simon
    de Groot, Mark C. H.
    de Mutsert, Renee
    Deary, Ian J.
    Dedoussis, George
    Demerath, Ellen W.
    den Hollander, Anneke I.
    Dennis, Joe G.
    Di Angelantonio, Emanuele
    Drenos, Fotios
    Du, Mengmeng
    Dunning, Alison M.
    Easton, Douglas F.
    Ebeling, Tapani
    Edwards, Todd L.
    Ellinor, Patrick T.
    Elliott, Paul
    Evangelou, Evangelos
    Farmaki, Aliki-Eleni
    Faul, Jessica D.
    Feitosa, Mary F.
    Feng, Shuang
    Ferrannini, Ele
    Ferrario, Marco M.
    Ferrieres, Jean
    Florez, Jose C.
    Ford, Ian
    Fornage, Myriam
    Franks, Paul W.
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Medicin.
    Frikke-Schmidt, Ruth
    Galesloot, Tessel E.
    Gan, Wei
    Gandin, Ilaria
    Gasparini, Paolo
    Giedraitis, Vilmantas
    Giri, Ayush
    Girotto, Giorgia
    Gordon, Scott D.
    Gordon-Larsen, Penny
    Gorski, Mathias
    Grarup, Niels
    Grove, Megan L.
    Gudnason, Vilmundur
    Gustafsson, Stefan
    Hansen, Torben
    Harris, Kathleen Mullan
    Harris, Tamara B.
    Hattersley, Andrew T.
    Hayward, Caroline
    He, Liang
    Heid, Iris M.
    Heikkila, Kauko
    Helgeland, Oyvind
    Hernesniemi, Jussi
    Hewitt, Alex W.
    Hocking, Lynne J.
    Hollensted, Mette
    Holmen, Oddgeir L.
    Hovingh, G. Kees
    Howson, Joanna M. M.
    Hoyng, Carel B.
    Huang, Paul L.
    Hveem, Kristian
    Ikram, M. Arfan
    Ingelsson, Erik
    Jackson, Anne U.
    Jansson, Jan-Håkan
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Medicin.
    Jarvik, Gail P.
    Jensen, Gorm B.
    Jhun, Min A.
    Jia, Yucheng
    Jiang, Xuejuan
    Johansson, Stefan
    Jorgensen, Marit E.
    Jorgensen, Torben
    Jousilahti, Pekka
    Jukema, J. Wouter
    Kahali, Bratati
    Kahn, Rene S.
    Kahonen, Mika
    Kamstrup, Pia R.
    Kanoni, Stavroula
    Kaprio, Jaakko
    Karaleftheri, Maria
    Kardia, Sharon L. R.
    Karpe, Fredrik
    Kee, Frank
    Keeman, Renske
    Kiemeney, Lambertus A.
    Kitajima, Hidetoshi
    Kluivers, Kirsten B.
    Kocher, Thomas
    Komulainen, Pirjo
    Kontto, Jukka
    Kooner, Jaspal S.
    Kooperberg, Charles
    Kovacs, Peter
    Kriebel, Jennifer
    Kuivaniemi, Helena
    Kury, Sebastien
    Kuusisto, Johanna
    La Bianca, Martina
    Laakso, Markku
    Lakka, Timo A.
    Lange, Ethan M.
    Lange, Leslie A.
    Langefeld, Carl D.
    Langenberg, Claudia
    Larson, Eric B.
    Lee, I-Te
    Lehtimaki, Terho
    Lewis, Cora E.
    Li, Huaixing
    Li, Jin
    Li-Gao, Ruifang
    Lin, Honghuang
    Lin, Li-An
    Lin, Xu
    Lind, Lars
    Lindstrom, Jaana
    Linneberg, Allan
    Liu, Yeheng
    Liu, Yongmei
    Lophatananon, Artitaya
    Luan, Jian'an
    Lubitz, Steven A.
    Lyytikainen, Leo-Pekka
    Mackey, David A.
    Madden, Pamela A. F.
    Manning, Alisa K.
    Mannisto, Satu
    Marenne, Gaelle
    Marten, Jonathan
    Martin, Nicholas G.
    Mazul, Angela L.
    Meidtner, Karina
    Metspalu, Andres
    Mitchell, Paul
    Mohlke, Karen L.
    Mook-Kanamori, Dennis O.
    Morgan, Anna
    Morris, Andrew D.
    Morris, Andrew P.
    Mueller-Nurasyid, Martina
    Munroe, Patricia B.
    Nalls, Mike A.
    Nauck, Matthias
    Nelson, Christopher P.
    Neville, Matt
    Nielsen, Sune F.
    Nikus, Kjell
    Njolstad, Pal R.
    Nordestgaard, Borge G.
    Ntalla, Ioanna
    O'Connel, Jeffrey R.
    Oksa, Heikki
    Loohuis, Loes M. Olde
    Ophoff, Roel A.
    Owen, Katharine R.
    Packard, Chris J.
    Padmanabhan, Sandosh
    Palmer, Colin N. A.
    Pasterkamp, Gerard
    Patel, Aniruddh P.
    Pattie, Alison
    Pedersen, Oluf
    Peissig, Peggy L.
    Peloso, Gina M.
    Pennell, Craig E.
    Perola, Markus
    Perry, James A.
    Perry, John R. B.
    Person, Thomas N.
    Pirie, Ailith
    Polasek, Ozren
    Posthuma, Danielle
    Raitakari, Olli T.
    Rasheed, Asif
    Rauramaa, Rainer
    Reilly, Dermot F.
    Reiner, Alex P.
    Renstrom, Frida
    Umeå universitet, Medicinska fakulteten, Enheten för biobanksforskning.
    Ridker, Paul M.
    Rioux, John D.
    Robertson, Neil
    Robino, Antonietta
    Rolandsson, Olov
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Allmänmedicin.
    Rudan, Igor
    Ruth, Katherine S.
    Saleheen, Danish
    Salomaa, Veikko
    Samani, Nilesh J.
    Sandow, Kevin
    Sapkota, Yadav
    Sattar, Naveed
    Schmidt, Marjanka K.
    Schreiner, Pamela J.
    Schulze, Matthias B.
    Scott, Robert A.
    Segura-Lepe, Marcelo P.
    Shah, Svati
    Sim, Xueling
    Sivapalaratnam, Suthesh
    Small, Kerrin S.
    Smith, Albert Vernon
    Smith, Jennifer A.
    Southam, Lorraine
    Spector, Timothy D.
    Speliotes, Elizabeth K.
    Starr, John M.
    Steinthorsdottir, Valgerdur
    Stringham, Heather M.
    Stumvoll, Michael
    Surendran, Praveen
    t Hart, Leen M.
    Tansey, Katherine E.
    Tardif, Jean-Claude
    Taylor, Kent D.
    Teumer, Alexander
    Thompson, Deborah J.
    Thorsteinsdottir, Unnur
    Thuesen, Betina H.
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    Tromp, Gerard
    Trompet, Stella
    Tsafantakis, Emmanouil
    Tuomilehto, Jaakko
    Tybjaerg-Hansen, Anne
    Tyrer, Jonathan P.
    Uher, Rudolf
    Uitterlinden, Andre G.
    Ulivi, Sheila
    van der Laan, Sander W.
    Van Der Leij, Andries R.
    van Duijn, Cornelia M.
    van Schoor, Natasja M.
    van Setten, Jessica
    Varbo, Anette
    Varga, Tibor V.
    Varma, Rohit
    Edwards, Digna R. Velez
    Vermeulen, Sita H.
    Vestergaard, Henrik
    Vitart, Veronique
    Vogt, Thomas F.
    Vozzi, Diego
    Walker, Mark
    Wang, Feijie
    Wang, Carol A.
    Wang, Shuai
    Wang, Yiqin
    Wareham, Nicholas J.
    Warren, Helen R.
    Wessel, Jennifer
    Willems, Sara M.
    Wilson, James G.
    Witte, Daniel R.
    Woods, Michael O.
    Wu, Ying
    Yaghootkar, Hanieh
    Yao, Jie
    Yao, Pang
    Yerges-Armstrong, Laura M.
    Young, Robin
    Zeggini, Eleftheria
    Zhan, Xiaowei
    Zhang, Weihua
    Zhao, Jing Hua
    Zhao, Wei
    Zheng, He
    Zhou, Wei
    Rotter, Jerome I.
    Boehnke, Michael
    Kathiresan, Sekar
    McCarthy, Mark I.
    Willer, Cristen J.
    Stefansson, Kari
    Borecki, Ingrid B.
    Liu, Dajiang J.
    North, Kari E.
    Heard-Costa, Nancy L.
    Pers, Tune H.
    Lindgren, Cecilia M.
    Oxvig, Claus
    Kutalik, Zoltan
    Rivadeneira, Fernando
    Loos, Ruth J. F.
    Frayling, Timothy M.
    Hirschhorn, Joel N.
    Deloukas, Panos
    Lettre, Guillaume
    Rare and low-frequency coding variants alter human adult height2017Ingår i: Nature, ISSN 0028-0836, E-ISSN 1476-4687, Vol. 542, nr 7640, s. 186-190Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Height is a highly heritable, classic polygenic trait with approximately 700 common associated variants identified through genome-wide association studies so far. Here, we report 83 height-associated coding variants with lower minor-allele frequencies (in the range of 0.1-4.8%) and effects of up to 2 centimetres per allele (such as those in IHH, STC2, AR and CRISPLD2), greater than ten times the average effect of common variants. In functional follow-up studies, rare height increasing alleles of STC2 (giving an increase of 1-2 centimetres per allele) compromised proteolytic inhibition of PAPP-A and increased cleavage of IGFBP-4 in vitro, resulting in higher bioavailability of insulin-like growth factors. These 83 height-associated variants overlap genes that are mutated in monogenic growth disorders and highlight new biological candidates (such as ADAMTS3, IL11RA and NOX4) and pathways (such as proteoglycan and glycosaminoglycan synthesis) involved in growth. Our results demonstrate that sufficiently large sample sizes can uncover rare and low-frequency variants of moderate-to-large effect associated with polygenic human phenotypes, and that these variants implicate relevant genes and pathways.

  • 159. McCaffery, Jeanne M.
    et al.
    Jablonski, Kathleen A.
    Franks, Paul W.
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Medicin. Department of Clinical Sciences, Lund University, Malmö, Sweden; Department of Nutrition, Harvard School of Public Health, Boston, MA.
    Delahanty, Linda M.
    Aroda, Vanita
    Marrero, David
    Hamman, Richard F.
    Horton, Edward S.
    Dagogo-Jack, Samuel
    Wylie-Rosett, Judith
    Barrett-Connor, Elizabeth
    Kitabchi, Abbas
    Knowler, William C.
    Wing, Rena R.
    Florez, Jose C.
    Replication of the Association of BDNF and MC4R Variants With Dietary Intake in the Diabetes Prevention Program2017Ingår i: Psychosomatic Medicine, ISSN 0033-3174, E-ISSN 1534-7796, Vol. 79, nr 2, s. 224-233Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Objective: Genomewide association studies (GWAS) have identified consistent associations with obesity, with a number of studies implicating eating behavior as a primary mechanism. Few studies have replicated genetic associations with dietary intake. This study evaluates the association between obesity susceptibility loci and dietary intake. Methods: Data were obtained as part of the Diabetes Prevention Program (DPP), a clinical trial of diabetes prevention in persons at high risk of diabetes. The association of 31 genomewide association studies identified obesity risk alleles with dietary intake, measured through a food frequency questionnaire, was investigated in 3,180 participants from DPP at baseline. Results: The minor allele at BDNF, identified as protective against obesity, was associated with lower total caloric intake (beta = -106.06, SE = 33.13; p = .0014) at experimentwide statistical significance (p = .0016), whereas association of MC4R rs571312 with higher caloric intake reached nominal significance (beta = 61.32, SE = 26.24; p = .0194). Among non-Hispanic white participants, the association of BDNF rs2030323 with total caloric intake was stronger (beta = -151.99, SE = 30.09; p < .0001), and association of FTO rs1421085 with higher caloric intake (beta = 56.72, SE = 20.69; p = .0061) and percentage fat intake (beta = 0.37, SE = 0.08; p =. 0418) was also observed. Conclusions: These results demonstrate with the strength of independent replication that BDNF rs2030323 is associated with 100 to 150 greater total caloric intake per allele, with additional contributions of MC4R and, in non-Hispanic white individuals, FTO. As it has been argued that an additional 100 kcal/d could account for the trends in weight gain, prevention focusing on genetic profiles with high dietary intake may help to quell adverse obesity trends.

  • 160. Meidtner, Karina
    et al.
    Podmore, Clara
    Kroger, Janine
    van der Schouw, Yvonne T.
    Bendinelli, Benedetta
    Agnoli, Claudia
    Arriola, Larraitz
    Barricarte, Aurelio
    Boeing, Heiner
    Cross, Amanda J.
    Dow, Courtney
    Ekblom, Kim
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Klinisk kemi.
    Fagherazzi, Guy
    Franks, Paul W.
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Avdelningen för medicin. Department of Clinical Sciences, Lund University, Malmö, Sweden.
    Gunter, Marc J.
    Huerta, Jose Maria
    Jakszyn, Paula
    Jenab, Mazda
    Katzke, Verena A.
    Key, Timothy J.
    Khaw, Kay Tee
    Kuhn, Tilman
    Kyro, Cecilie
    Mancini, Francesca Romana
    Melander, Olle
    Nilsson, Peter M.
    Overvad, Kim
    Palli, Domenico
    Panico, Salvatore
    Quiros, J. Ramon
    Rodriguez-Barranco, Miguel
    Sacerdote, Carlotta
    Sluijs, Ivonne
    Stepien, Magdalena
    Tjonneland, Anne
    Tumino, Rosario
    Forouhi, Nita G.
    Sharp, Stephen J.
    Langenberg, Claudia
    Schulze, Matthias B.
    Riboli, Elio
    Wareham, Nicholas J.
    Interaction of Dietary and Genetic Factors Influencing Body Iron Status and Risk of Type 2 Diabetes Within the EPIC-InterAct Study2018Ingår i: Diabetes Care, ISSN 0149-5992, E-ISSN 1935-5548, Vol. 41, nr 2, s. 277-285Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    OBJECTIVE: Meat intake has been consistently shown to be positively associated with incident type 2 diabetes. Part of that association may be mediated by body iron status, which is influenced by genetic factors. We aimed to test for interactions of genetic and dietary factors influencing body iron status in relation to the risk of incident type 2 diabetes.

    RESEARCH DESIGN AND METHODS: The case-cohort comprised 9,347 case subjects and 12,301 subcohort participants from eight European countries. Single nucleotide polymorphisms (SNPs) were selected from genome-wide association studies on iron status biomarkers and candidate gene studies. A ferritin-related gene score was constructed. Multiplicative and additive interactions of heme iron and SNPs as well as the gene score were evaluated using Cox proportional hazards regression.

    RESULTS: Higher heme iron intake (per 1 SD) was associated with higher ferritin levels (β = 0.113 [95% CI 0.082; 0.144]), but not with transferrin (−0.019 [−0.043; 0.006]) or transferrin saturation (0.016 [−0.006; 0.037]). Five SNPs located in four genes (rs1799945 [HFE H63D], rs1800562 [HFE C282Y], rs236918 [PCK7], rs744653 [SLC40A1], and rs855791 [TMPRSS6V736A]) were associated with ferritin. We did not detect an interaction of heme iron and the gene score on the risk of diabetes in the overall study population (Padd = 0.16, Pmult = 0.21) but did detect a trend toward a negative interaction in men (Padd = 0.04, Pmult = 0.03).

    CONCLUSIONS: We found no convincing evidence that the interplay of dietary and genetic factors related to body iron status associates with type 2 diabetes risk above the level expected from the sum or product of the two individual exposures.

  • 161. Mesa, José L
    et al.
    Loos, Ruth J F
    Franks, Paul
    Umeå universitet, Medicinsk fakultet, Folkhälsa och klinisk medicin, Medicin.
    Ong, Ken K
    Luan, Jian'an
    O'Rahilly, Stephen
    Wareham, Nicholas J
    Barroso, Inês
    Lamin A/C polymorphisms, type 2 diabetes, and the metabolic syndrome: case-control and quantitative trait studies.2007Ingår i: Diabetes, ISSN 0012-1797, Vol. 56, nr 3, s. 884-9Artikel i tidskrift (Refereegranskat)
  • 162. Moore, Allan F
    et al.
    Jablonski, Kathleen A
    McAteer, Jarred B
    Saxena, Richa
    Pollin, Toni I
    Franks, Paul W
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Medicin.
    Hanson, Robert L
    Shuldiner, Alan R
    Knowler, William C
    Altshuler, David
    Florez, Jose C
    Extension of type 2 diabetes genome-wide association scan results in the diabetes prevention program2008Ingår i: Diabetes, ISSN 0012-1797, E-ISSN 1939-327X, Vol. 57, nr 9, s. 2503-2510Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    OBJECTIVE: Genome-wide association scans (GWASs) have identified novel diabetes-associated genes. We evaluated how these variants impact diabetes incidence, quantitative glycemic traits, and response to preventive interventions in 3,548 subjects at high risk of type 2 diabetes enrolled in the Diabetes Prevention Program (DPP), which examined the effects of lifestyle intervention, metformin, and troglitazone versus placebo.

    RESEARCH DESIGN AND METHODS: We genotyped selected single nucleotide polymorphisms (SNPs) in or near diabetes-associated loci, including EXT2, CDKAL1, CDKN2A/B, IGF2BP2, HHEX, LOC387761, and SLC30A8 in DPP participants and performed Cox regression analyses using genotype, intervention, and their interactions as predictors of diabetes incidence. We evaluated their effect on insulin resistance and secretion at 1 year.

    RESULTS: None of the selected SNPs were associated with increased diabetes incidence in this population. After adjustments for ethnicity, baseline insulin secretion was lower in subjects with the risk genotype at HHEX rs1111875 (P = 0.01); there were no significant differences in baseline insulin sensitivity. Both at baseline and at 1 year, subjects with the risk genotype at LOC387761 had paradoxically increased insulin secretion; adjustment for self-reported ethnicity abolished these differences. In ethnicity-adjusted analyses, we noted a nominal differential improvement in beta-cell function for carriers of the protective genotype at CDKN2A/B after 1 year of troglitazone treatment (P = 0.01) and possibly lifestyle modification (P = 0.05).

    CONCLUSIONS: We were unable to replicate the GWAS findings regarding diabetes risk in the DPP. We did observe genotype associations with differences in baseline insulin secretion at the HHEX locus and a possible pharmacogenetic interaction at CDKNA2/B.

  • 163. Mutie, Pascal M.
    et al.
    Giordano, Giuseppe N.
    Franks, Paul W.
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Medicin. Lund Univ, Skane Univ Hosp, Dept Clin Sci, Harvard Sch Publ Hlth, Univ Oxford, Radcliff Dept Med.
    Lifestyle precision medicine: the next generation in type 2 diabetes prevention?2017Ingår i: BMC Medicine, ISSN 1741-7015, E-ISSN 1741-7015, Vol. 15, artikel-id 171Artikel, forskningsöversikt (Refereegranskat)
    Abstract [en]

    The driving force behind the current global type 2 diabetes epidemic is insulin resistance in overweight and obese individuals. Dietary factors, physical inactivity, and sedentary behaviors are the major modifiable risk factors for obesity. Nevertheless, many overweight/obese people do not develop diabetes and lifestyle interventions focused on weight loss and diabetes prevention are often ineffective. Traditionally, chronically elevated blood glucose concentrations have been the hallmark of diabetes; however, many individuals will either remain 'prediabetic' or regress to normoglycemia. Thus, there is a growing need for innovative strategies to tackle diabetes at scale. The emergence of biomarker technologies has allowed more targeted therapeutic strategies for diabetes prevention (precision medicine), though largely confined to pharmacotherapy. Unlike most drugs, lifestyle interventions often have systemic health-enhancing effects. Thus, the pursuance of lifestyle precision medicine in diabetes seems rational. Herein, we review the literature on lifestyle interventions and diabetes prevention, describing the biological systems that can be characterized at scale in human populations, linking them to lifestyle in diabetes, and consider some of the challenges impeding the clinical translation of lifestyle precision medicine.

  • 164. Nelson, C. P.
    et al.
    Hamby, S. E.
    Saleheen, D.
    Hopewell, J. C.
    Zeng, L.
    Assimes, T. L.
    Kanoni, S.
    Willenborg, C.
    Burgess, S.
    Amouyel, P.
    Anand, S.
    Blankenberg, S.
    Boehm, B. O.
    Clarke, R. J.
    Collins, R.
    Dedoussis, G.
    Farrall, M.
    Franks, Paul W.
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Medicin. Department of Clinical Sciences, Lund University Diabetes Center, Skåne University Hospital; Department of Nutrition, Harvard School of Public Health, USA.
    Groop, L.
    Hall, A. S.
    Hamsten, A.
    Hengstenberg, C.
    Hovingh, G. Kees
    Ingelsson, E.
    Kathiresan, S.
    Kee, F.
    Koenig, I. R.
    Kooner, J.
    Lehtimaeki, T.
    Maerz, W.
    McPherson, R.
    Metspalu, A.
    Nieminen, M. S.
    O'Donnell, C. J.
    Palmer, C. N. A.
    Peters, A.
    Perola, M.
    Reilly, M. P.
    Ripatti, S.
    Roberts, R.
    Salomaa, V.
    Shah, S. H.
    Schreiber, S.
    Siegbahn, A.
    Thorsteinsdottir, U.
    Veronesi, G.
    Wareham, N.
    Willer, C. J.
    Zalloua, P. A.
    Erdmann, J.
    Deloukas, P.
    Watkins, H.
    Schunkert, H.
    Danesh, J.
    Thompson, J. R.
    Samani, N. J.
    Hallmans, Göran
    Umeå universitet, Medicinska fakulteten, Enheten för biobanksforskning. Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Näringsforskning.
    Genetically Determined Height and Coronary Artery Disease2015Ingår i: New England Journal of Medicine, ISSN 0028-4793, E-ISSN 1533-4406, Vol. 372, nr 17, s. 1608-1618Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    BACKGROUND The nature and underlying mechanisms of an inverse association between adult height and the risk of coronary artery disease (CAD) are unclear.

    METHODS We used a genetic approach to investigate the association between height and CAD, using 180 height-associated genetic variants. We tested the association between a change in genetically determined height of 1 SD (6.5 cm) with the risk of CAD in 65,066 cases and 128,383 controls. Using individual-level genotype data from 18,249 persons, we also examined the risk of CAD associated with the presence of various numbers of height-associated alleles. To identify putative mechanisms, we analyzed whether genetically determined height was associated with known cardiovascular risk factors and performed a pathway analysis of the height-associated genes.

    RESULTS We observed a relative increase of 13.5% (95% confidence interval [CI], 5.4 to 22.1; P<0.001) in the risk of CAD per 1-SD decrease in genetically determined height. There was a graded relationship between the presence of an increased number of height-raising variants and a reduced risk of CAD (odds ratio for height quar-tile 4 versus quartile 1, 0.74; 95% CI, 0.68 to 0.84; P<0.001). Of the 12 risk factors that we studied, we observed significant associations only with levels of low-density lipoprotein cholesterol and triglycerides (accounting for approximately 30% of the association). We identified several overlapping pathways involving genes associated with both development and atherosclerosis.

    CONCLUSIONS There is a primary association between a genetically determined shorter height and an increased risk of CAD, a link that is partly explained by the association between shorter height and an adverse lipid profile. Shared biologic processes that determine achieved height and the development of atherosclerosis may explain some of the association.

  • 165. Nelson, Christopher P.
    et al.
    Goel, Anuj
    Butterworth, Adam S.
    Kanoni, Stavroula
    Webb, Tom R.
    Marouli, Eirini
    Zeng, Lingyao
    Ntalla, Ioanna
    Lai, Florence Y.
    Hopewell, Jemma C.
    Giannakopoulou, Olga
    Jiang, Tao
    Hamby, Stephen E.
    Di Angelantonio, Emanuele
    Assimes, Themistocles L.
    Bottinger, Erwin P.
    Chambers, John C.
    Clarke, Robert
    Palmer, Colin N. A.
    Cubbon, Richard M.
    Ellinor, Patrick
    Ermel, Raili
    Evangelou, Evangelos
    Franks, Paul W.
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Medicin. Department of Clinical Sciences, Genetic & Molecular Epidemiology Unit, Lund University Diabetes Center, Skåne University Hospital, Lund University, Malmö, Sweden; Department of Nutrition, Harvard T.H. Chan School of Public Health, Harvard University, Boston, Massachusetts, USA.
    Grace, Christopher
    Gu, Dongfeng
    Hingorani, Aroon D.
    Howson, Joanna M. M.
    Ingelsson, Erik
    Kastrati, Adnan
    Kessler, Thorsten
    Kyriakou, Theodosios
    Lehtimaki, Terho
    Lu, Xiangfeng
    Lu, Yingchang
    Maerz, Winfried
    McPherson, Ruth
    Metspalu, Andres
    Pujades-Rodriguez, Mar
    Ruusalepp, Arno
    Schadt, Eric E.
    Schmidt, Amand F.
    Sweeting, Michael J.
    Zalloua, Pierre A.
    AlGhalayini, Kamal
    Keavney, Bernard D.
    Kooner, Jaspal S.
    Loos, Ruth J. F.
    Patel, Riyaz S.
    Rutter, Martin K.
    Tomaszewski, Maciej
    Tzoulaki, Ioanna
    Zeggini, Eleftheria
    Erdmann, Jeanette
    Dedoussis, George
    Bjorkegren, Johan L. M.
    Schunkert, Heribert
    Farrall, Martin
    Danesh, John
    Samani, Nilesh J.
    Watkins, Hugh
    Deloukas, Panos
    Association analyses based on false discovery rate implicate new loci for coronary artery disease2017Ingår i: Nature Genetics, ISSN 1061-4036, E-ISSN 1546-1718, Vol. 49, nr 9, s. 1385-1391Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Genome-wide association studies (GWAS) in coronary artery disease (CAD) had identified 66 loci at 'genome-wide significance' (P < 5 x 10(-8)) at the time of this analysis, but a much larger number of putative loci at a false discovery rate (FDR) of 5% (refs. 1-4). Here we leverage an interim release of UK Biobank (UKBB) data to evaluate the validity of the FDR approach. We tested a CAD phenotype inclusive of angina (SOFT; n(cases) = 10,801) as well as a stricter definition without angina (HARD; n(cases) = 6,482) and selected cases with the former phenotype to conduct a meta-analysis using the two most recent CAD GWAS(2,3). This approach identified 13 new loci at genome-wide significance, 12 of which were on our previous list of loci meeting the 5% FDR threshold(2), thus providing strong support that the remaining loci identified by FDR represent genuine signals. The 304 independent variants associated at 5% FDR in this study explain 21.2% of CAD heritability and identify 243 loci that implicate pathways in blood vessel morphogenesis as well as lipid metabolism, nitric oxide signaling and inflammation.

  • 166. Nettleton, Jennifer A
    et al.
    Follis, Jack L
    Ngwa, Julius S
    Smith, Caren E
    Ahmad, Shafqat
    Tanaka, Toshiko
    Wojczynski, Mary K
    Voortman, Trudy
    Lemaitre, Rozenn N
    Kristiansson, Kati
    Nuotio, Marja-Liisa
    Houston, Denise K
    Perälä, Mia-Maria
    Qi, Qibin
    Sonestedt, Emily
    Manichaikul, Ani
    Kanoni, Stavroula
    Ganna, Andrea
    Mikkilä, Vera
    North, Kari E
    Siscovick, David S
    Harald, Kennet
    Mckeown, Nicola M
    Johansson, Ingegerd
    Umeå universitet, Medicinska fakulteten, Institutionen för odontologi. Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Näringsforskning.
    Rissanen, Harri
    Liu, Yongmei
    Lahti, Jari
    Hu, Frank B
    Bandinelli, Stefania
    Rukh, Gull
    Rich, Stephen
    Booij, Lisanne
    Dmitriou, Maria
    Ax, Erika
    Raitakari, Olli
    Mukamal, Kenneth
    Männistö, Satu
    Hallmans, Göran
    Umeå universitet, Medicinska fakulteten, Enheten för biobanksforskning. Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Näringsforskning.
    Jula, Antti
    Ericson, Ulrika
    Jacobs, David R, Jr
    Van Rooij, Frank J A
    Deloukas, Panos
    Sjögren, Per
    Kähönen, Mika
    Djousse, Luc
    Perola, Markus
    Barroso, Inês
    Hofman, Albert
    Stirrups, Kathleen
    Viikari, Jorma
    Uitterlinden, André G
    Kalafati, Ioanna P
    Franco, Oscar H.
    Mozaffarian, Dariush
    Salomaa, Veikko
    Borecki, Ingrid B
    Knekt, Paul
    Kritchevsky, Stephen B
    Eriksson, Johan G
    Dedoussis, George V
    Qi, Lu
    Ferrucci, Luigi
    Orho-Melander, Marju
    Zillikens, M Carola
    Ingelsson, Erik
    Lehtimäki, Terho
    Renström, Frida
    Umeå universitet, Medicinska fakulteten, Enheten för biobanksforskning. Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Näringsforskning. Department of Clinical Sciences, Genetic and Molecular Epidemiology Unit, Lund University, Sweden.
    Cupples, L Adrienne
    Loos, Ruth J F
    Franks, Paul W
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Medicin. Department of Clinical Sciences, Genetic and Molecular Epidemiology Unit, Lund University, Sweden; Department of Nutrition, Harvard Chan School of Public Health, Boston, MA, USA.
    Gene x dietary pattern interactions in obesity: analysis of up to 68 317 adults of European ancestry2015Ingår i: Human Molecular Genetics, ISSN 0964-6906, E-ISSN 1460-2083, Vol. 24, nr 16, s. 4728-4738Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Obesity is highly heritable. Genetic variants showing robust associationswith obesity traits have been identified through genome wide association studies. We investigated whether a composite score representing healthy diet modifies associations of these variants with obesity traits. Totally, 32 body mass index (BMI)- and 14 waist-hip ratio (WHR)-associated single nucleotide polymorphismswere genotyped, and genetic risk scores (GRS) were calculated in 18 cohorts of European ancestry (n = 68 317). Diet score was calculated based on self-reported intakes of whole grains, fish, fruits, vegetables, nuts/seeds (favorable) and red/processed meats, sweets, sugar-sweetened beverages and fried potatoes (unfavorable). Multivariable adjusted, linear regression within each cohort followed by inverse variance-weighted, fixed-effects meta-analysis was used to characterize: (a) associations of each GRS with BMI and BMI-adjustedWHR and (b) diet score modification of genetic associations with BMI and BMI-adjusted WHR. Nominally significant interactions (P = 0.006-0.04) were observed between the diet score and WHR-GRS (but not BMI-GRS), two WHR loci (GRB14 rs10195252; LYPLAL1 rs4846567) and two BMI loci (LRRN6C rs10968576; MTIF3 rs4771122), for the respective BMI-adjustedWHR or BMI outcomes. Although the magnitudes of these select interactions were small, our data indicated that associations between genetic predisposition and obesity traits were stronger with a healthier diet. Our findings generate interesting hypotheses; however, experimental and functional studies are needed to determine their clinical relevance.

  • 167. Nettleton, Jennifer A.
    et al.
    Hivert, Marie-France
    Lemaitre, Rozenn N.
    McKeown, Nicola M.
    Mozaffarian, Dariush
    Tanaka, Toshiko
    Wojczynski, Mary K.
    Hruby, Adela
    Djousse, Luc
    Ngwa, Julius S.
    Follis, Jack L.
    Dimitriou, Maria
    Ganna, Andrea
    Houston, Denise K.
    Kanoni, Stavroula
    Mikkila, Vera
    Manichaikul, Ani
    Ntalla, Ioanna
    Renström, Frida
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Medicin.
    Sonestedt, Emily
    van Rooij, Frank J. A.
    Bandinelli, Stefania
    de Koning, Lawrence
    Ericson, Ulrika
    Hassanali, Neelam
    Kiefte-de Jong, Jessica C.
    Lohman, Kurt K.
    Raitakari, Olli
    Papoutsakis, Constantina
    Sjogren, Per
    Stirrups, Kathleen
    Ax, Erika
    Deloukas, Panos
    Groves, Christopher J.
    Jacques, Paul F.
    Johansson, Ingegerd
    Umeå universitet, Medicinska fakulteten, Institutionen för odontologi, Kariologi.
    Liu, Yongmei
    McCarthy, Mark I.
    North, Kari
    Viikari, Jorma
    Zillikens, M. Carola
    Dupuis, Josee
    Hofman, Albert
    Kolovou, Genovefa
    Mukamal, Kenneth
    Prokopenko, Inga
    Rolandsson, Olov
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Allmänmedicin.
    Seppala, Ilkka
    Cupples, L. Adrienne
    Hu, Frank B.
    Kahonen, Mika
    Uitterlinden, Andre G.
    Borecki, Ingrid B.
    Ferrucci, Luigi
    Jacobs, David R., Jr.
    Kritchevsky, Stephen B.
    Orho-Melander, Marju
    Pankow, James S.
    Lehtimaki, Terho
    Witteman, Jacqueline C. M.
    Ingelsson, Erik
    Siscovick, David S.
    Dedoussis, George
    Meigs, James B.
    Franks, Paul W.
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Medicin.
    Meta-analysis investigating associations between healthy diet and fasting glucose and insulin levels and modification by loci associated with glucose homeostasis in data from 15 cohorts2013Ingår i: American Journal of Epidemiology, ISSN 0002-9262, E-ISSN 1476-6256, Vol. 177, nr 2, s. 103-115Artikel, forskningsöversikt (Refereegranskat)
    Abstract [en]

    Whether loci that influence fasting glucose (FG) and fasting insulin (FI) levels, as identified by genome-wide association studies, modify associations of diet with FG or FI is unknown. We utilized data from 15 US and European cohort studies comprising 51,289 persons without diabetes to test whether genotype and diet interact to influence FG or FI concentration. We constructed a diet score using study-specific quartile rankings for intakes of whole grains, fish, fruits, vegetables, and nuts/seeds (favorable) and red/processed meats, sweets, sugared beverages, and fried potatoes (unfavorable). We used linear regression within studies, followed by inverse-variance-weighted meta-analysis, to quantify 1) associations of diet score with FG and FI levels and 2) interactions of diet score with 16 FG-associated loci and 2 FI-associated loci. Diet score (per unit increase) was inversely associated with FG ( 0.004 mmol/L, 95 confidence interval: 0.005, 0.003) and FI ( 0.008 ln-pmol/L, 95 confidence interval: 0.009, 0.007) levels after adjustment for demographic factors, lifestyle, and body mass index. Genotype variation at the studied loci did not modify these associations. Healthier diets were associated with lower FG and FI concentrations regardless of genotype at previously replicated FG- and FI-associated loci. Studies focusing on genomic regions that do not yield highly statistically significant associations from main-effect genome-wide association studies may be more fruitful in identifying diet-gene interactions.

  • 168. Nettleton, Jennifer A
    et al.
    McKeown, Nicola M
    Kanoni, Stavroula
    Lemaitre, Rozenn N
    Hivert, Marie-France
    Ngwa, Julius
    van Rooij, Frank J A
    Sonestedt, Emily
    Wojczynski, Mary K
    Ye, Zheng
    Tanaka, Toshiko
    Garcia, Melissa
    Anderson, Jennifer S
    Follis, Jack L
    Djousse, Luc
    Mukamal, Kenneth
    Papoutsakis, Constantina
    Mozaffarian, Dariush
    Zillikens, M Carola
    Bandinelli, Stefania
    Bennett, Amanda J
    Borecki, Ingrid B
    Feitosa, Mary F
    Ferrucci, Luigi
    Forouhi, Nita G
    Groves, Christopher J
    Hallmans, Göran
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Näringsforskning.
    Harris, Tamara
    Hofman, Albert
    Houston, Denise K
    Hu, Frank B
    Johansson, Ingegerd
    Umeå universitet, Medicinska fakulteten, Institutionen för odontologi.
    Kritchevsky, Stephen B
    Langenberg, Claudia
    Launer, Lenore
    Liu, Yongmei
    Loos, Ruth J
    Nalls, Michael
    Orho-Melander, Marju
    Renström, Frida
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Medicin.
    Rice, Kenneth
    Riserus, Ulf
    Rolandsson, Olov
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Allmänmedicin.
    Rotter, Jerome I
    Saylor, Georgia
    Sijbrands, Eric JG
    Sjögren, Per
    Smith, Albert
    Steingrímsdóttir, Laufey
    Uitterlinden, André G
    Wareham, Nicholas J
    Prokopenko, Inga
    Pankow, James S
    van Duijn, Cornelia M
    Flores, Jose C
    Witteman, Jaqueline CM
    Dupuis, Josée
    Dedoussis, George V
    Ordovas, Jose M
    Ingelsson, Erik
    Cupples, L Adrienne
    Siscovick, David S
    Franks, Paul W
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Medicin.
    Meigs, James B
    Interactions of dietary whole-grain intake with fasting glucose- and insulin-related genetic loci in individuals of European descent: a meta-analysis of 14 cohort studies2010Ingår i: Diabetes Care, ISSN 0149-5992, E-ISSN 1935-5548, Vol. 33, nr 12, s. 2684-2691Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Our results support the favorable association of whole-grain intake with fasting glucose and insulin and suggest a potential interaction between variation in GCKR and whole-grain intake in influencing fasting insulin concentrations.

  • 169. Njølstad, Pål Rasmus
    et al.
    Andreassen, Ole Andreas
    Brunak, Søren
    Borglum, Anders D.
    Dillner, Joakim
    Esko, Tonu
    Franks, Paul W.
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Avdelningen för medicin. Genetic and Molecular Epidemiology Unit, Lund University Diabetes Centre, Lund University, Malmö, Sweden; Department of Nutrition, Harvard T. H. Chan School of Public Health, Boston, MA, USA; Radclife Department of Medicine, University of Oxford, Oxford, UK.
    Freimer, Nelson
    Groop, Leif
    Heimer, Hakon
    Hougaard, David M.
    Hovig, Eivind
    Hveem, Kristian
    Jalanko, Anu
    Kaprio, Jaakko
    Knudsen, Gun Peggy
    Melbye, Mads
    Metspalu, Andres
    Mortensen, Preben Bo
    Palmgren, Juni
    Palotie, Aarno
    Reed, Wenche
    Stefansson, Hreinn
    Stitziel, Nathan O.
    Sullivan, Patrick F.
    Thorsteinsdottir, Unnur
    Vaudel, Marc
    Vuorio, Eero
    Werge, Thomas
    Stoltenberg, Camilla
    Stefansson, Kari
    Roadmap for a precision-medicine initiative in the Nordic region2019Ingår i: Nature Genetics, ISSN 1061-4036, E-ISSN 1546-1718, Vol. 51, nr 6, s. 924-930Artikel i tidskrift (Övrigt vetenskapligt)
    Abstract [en]

    The Nordic region, comprising primarily Denmark, Estonia, Finland, Iceland, Norway and Sweden, has many of the necessary characteristics for being at the forefront of genome-based precision medicine. These include egalitarian and universal healthcare, expertly curated patient and population registries, biobanks, large population-based prospective cohorts linked to registries and biobanks, and a widely embraced sense of social responsibility that motivates public engagement in biomedical research. However, genome-based precision medicine can be achieved only through coordinated action involving all actors in the healthcare sector. Now is an opportune time to organize scientists in the Nordic region, together with other stakeholders including patient representatives, governments, pharmaceutical companies, academic institutions and funding agencies, to initiate a Nordic Precision Medicine Initiative. We present a roadmap for how this organization can be created. The Initiative should facilitate research, clinical trials and knowledge transfer to meet regional and global health challenges.

  • 170.
    Nordström, Anna
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Yrkes- och miljömedicin.
    Hadrévi, Jenny
    Umeå universitet, Medicinska fakulteten, Institutionen för samhällsmedicin och rehabilitering, Idrottsmedicin.
    Olsson, Tommy
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Medicin.
    Franks, Paul W.
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Medicin. Department of Clinical Sciences, Genetic and Molecular Epidemiology Unit, Lund University Diabetes Centre, Malmö, Sweden; Department of Nutrition, Harvard School of Public Health, Boston, Massachusetts 02115.
    Nordström, Peter
    Umeå universitet, Medicinska fakulteten, Institutionen för samhällsmedicin och rehabilitering, Geriatrik. Lunds Universitet.
    The Higher Prevalence of Type 2 Diabetes in Men Than in Women is Associated with Differences in Visceral Fat Mass2016Ingår i: Journal of Clinical Endocrinology and Metabolism, ISSN 0021-972X, E-ISSN 1945-7197, Vol. 101, nr 10, s. 3740-3746Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Context: We have previously found that visceral fat is a stronger predictor for cardiovascular risk factors than body mass index (BMI). Objective: To investigate the prevalence of diabetes in elderly men and women in relation to objectively assessed visceral fat volume. Design and settings: The cohort consisted of a population-based sample of 705 men and 688 women, all aged 70 years at the time of examination. Main outcome measures: Associations between body fat estimates, plasma glucose level and diabetes prevalence were investigated using multivariable-adjusted statistical models.Results:Theprevalence of type2 diabetes was 14.6% in men and 9.1% inwomen (p0.001). Mean BMI was slightly higher in men than in women (27. 3 vs. 26.6 kg/m2, p 0.01), with a greater difference in mean visceral fat mass (1987 vs. 1087 g, p 0.001). After adjustment for physical activity and smoking, men had about twice the odds of having type 2 diabetes compared with women (OR, 1.95; 95% CI, 1.38–2.76). The inclusion of BMI in this model did not change the risk associated with male sex (OR, 1.93; 95% CI, 1.34–2.77). However, when visceral fat was included as a covariate, male sex was not associated with increased risk of type 2 diabetes (OR, 0.77; 95% CI, 0.51–1.18).Conclusions: The higher prevalence of type 2 diabetes in older men than in older women was associated with larger amount of visceral fat in men. In contrast, differences in BMI was not associated with this difference.

  • 171.
    Nordström, Peter
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för samhällsmedicin och rehabilitering, Geriatrik. Umeå universitet, Medicinska fakulteten, Institutionen för kirurgisk och perioperativ vetenskap, Idrottsmedicin.
    Franks, Paul
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Medicin.
    Gustafson, Yngve
    Umeå universitet, Medicinska fakulteten, Institutionen för samhällsmedicin och rehabilitering, Geriatrik.
    Nordström, Anna
    Umeå universitet, Medicinska fakulteten, Institutionen för kirurgisk och perioperativ vetenskap, Idrottsmedicin.
    Cognitive function in young men and the later risk of fractures2012Ingår i: Journal of Bone and Mineral Research, ISSN 0884-0431, E-ISSN 1523-4681, Vol. 27, nr 11, s. 2291-2297Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Dementia has been associated with an increased risk of fractures. These associations may be explained by an impaired cognitive function, as well as comorbid illness and toxic reaction from drugs. To investigate whether cognitive function in young, healthy individuals already affects the risk of fractures, overall cognitive function scores were calculated from four cognitive tests accomplished during a national conscriptions test in 960,956 men with a mean age of 18 years. Incident fractures were searched in national registers. During a median follow-up of 30 years (range 0 to 41 years), 65,313 men had one fracture and 2589 men had a hip fracture. Compared with men with no fracture, overall cognitive function at baseline was 3.5% lower for men sustaining one fracture and 5.5% lower for men sustaining a hip fracture (p < 0.001 for both). When comparing the lowest and the highest decile, low overall cognitive function scores increased the risk one fracture (hazard ratio [HR] = 1.55, 95% confidence interval [CI] 1.50-1.61) and a hip fracture (HR = 2.12, 95% CI 1.77-2.55), after adjustment for confounders. A higher education (university level versus elementary school) was associated with a decreased risk of a fracture (HR = 0.67, 95% CI 0.65-0.69) and a hip fracture (HR = 0.51, 95% CI 0.45-0.57). The effects of education and cognitive function were reduced when also adjusting for total income and disability pension. In summary, low cognitive function and education in young men were associated with the later risk of especially hip fractures. These associations may partly be mediated by socioeconomic factors. © 2012 American Society for Bone and Mineral Research.

  • 172. Nöthlings, U
    et al.
    Boeing, H
    Maskarinec, G
    Sluik, D
    Teucher, B
    Kaaks, R
    Tjønneland, A
    Halkjaer, J
    Dethlefsen, C
    Overvad, K
    Amiano, P
    Toledo, E
    Bendinelli, B
    Grioni, S
    Tumino, R
    Sacerdote, C
    Mattiello, A
    Beulens, J W J
    Iestra, J A
    Spijkerman, A M W
    van der A, D L
    Nilsson, P
    Sonestedt, E
    Rolandsson, Olov
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Allmänmedicin.
    Franks, Paul W
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Medicin.
    Vergnaud, A-C
    Romaguera, D
    Norat, T
    Kolonel, L N
    Food intake of individuals with and without diabetes across different countries and ethnic groups.2011Ingår i: European Journal of Clinical Nutrition, ISSN 0954-3007, E-ISSN 1476-5640, Vol. 65, nr 5, s. 635-41Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Background/Objectives:Given the importance of nutrition therapy in diabetes management, we hypothesized that food intake differs between individuals with and without diabetes. We investigated this hypothesis in two large prospective studies including different countries and ethnic groups.

    Subjects/Methods:Study populations were the European Prospective Investigation into Cancer and Nutrition Study (EPIC) and the Multiethnic Cohort Study (MEC). Dietary intake was assessed by food frequency questionnaires, and calibrated using 24h-recall information for the EPIC Study. Only confirmed self-reports of diabetes at cohort entry were included: 6192 diabetes patients in EPIC and 13 776 in the MEC. For the cross-sectional comparison of food intake and lifestyle variables at baseline, individuals with and without diabetes were matched 1:1 on sex, age in 5-year categories, body mass index in 2.5 kg/m(2) categories and country.

    Results:Higher intake of soft drinks (by 13 and 44% in the EPIC and MEC), and lower consumption of sweets, juice, wine and beer (>10% difference) were observed in participants with diabetes compared with those without. Consumption of vegetables, fish and meat was slightly higher in individuals with diabetes in both studies, but the differences were <10%. Findings were more consistent across different ethnic groups than countries, but generally showed largely similar patterns.

    Conclusions:Although diabetes patients are expected to undergo nutritional education, we found only small differences in dietary behavior in comparison with cohort members without diabetes. These findings suggest that emphasis on education is needed to improve the current behaviors to assist in the prevention of complications.

  • 173. Palmer, Nicholette D
    et al.
    McDonough, Caitrin W
    Hicks, Pamela J
    Roh, Bong H
    Wing, Maria R
    An, S Sandy
    Hester, Jessica M
    Cooke, Jessica N
    Bostrom, Meredith A
    Rudock, Megan E
    Talbert, Matthew E
    Lewis, Joshua P
    Ferrara, Assiamira
    Lu, Lingyi
    Ziegler, Julie T
    Sale, Michele M
    Divers, Jasmin
    Shriner, Daniel
    Adeyemo, Adebowale
    Rotimi, Charles N
    Ng, Maggie C Y
    Langefeld, Carl D
    Freedman, Barry I
    Bowden, Donald W
    Voight, Benjamin F
    Scott, Laura J
    Steinthorsdottir, Valgerdur
    Morris, Andrew P
    Dina, Christian
    Welch, Ryan P
    Zeggini, Eleftheria
    Huth, Cornelia
    Aulchenko, Yurii S
    Thorleifsson, Gudmar
    McCulloch, Laura J
    Ferreira, Teresa
    Grallert, Harald
    Amin, Najaf
    Wu, Guanming
    Willer, Cristen J
    Raychaudhuri, Soumya
    McCarroll, Steve A
    Langenberg, Claudia
    Hofmann, Oliver M
    Dupuis, Josée
    Qi, Lu
    Segrè, Ayellet V
    van Hoek, Mandy
    Navarro, Pau
    Ardlie, Kristin
    Balkau, Beverley
    Benediktsson, Rafn
    Bennett, Amanda J
    Blagieva, Roza
    Boerwinkle, Eric
    Bonnycastle, Lori L
    Boström, Kristina Bengtsson
    Bravenboer, Bert
    Bumpstead, Suzannah
    Burtt, Noël P
    Charpentier, Guillaume
    Chines, Peter S
    Cornelis, Marilyn
    Couper, David J
    Crawford, Gabe
    Doney, Alex S F
    Elliott, Katherine S
    Elliott, Amanda L
    Erdos, Michael R
    Fox, Caroline S
    Franklin, Christopher S
    Ganser, Martha
    Gieger, Christian
    Grarup, Niels
    Green, Todd
    Griffin, Simon
    Groves, Christopher J
    Guiducci, Candace
    Hadjadj, Samy
    Hassanali, Neelam
    Herder, Christian
    Isomaa, Bo
    Jackson, Anne U
    Johnson, Paul R V
    Jørgensen, Torben
    Kao, Wen H L
    Klopp, Norman
    Kong, Augustine
    Kraft, Peter
    Kuusisto, Johanna
    Lauritzen, Torsten
    Li, Man
    Lieverse, Aloysius
    Lindgren, Cecilia M
    Lyssenko, Valeriya
    Marre, Michel
    Meitinger, Thomas
    Midthjell, Kristian
    Morken, Mario A
    Narisu, Narisu
    Nilsson, Peter
    Owen, Katharine R
    Payne, Felicity
    Perry, John R B
    Petersen, Ann-Kristin
    Platou, Carl
    Proença, Christine
    Prokopenko, Inga
    Rathmann, Wolfgang
    Rayner, N William
    Robertson, Neil R
    Rocheleau, Ghislain
    Roden, Michael
    Sampson, Michael J
    Saxena, Richa
    Shields, Beverley M
    Shrader, Peter
    Sigurdsson, Gunnar
    Sparsø, Thomas
    Strassburger, Klaus
    Stringham, Heather M
    Sun, Qi
    Swift, Amy J
    Thorand, Barbara
    Tichet, Jean
    Tuomi, Tiinamaija
    van Dam, Rob M
    van Haeften, Timon W
    van Herpt, Thijs
    van Vliet-Ostaptchouk, Jana V
    Walters, G Bragi
    Weedon, Michael N
    Wijmenga, Cisca
    Witteman, Jacqueline
    Bergman, Richard N
    Cauchi, Stephane
    Collins, Francis S
    Gloyn, Anna L
    Gyllensten, Ulf
    Hansen, Torben
    Hide, Winston A
    Hitman, Graham A
    Hofman, Albert
    Hunter, David J
    Hveem, Kristian
    Laakso, Markku
    Mohlke, Karen L
    Morris, Andrew D
    Palmer, Colin N A
    Pramstaller, Peter P
    Rudan, Igor
    Sijbrands, Eric
    Stein, Lincoln D
    Tuomilehto, Jaakko
    Uitterlinden, Andre
    Walker, Mark
    Wareham, Nicholas J
    Watanabe, Richard M
    Abecasis, Goncalo R
    Boehm, Bernhard O
    Campbell, Harry
    Daly, Mark J
    Hattersley, Andrew T
    Hu, Frank B
    Meigs, James B
    Pankow, James S
    Pedersen, Oluf
    Wichmann, H-Erich
    Barroso, Inês
    Florez, Jose C
    Frayling, Timothy M
    Groop, Leif
    Sladek, Rob
    Thorsteinsdottir, Unnur
    Wilson, James F
    Illig, Thomas
    Froguel, Philippe
    van Duijn, Cornelia M
    Stefansson, Kari
    Altshuler, David
    Boehnke, Michael
    McCarthy, Mark I
    Soranzo, Nicole
    Wheeler, Eleanor
    Glazer, Nicole L
    Bouatia-Naji, Nabila
    Mägi, Reedik
    Randall, Joshua
    Johnson, Toby
    Elliott, Paul
    Rybin, Denis
    Henneman, Peter
    Dehghan, Abbas
    Hottenga, Jouke Jan
    Song, Kijoung
    Goel, Anuj
    Egan, Josephine M
    Lajunen, Taina
    Doney, Alex
    Kanoni, Stavroula
    Cavalcanti-Proença, Christine
    Kumari, Meena
    Timpson, Nicholas J
    Zabena, Carina
    Ingelsson, Erik
    An, Ping
    O'Connell, Jeffrey
    Luan, Jian'an
    Elliott, Amanda
    McCarroll, Steven A
    Roccasecca, Rosa Maria
    Pattou, François
    Sethupathy, Praveen
    Ariyurek, Yavuz
    Barter, Philip
    Beilby, John P
    Ben-Shlomo, Yoav
    Bergmann, Sven
    Bochud, Murielle
    Bonnefond, Amélie
    Borch-Johnsen, Knut
    Böttcher, Yvonne
    Brunner, Eric
    Bumpstead, Suzannah J
    Chen, Yii-Der Ida
    Chines, Peter
    Clarke, Robert
    Coin, Lachlan J M
    Cooper, Matthew N
    Crisponi, Laura
    Day, Ian N M
    de Geus, Eco J C
    Delplanque, Jerome
    Fedson, Annette C
    Fischer-Rosinsky, Antje
    Forouhi, Nita G
    Frants, Rune
    Franzosi, Maria Grazia
    Galan, Pilar
    Goodarzi, Mark O
    Graessler, Jürgen
    Grundy, Scott
    Gwilliam, Rhian
    Hallmans, Göran
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Näringsforskning.
    Hammond, Naomi
    Han, Xijing
    Hartikainen, Anna-Liisa
    Hayward, Caroline
    Heath, Simon C
    Hercberg, Serge
    Hicks, Andrew A
    Hillman, David R
    Hingorani, Aroon D
    Hui, Jennie
    Hung, Joe
    Jula, Antti
    Kaakinen, Marika
    Kaprio, Jaakko
    Kesaniemi, Y Antero
    Kivimaki, Mika
    Knight, Beatrice
    Koskinen, Seppo
    Kovacs, Peter
    Kyvik, Kirsten Ohm
    Lathrop, G Mark
    Lawlor, Debbie A
    Le Bacquer, Olivier
    Lecoeur, Cécile
    Li, Yun
    Mahley, Robert
    Mangino, Massimo
    Manning, Alisa K
    Martínez-Larrad, María Teresa
    McAteer, Jarred B
    McPherson, Ruth
    Meisinger, Christa
    Melzer, David
    Meyre, David
    Mitchell, Braxton D
    Mukherjee, Sutapa
    Naitza, Silvia
    Neville, Matthew J
    Oostra, Ben A
    Orrù, Marco
    Pakyz, Ruth
    Paolisso, Giuseppe
    Pattaro, Cristian
    Pearson, Daniel
    Peden, John F
    Pedersen, Nancy L
    Perola, Markus
    Pfeiffer, Andreas F H
    Pichler, Irene
    Polasek, Ozren
    Posthuma, Danielle
    Potter, Simon C
    Pouta, Anneli
    Province, Michael A
    Psaty, Bruce M
    Rayner, Nigel W
    Rice, Kenneth
    Ripatti, Samuli
    Rivadeneira, Fernando
    Rolandsson, Olov
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Allmänmedicin.
    Sandbaek, Annelli
    Sandhu, Manjinder
    Sanna, Serena
    Sayer, Avan Aihie
    Scheet, Paul
    Seedorf, Udo
    Sharp, Stephen J
    Shields, Beverley
    Sijbrands, Eric J G
    Silveira, Angela
    Simpson, Laila
    Singleton, Andrew
    Smith, Nicholas L
    Sovio, Ulla
    Swift, Amy
    Syddall, Holly
    Syvänen, Ann-Christine
    Tanaka, Toshiko
    Tönjes, Anke
    Uitterlinden, André G
    van Dijk, Ko Willems
    Varma, Dhiraj
    Visvikis-Siest, Sophie
    Vitart, Veronique
    Vogelzangs, Nicole
    Waeber, Gérard
    Wagner, Peter J
    Walley, Andrew
    Ward, Kim L
    Watkins, Hugh
    Wild, Sarah H
    Willemsen, Gonneke
    Witteman, Jaqueline C M
    Yarnell, John W G
    Zelenika, Diana
    Zethelius, Björn
    Zhai, Guangju
    Zhao, Jing Hua
    Zillikens, M Carola
    Borecki, Ingrid B
    Loos, Ruth J F
    Meneton, Pierre
    Magnusson, Patrik K E
    Nathan, David M
    Williams, Gordon H
    Silander, Kaisa
    Salomaa, Veikko
    Smith, George Davey
    Bornstein, Stefan R
    Schwarz, Peter
    Spranger, Joachim
    Karpe, Fredrik
    Shuldiner, Alan R
    Cooper, Cyrus
    Dedoussis, George V
    Serrano-Ríos, Manuel
    Lind, Lars
    Palmer, Lyle J
    Franks, Paul W
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Medicin.
    Ebrahim, Shah
    Marmot, Michael
    Kao, W H Linda
    Pramstaller, Peter Paul
    Wright, Alan F
    Stumvoll, Michael
    Hamsten, Anders
    Buchanan, Thomas A
    Valle, Timo T
    Rotter, Jerome I
    Siscovick, David S
    Penninx, Brenda W J H
    Boomsma, Dorret I
    Deloukas, Panos
    Spector, Timothy D
    Ferrucci, Luigi
    Cao, Antonio
    Scuteri, Angelo
    Schlessinger, David
    Uda, Manuela
    Ruokonen, Aimo
    Jarvelin, Marjo-Riitta
    Waterworth, Dawn M
    Vollenweider, Peter
    Peltonen, Leena
    Mooser, Vincent
    Sladek, Robert
    A genome-wide association search for type 2 diabetes genes in African Americans.2012Ingår i: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 7, nr 1, s. e29202-Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    African Americans are disproportionately affected by type 2 diabetes (T2DM) yet few studies have examined T2DM using genome-wide association approaches in this ethnicity. The aim of this study was to identify genes associated with T2DM in the African American population. We performed a Genome Wide Association Study (GWAS) using the Affymetrix 6.0 array in 965 African-American cases with T2DM and end-stage renal disease (T2DM-ESRD) and 1029 population-based controls. The most significant SNPs (n = 550 independent loci) were genotyped in a replication cohort and 122 SNPs (n = 98 independent loci) were further tested through genotyping three additional validation cohorts followed by meta-analysis in all five cohorts totaling 3,132 cases and 3,317 controls. Twelve SNPs had evidence of association in the GWAS (P<0.0071), were directionally consistent in the Replication cohort and were associated with T2DM in subjects without nephropathy (P<0.05). Meta-analysis in all cases and controls revealed a single SNP reaching genome-wide significance (P<2.5×10(-8)). SNP rs7560163 (P = 7.0×10(-9), OR (95% CI) = 0.75 (0.67-0.84)) is located intergenically between RND3 and RBM43. Four additional loci (rs7542900, rs4659485, rs2722769 and rs7107217) were associated with T2DM (P<0.05) and reached more nominal levels of significance (P<2.5×10(-5)) in the overall analysis and may represent novel loci that contribute to T2DM. We have identified novel T2DM-susceptibility variants in the African-American population. Notably, T2DM risk was associated with the major allele and implies an interesting genetic architecture in this population. These results suggest that multiple loci underlie T2DM susceptibility in the African-American population and that these loci are distinct from those identified in other ethnic populations.

  • 174. Pan, Qing
    et al.
    Delahanty, Linda M.
    Jablonski, Kathleen A.
    Knowler, William C.
    Kahn, Steven E.
    Florez, Jose C.
    Franks, Paul W.
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Medicin. Harvard University, USA and Lund University, Sweden.
    Variation at the Melanocortin 4 Receptor Gene and Response to Weight-Loss Interventions in the Diabetes Prevention Program2013Ingår i: Obesity, ISSN 1930-7381, E-ISSN 1930-739X, Vol. 21, nr 9, s. E520-E526Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Objective: To assess associations and genotype x treatment interactions for melanocortin 4 receptor (MC4R) locus variants and obesity-related traits.

    Design and Methods: Diabetes prevention program (DPP) participants (N = 3,819, of whom 3,356 were genotyped for baseline and 3,234 for longitudinal analyses) were randomized into intensive lifestyle modification (diet, exercise, weight loss), metformin or placebo control. Adiposity was assessed in a subgroup (n = 909) using computed tomography. All analyses were adjusted for age, sex, ethnicity and treatment.

    Results: The rs1943218 minor allele was nominally associated with short-term (6 month; P = 0.032) and long-term (2 year; P = 0.038) weight change. Eight SNPs modified response to treatment on short-term (rs17066856, rs9966412, rs17066859, rs8091237, rs17066866, rs7240064) or long-term (rs12970134, rs17066866) reduction in body weight, or diabetes incidence (rs17066829) (all P-interaction < 0.05).

    Conclusion: This is the first study to comprehensively assess the role of MC4R variants and weight regulation in a weight loss intervention trial. One MC4R variant was directly associated with obesity-related traits or diabetes; numerous other variants appear to influence body weight and diabetes risk by modifying the protective effects of the DPP interventions.

  • 175. Papandonatos, George D
    et al.
    Pan, Qing
    Pajewski, Nicholas M
    Delahanty, Linda M
    Peter, Inga
    Erar, Bahar
    Ahmad, Shafqat
    Harden, Maegan
    Chen, Ling
    Fontanillas, Pierre
    Wagenknecht, Lynne E
    Kahn, Steven E
    Wing, Rena R
    Jablonski, Kathleen A
    Huggins, Gordon S
    Knowler, William C
    Florez, Jose C
    McCaffery, Jeanne M
    Franks, Paul W
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Medicin. Genetic and Molecular Epidemiology Unit, Department of Clinical Sciences, Lund University, Skåne University Hospital Malmö, Malmö, Sweden; Department of Nutrition, Harvard T.H. Chan School of Public Health, Boston, MA.
    Genetic Predisposition to Weight Loss and Regain With Lifestyle Intervention: Analyses From the Diabetes Prevention Program and the Look AHEAD Randomized Controlled Trials2015Ingår i: Diabetes, ISSN 0012-1797, E-ISSN 1939-327X, Vol. 64, nr 12, s. 4312-4321Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Clinically relevant weight loss is achievable through lifestyle modification, but unintentional weight regain is common. We investigated whether recently discovered genetic variants affect weight loss and/or weight regain during behavioral intervention. Participants at high-risk of type 2 diabetes (Diabetes Prevention Program [DPP]; N = 917/907 intervention/comparison) or with type 2 diabetes (Look AHEAD [Action for Health in Diabetes]; N = 2,014/1,892 intervention/comparison) were from two parallel arm (lifestyle vs. comparison) randomized controlled trials. The associations of 91 established obesity-predisposing loci with weight loss across 4 years and with weight regain across years 2-4 after a minimum of 3% weight loss were tested. Each copy of the minor G allele of MTIF3 rs1885988 was consistently associated with greater weight loss following lifestyle intervention over 4 years across the DPP and Look AHEAD. No such effect was observed across comparison arms, leading to a nominally significant single nucleotide polymorphism x treatment interaction (P = 4.3 x 10-3). However, this effect was not significant at a study-wise significance level (Bonferroni threshold P < 5.8 x 10-4). Most obesity-predisposing gene variants were not associated with weight loss or regain within the DPP and Look AHEAD trials, directly or via interactions with lifestyle.

  • 176. Patel, Pinal S
    et al.
    Forouhi, Nita G
    Kuijsten, Anneleen
    Schulze, Matthias B
    van Woudenbergh, Geertruida J
    Ardanaz, Eva
    Amiano, Pilar
    Arriola, Larraitz
    Balkau, Beverley
    Barricarte, Aurelio
    Beulens, Joline WJ
    Boeing, Heiner
    Buijsse, Brian
    Crowe, Francesca L
    de Lauzon-Guillan, Blandine
    Fagherazzi, Guy
    Franks, Paul W
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Medicin.
    Gonzalez, Carlos
    Grioni, Sara
    Halkjaer, Jytte
    Maria Huerta, Jose
    Key, Timothy J
    Kuehn, Tilman
    Masala, Giovanna
    Nilsson, Peter
    Overvad, Kim
    Panico, Salvatore
    Ramon Quiros, Jose
    Rolandsson, Olov
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Allmänmedicin.
    Sacerdote, Carlotta
    Sanchez, Maria-Jose
    Schmidt, Erik B
    Slimani, Nadia
    Spijkerman, Annemieke MW
    Teucher, Birgit
    Tjonneland, Anne
    Tormo, Maria-Jose
    Tumino, Rosario
    van der A, Daphne L
    van der Schouw, Yvonne T
    Sharp, Stephen J
    Langenberg, Claudia
    Feskens, Edith JM
    Riboli, Elio
    Wareham, Nicholas J
    The prospective association between total and type of fish intake and type 2 diabetes in 8 European countries: EPIC-InterAct Study2012Ingår i: American Journal of Clinical Nutrition, ISSN 0002-9165, E-ISSN 1938-3207, Vol. 95, nr 6, s. 1445-1453Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Background: Epidemiologic evidence of an association between fish intake and type 2 diabetes (T2D) is inconsistent and unresolved.

    Objective: The objective was to examine the association between total and type of fish intake and T2D in 8 European countries.

    Design: This was a case-cohort study, nested within the European Prospective Investigation into Cancer and Nutrition (EPIC) study, with 3.99 million person-years of follow-up, 12,403 incident diabetes cases, and a random subcohort of 16,835 individuals from 8 European countries. Habitual fish intake (lean fish, fatty fish, total fish, shellfish, and combined fish and shellfish) was assessed by country-specific dietary questionnaires. HRs were estimated in each country by using Prentice-weighted Cox regression models and pooled by using a random-effects meta-analysis.

    Results: No overall association was found between combined fish and shellfish intake and incident T2D per quartile (adjusted HR: 1.00; 95% Cl: 0.94, 1.06; P-trend = 0.99). Total fish, lean fish, and shellfish intakes separately were also not associated with T2D, but fatty fish intake was weakly inversely associated with T2D: adjusted HR per quartile 0.97 (0.94, 1.00), with an HR of 0.84 (0.70, 1.01), 0.85 (0.76, 0.95), and 0.87 (0.78, 0.97) for a comparison of the second, third, and fourth quartiles with the lowest quartile of intake, respectively (P-trend = 0.06).

    Conclusions: These findings suggest that lean fish, total fish, and shellfish intakes are not associated with incident diabetes but that fatty fish intake may be weakly inversely associated. Replication of these findings in other populations and investigation of the mechanisms underlying these associations are warranted. Meanwhile, current public health recommendations on fish intake should remain unchanged. Am J Clin Nutr 2012;95:1445-53,

  • 177. Peters, Tricia
    et al.
    Brage, Soren
    Westgate, Kate
    Franks, Paul W.
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Medicin.
    Gradmark, Anna
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Medicin.
    Diaz, Maria Jose Tormo
    Huerta, Jose Maria
    Bendinelli, Benedetta
    Vigl, Mattheaus
    Boeing, Heiner
    Wendel-Vos, Wanda
    Spijkerman, Annemieke
    Benjaminsen-Borch, Kristin
    Valanou, Elisavet
    Guillain, Blandine de Lauzon
    Clavel-Chapelon, Francoise
    Sharp, Stephen
    Kerrison, Nicola
    Langenberg, Claudia
    Arriola, Larraitz
    Barricarte, Aurelio
    Gonzales, Carlos
    Grioni, Sara
    Kaaks, Rudolf
    Key, Timothy
    Khaw, Kay Tee
    May, Anne
    Nilsson, Peter
    Norat, Teresa
    Overvad, Kim
    Palli, Domenico
    Panico, Salvatore
    Quiros, Jose Ramon
    Ricceri, Fulvio
    Sanchez, Maria-Jose
    Slimani, Nadia
    Tjonneland, Anne
    Tumino, Rosario
    Feskens, Edith
    Riboli, Elio
    Ekelund, Ulf
    Wareham, Nick
    Validity of a short questionnaire to assess physical activity in 10 European countries2012Ingår i: European Journal of Epidemiology, ISSN 0393-2990, E-ISSN 1573-7284, Vol. 27, nr 1, s. 15-25Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    To accurately examine associations of physical activity (PA) with disease outcomes, a valid method of assessing free-living activity is required. We examined the validity of a brief PA questionnaire (PAQ) used in the European Prospective Investigation into Cancer and Nutrition (EPIC). PA energy expenditure (PAEE) and time spent in moderate and vigorous physical activity (MVPA) was measured in 1,941 healthy individuals from 10 European countries using individually-calibrated combined heart-rate and movement sensing. Participants also completed the short EPIC-PAQ, which refers to past year's activity. Pearson (r) and Spearman (sigma) correlation coefficients were calculated for each country, and random effects meta-analysis was used to calculate the combined correlation across countries to estimate the validity of two previously- and one newly-derived ordered, categorical PA indices ("Cambridge index", "total PA index", and "recreational index") that categorized individuals as inactive, moderately inactive, moderately active, or active. The strongest associations with PAEE and MVPA were observed for the Cambridge index (r = 0.33 and r = 0.25, respectively). No significant heterogeneity by country was observed for this index (I-2 = 36.3%, P = 0.12; I-2 = 0.0%, P = 0.85), whereas heterogeneity was suggested for other indices (I-2 > 48%, P < 0.05, I-2 > 47%, P < 0.05). PAEE increased linearly across self-reported PA categories (P for trend < 0.001), with an average difference of approximately 460 kJ/d for men and 365 kJ/d for women, between categories of the Cambridge index. The EPIC-PAQ is suitable for categorizing European men and women into four distinct categories of overall physical activity. The difference in PAEE between categories may be useful when estimating effect sizes from observational research.

  • 178. Podmore, Clara
    et al.
    Meidtner, Karina
    Schulze, Matthias B.
    Scott, Robert A.
    Ramond, Anna
    Butterworth, Adam S.
    Di Angelantonio, Emanuele
    Danesh, John
    Arriola, Larraitz
    Barricarte, Aurelio
    Boeing, Heiner
    Clavel-Chapelon, Francoise
    Cross, Amanda J.
    Dahm, Christina C.
    Fagherazzi, Guy
    Franks, Paul W.
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Medicin.
    Gavrila, Diana
    Grioni, Sara
    Gunter, Marc J.
    Gusto, Gaelle
    Jakszyn, Paula
    Katzke, Verena
    Key, Timothy J.
    Kuhn, Tilman
    Mattiello, Amalia
    Nilsson, Peter M.
    Olsen, Anja
    Overvad, Kim
    Palli, Domenico
    Ramon Quiros, J.
    Rolandsson, Olov
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Allmänmedicin.
    Sacerdote, Carlotta
    Sanchez-Cantalejo, Emilio
    Slimani, Nadia
    Sluijs, Ivonne
    Spijkerman, Annemieke M. W.
    Tjonneland, Anne
    Tumino, Rosario
    van der A, Daphne L.
    van der Schouw, Yvonne T.
    Feskens, Edith J. M.
    Forouhi, Nita G.
    Sharp, Stephen J.
    Riboli, Elio
    Langenberg, Claudia
    Wareham, Nicholas J.
    Association of Multiple Biomarkers of Iron Metabolism and Type 2 Diabetes: The EPIC-InterAct Study2016Ingår i: Diabetes Care, ISSN 0149-5992, E-ISSN 1935-5548, Vol. 39, nr 4, s. 572-581Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    OBJECTIVE Observational studies show an association between ferritin and type 2 diabetes (T2D), suggesting a role of high iron stores in T2D development. However, ferritin is influenced by factors other than iron stores, which is less the case for other biomarkers of iron metabolism. We investigated associations of ferritin, transferrin saturation (TSAT), serum iron, and transferrin with T2D incidence to clarify the role of iron in the pathogenesis of T2D.

    RESEARCH DESIGN AND METHODS The European Prospective Investigation into Cancer and Nutrition-InterAct study includes 12,403 incident T2D cases and a representative subcohort of 16,154 individuals from a European cohort with 3.99 million person-years of follow-up. We studied the prospective association of ferritin, TSAT, serum iron, and transferrin with incident T2D in 11,052 cases and a random subcohort of 15,182 individuals and assessed whether these associations differed by subgroups of the population.

    RESULTS Higher levels of ferritin and transferrin were associated with a higher risk of T2D (hazard ratio [HR] [95% CI] in men and women, respectively: 1.07 [1.01-1.12] and 1.12 [1.05-1.19] per 100mg/L higher ferritin level; 1.11 [1.00-1.24] and 1.22 [1.12-1.33] per 0.5 g/L higher transferrin level) after adjustment for age, center, BMI, physical activity, smoking status, education, hs-CRP, alanine aminotransferase, and g-glutamyl transferase. Elevated TSAT (>= 45% vs. <45%) was associated with a lower risk of T2D in women (0.68 [0.54-0.86]) but was not statistically significantly associated in men (0.90 [0.75-1.08]). Serum iron was not associated with T2D. The association of ferritin with T2D was stronger among leaner individuals (P-interaction < 0.01).

    CONCLUSIONS The pattern of association of TSAT and transferrin with T2D suggests that the underlying relationship between iron stores and T2D is more complex than the simple link suggested by the association of ferritin with T2D.

  • 179. Pomeroy, Jeremy
    et al.
    Renström, Frida
    Gradmark, Anna
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Medicin.
    Mogren, Ingrid
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk vetenskap, Obstetrik och gynekologi.
    Persson, Margareta
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk vetenskap, Obstetrik och gynekologi.
    Bluck, Les
    Wright, Antony
    Kahn, Steven E.
    Domellöf, Magnus
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk vetenskap, Pediatrik.
    Franks, Paul W.
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Medicin.
    Maternal Physical Activity and Insulin Action in Pregnancy and Their Relationships With Infant Body Composition2013Ingår i: Diabetes Care, ISSN 0149-5992, E-ISSN 1935-5548, Vol. 36, nr 2, s. 267-269Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    OBJECTIVE-We sought to assess the association between maternal gestational physical activity and insulin action and body composition in early infancy. RESEARCH DESIGN AND METHODS-At 28-32 weeks' gestation, pregnant women participating in an observational study in Sweden underwent assessments of height, weight, and body composition, an oral glucose tolerance test, and 10 days of objective physical activity assessment. Thirty mothers and infants returned at 11-19 weeks postpartum. Infants underwent assessments of weight, length, and body composition. RESULTS-Early insulin response was correlated with total physical activity (r = 0.47; P = 0.007). Early insulin response (r = -0.36; P = 0.045) and total physical activity (r = 0.52; P = 0.037) were also correlated with infant fat-free mass. No maternal variable was significantly correlated with infant adiposity. CONCLUSIONS-The relationships between maternal physical activity, insulin response, and infant fat-free mass suggest that physical activity during pregnancy may affect metabolic outcomes in the mother and her offspring. 

  • 180. Pomeroy, Jeremy
    et al.
    Renström, Frida
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Medicin.
    Gradmark, Anna
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Medicin.
    Steiginga, S
    Persson, M
    Wright, A
    Bluck, L
    Domellöf, M
    Kahn, SE
    Mogren, I
    Franks, Paul W
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Medicin.
    Metabolic risk-factor profiles in infants in relation to those of their mothers during pregnancy2011Övrigt (Övrigt vetenskapligt)
    Abstract [en]

    Background Maternal characteristics during pregnancy such as BMI, weight gain, and glucose tolerance have been associated with anthropometric traits in their offspring. Here we extend these observations looking at the associations between maternal body composition, weight gain by trimester, and glucose tolerance and anthropometrics in their infants.

    Materials and methods Participants were 31 (16 female) singleton babies and their mothers (aged 25-35 yrs) in the eastern area of the county of Västerbotten in Sweden. Maternal weight was measured at gestational weeks 10-12, 28-32, and 37-41. Maternal body composition was assessed using isotope dilution and gestational glucose tolerance was assessed with a 2-hour, 75-gram oral glucose challenge at 28-32 weeks gestation. Infant body composition was assessed at 11-19 weeks of age using air- displacement plethysmography. The relationships between maternal and infant variables were assessed with Spearman correlations.

    Results Mid-pregnancy weight gain was significantly positively related to fat mass (r=0.41, p= 0.022) but not fat-free mass whereas late-pregnancy weight gain was significantly positively related to infant fat-free mass (r=0.37, p=0.04) but not fat mass. Maternal weight, body composition, or glucose tolerance was not significantly related to infant body composition. Early infancy growth (weight-for-length growth z-score) from 0 to 4 months was significantly related to infant percent fat (r=0.48, p=0.006). Gestational weight gain by trimester is differently related to body composition assessed in early infancy. Additionally, greater early infancy growth is associated with higher percent fat at 4 months of age. Both of these findings might identify targets for interventions conducted in pregnancy and during early life.

  • 181.
    Pomeroy, Jeremy
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Medicin. Phoenix Epidemiology and Clinical Research Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Phoenix, Ariz., USA.
    Söderberg, Anna M
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Medicin.
    Franks, Paul W
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Medicin.
    Gene-lifestyle interactions and their consequences on human health.2009Ingår i: Genetics and Sports / [ed] Collins M., S. Karger, 2009, Vol. 54, s. 110-135Kapitel i bok, del av antologi (Refereegranskat)
    Abstract [en]

    Our genes are the conduit through which the environment communicates to the cells in our bodies. The responses to these signals include hormonal, metabolic and neurological changes to tissues and organs that manifest as phenotypes - measurable responses to gene transcription and translation. Thus, the health consequences of lifestyle behaviors such as physical activity, which can be broadly defined as 'environmental' exposures, are channeled through our genes. The extent to which these signals are conveyed depends in part on the structure and function of our genome. Hence, even when exposed to the same exercise regimes or doses of physical activity, responses vary markedly from one person to the next; some experience marked changes in disease phenotypes such as lipid and glucose concentrations, adiposity, or blood pressure levels, whilst others appear unresponsive. It is this process that underlies the concept that we will discuss in this chapter, a concept termed gene-lifestyle interaction. The aims of this chapter are (a) to convey to the reader the fundamental principles of gene-lifestyle interaction; (b) to describe the historical basis to this area of research; (c)to explain how understanding gene-lifestyle interactions might enhance our knowledge of the molecular mechanisms of disease; (d) to speculate on the ways in which information of gene-lifestyle interactions might eventually facilitate disease prevention, and (e) to overview the published literature which has focused on obesity as an outcome.

  • 182. Poveda, Alaitz
    et al.
    Chen, Yan
    Brändström, Anders
    Umeå universitet, Samhällsvetenskapliga fakulteten, Enheten för demografi och åldrandeforskning (CEDAR).
    Engberg, Elisabeth
    Umeå universitet, Samhällsvetenskapliga fakulteten, Enheten för demografi och åldrandeforskning (CEDAR).
    Hallmans, Göran
    Umeå universitet, Medicinska fakulteten, Enheten för biobanksforskning.
    Johansson, Ingegerd
    Umeå universitet, Medicinska fakulteten, Enheten för biobanksforskning.
    Renström, Frida
    Umeå universitet, Medicinska fakulteten, Enheten för biobanksforskning. Genetic and Molecular Epidemiology Unit, Department of Clinical Sciences, Clinical Research Centre, Lund University, Jan Waldenströms gata 35, Building 91, Skåne University Hospital, SE-20502 Malmö, Sweden.
    Kurbasic, Azra
    Franks, Paul W.
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Medicin. Genetic and Molecular Epidemiology Unit, Department of Clinical Sciences, Clinical Research Centre, Lund University, Jan Waldenströms gata 35, Building 91, Skåne University Hospital, SE-20502 Malmö, Sweden; Department of Nutrition, Harvard T. H. Chan School of Public Health, Boston, MA, USA.
    The heritable basis of gene-environment interactions in cardiometabolic traits2017Ingår i: Diabetologia, ISSN 0012-186X, E-ISSN 1432-0428, Vol. 60, nr 3, s. 442-452Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Aims/hypothesis Little is known about the heritable basis of gene-environment interactions in humans. We therefore screened multiple cardiometabolic traits to assess the probability that they are influenced by genotype-environment interactions.

    Methods Fourteen established environmental risk exposures and 11 cardiometabolic traits were analysed in the VIKING study, a cohort of 16,430 Swedish adults from 1682 extended pedigrees with available detailed genealogical, phenotypic and demographic information, using a maximum likelihood variance decomposition method in Sequential Oligogenic Linkage Analysis Routines software.

    Results All cardiometabolic traits had statistically significant heritability estimates, with narrow-sense heritabilities (h (2)) ranging from 24% to 47%. Genotype-environment interactions were detected for age and sex (for the majority of traits), physical activity (for triacylglycerols, 2 h glucose and diastolic BP), smoking (for weight), alcohol intake (for weight, BMI and 2 h glucose) and diet pattern (for weight, BMI, glycaemic traits and systolic BP). Genotype-age interactions for weight and systolic BP, genotype-sex interactions for BMI and triacylglycerols and genotype-alcohol intake interactions for weight remained significant after multiple test correction.

    Conclusion/hypothesis Age, sex and alcohol intake are likely to be major modifiers of genetic effects for a range of cardiometabolic traits. This information may prove valuable for studies that seek to identify specific loci that modify the effects of lifestyle in cardiometabolic disease.

  • 183. Poveda, Alaitz
    et al.
    Koivula, Robert W.
    Ahmad, Shafqat
    Barroso, Ines
    Hallmans, Göran
    Umeå universitet, Medicinska fakulteten, Enheten för biobanksforskning.
    Johansson, Ingegerd
    Umeå universitet, Medicinska fakulteten, Institutionen för odontologi.
    Renstrom, Frida
    Umeå universitet, Medicinska fakulteten, Enheten för biobanksforskning. Lund Univ, Dept Clin Sci, Genet & Mol Epidemiol Unit, Malmö, Sweden.
    Franks, Paul W.
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Medicin.
    Innate biology versus lifestyle behaviour in the aetiology of obesity and type 2 diabetes: the GLACIER Study2016Ingår i: Diabetologia, ISSN 0012-186X, E-ISSN 1432-0428, Vol. 59, nr 3, s. 462-471Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Aims/hypothesis We compared the ability of genetic (established type 2 diabetes, fasting glucose, 2 h glucose and obesity variants) and modifiable lifestyle (diet, physical activity, smoking, alcohol and education) risk factors to predict incident type 2 diabetes and obesity in a population-based prospective cohort of 3,444 Swedish adults studied sequentially at baseline and 10 years later. Methods Multivariable logistic regression analyses were used to assess the predictive ability of genetic and lifestyle risk factors on incident obesity and type 2 diabetes by calculating the AUC. Results The predictive accuracy of lifestyle risk factors was similar to that yielded by genetic information for incident type 2 diabetes (AUC 75% and 74%, respectively) and obesity (AUC 68% and 73%, respectively) in models adjusted for age, age2 and sex. The addition of genetic information to the lifestyle model significantly improved the prediction of type 2 diabetes (AUC 80%; p = 0.0003) and obesity (AUC 79%; p < 0.0001) and resulted in a net reclassification improvement of 58% for type 2 diabetes and 64% for obesity. Conclusions/interpretation These findings illustrate that lifestyle and genetic information separately provide a similarly high degree of long-range predictive accuracy for obesity and type 2 diabetes.

  • 184.
    Qi, Qibin
    et al.
    Albert Einstein Coll Med, Dept Epidemiol, Bronx, NY 10467 USA.
    Kilpeläinen, Tuomas O
    Downer, Mary K
    Tanaka, Toshiko
    Smith, Caren E
    Sluijs, Ivonne
    Sonestedt, Emily
    Chu, Audrey Y
    Renström, Frida
    Lin, Xiaochen
    Angquist, Lars H
    Huang, Jinyan
    Liu, Zhonghua
    Li, Yanping
    Asif Ali, Muhammad
    Xu, Min
    Ahluwalia, Tarunveer Singh
    Boer, Jolanda M A
    Chen, Peng
    Daimon, Makoto
    Eriksson, Johan
    Perola, Markus
    Friedlander, Yechiel
    Gao, Yu-Tang
    Heppe, Denise H M
    Holloway, John W
    Houston, Denise K
    Kanoni, Stavroula
    Kim, Yu-Mi
    Laaksonen, Maarit A
    Jääskeläinen, Tiina
    Lee, Nanette R
    Lehtimäki, Terho
    Lemaitre, Rozenn N
    Lu, Wei
    Luben, Robert N
    Manichaikul, Ani
    Männistö, Satu
    Marques-Vidal, Pedro
    Monda, Keri L
    Ngwa, Julius S
    Perusse, Louis
    van Rooij, Frank J A
    Xiang, Yong-Bing
    Wen, Wanqing
    Wojczynski, Mary K
    Zhu, Jingwen
    Borecki, Ingrid B
    Bouchard, Claude
    Cai, Qiuyin
    Cooper, Cyrus
    Dedoussis, George V
    Deloukas, Panos
    Ferrucci, Luigi
    Forouhi, Nita G
    Hansen, Torben
    Christiansen, Lene
    Hofman, Albert
    Johansson, Ingegerd
    Umeå universitet, Medicinska fakulteten, Institutionen för odontologi.
    Jørgensen, Torben
    Karasawa, Shigeru
    Khaw, Kay-Tee
    Kim, Mi-Kyung
    Kristiansson, Kati
    Li, Huaixing
    Lin, Xu
    Liu, Yongmei
    Lohman, Kurt K
    Long, Jirong
    Mikkilä, Vera
    Mozaffarian, Dariush
    North, Kari
    Pedersen, Oluf
    Raitakari, Olli
    Rissanen, Harri
    Tuomilehto, Jaakko
    van der Schouw, Yvonne T
    Uitterlinden, André G
    Carola Zillikens, M
    Franco, Oscar H
    Shyong Tai, E
    Ou Shu, Xiao
    Siscovick, David S
    Toft, Ulla
    Monique Verschuren, W M
    Vollenweider, Peter
    Wareham, Nicholas J
    Witteman, Jacqueline C M
    Zheng, Wei
    Ridker, Paul M
    Kang, Jae H
    Liang, Liming
    Jensen, Majken K
    Curhan, Gary C
    Pasquale, Louis R
    Hunter, David J
    Mohlke, Karen L
    Uusitupa, Matti
    Adrienne Cupples, L
    Rankinen, Tuomo
    Orho-Melander, Marju
    Wang, Tao
    Chasman, Daniel I
    Franks, Paul
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Medicin. Harvard Univ, Sch Publ Hlth, Dept Nutr, Boston, MA 02115 USA; Harvard Univ, Sch Publ Hlth, Dept Epidemiol, Boston, MA 02115 USA; Lund Univ, Dept Clin Sci, Genet & Mol Epidemiol Unit, Malmo, Sweden.
    Sørensen, Thorkild I A
    Hu, Frank B
    Loos, Ruth J F
    Nettleton, Jennifer A
    Qi, Lu
    FTO genetic variants, dietary intake and body mass index: insights from 177 330 individuals2014Ingår i: Human Molecular Genetics, ISSN 0964-6906, E-ISSN 1460-2083, Vol. 23, nr 25, s. 6961-6972Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    FTO is the strongest known genetic susceptibility locus for obesity. Experimental studies in animals suggest the potential roles of FTO in regulating food intake. The interactive relation among FTO variants, dietary intake and body mass index (BMI) is complex and results from previous often small-scale studies in humans are highly inconsistent. We performed large-scale analyses based on data from 177 330 adults (154 439 Whites, 5776 African Americans and 17 115 Asians) from 40 studies to examine: (i) the association between the FTO-rs9939609 variant (or a proxy single-nucleotide polymorphism) and total energy and macronutrient intake and (ii) the interaction between the FTO variant and dietary intake on BMI. The minor allele (A-allele) of the FTO-rs9939609 variant was associated with higher BMI in Whites (effect per allele = 0.34 [0.31, 0.37] kg/m(2), P = 1.9 × 10(-105)), and all participants (0.30 [0.30, 0.35] kg/m(2), P = 3.6 × 10(-107)). The BMI-increasing allele of the FTO variant showed a significant association with higher dietary protein intake (effect per allele = 0.08 [0.06, 0.10] %, P = 2.4 × 10(-16)), and relative weak associations with lower total energy intake (-6.4 [-10.1, -2.6] kcal/day, P = 0.001) and lower dietary carbohydrate intake (-0.07 [-0.11, -0.02] %, P = 0.004). The associations with protein (P = 7.5 × 10(-9)) and total energy (P = 0.002) were attenuated but remained significant after adjustment for BMI. We did not find significant interactions between the FTO variant and dietary intake of total energy, protein, carbohydrate or fat on BMI. Our findings suggest a positive association between the BMI-increasing allele of FTO variant and higher dietary protein intake and offer insight into potential link between FTO, dietary protein intake and adiposity.

  • 185. Randall, Joshua C
    et al.
    Winkler, Thomas W
    Kutalik, Zoltán
    Berndt, Sonja I
    Jackson, Anne U
    Monda, Keri L
    Kilpeläinen, Tuomas O
    Esko, Tõnu
    Mägi, Reedik
    Li, Shengxu
    Workalemahu, Tsegaselassie
    Feitosa, Mary F
    Croteau-Chonka, Damien C
    Day, Felix R
    Fall, Tove
    Ferreira, Teresa
    Gustafsson, Stefan
    Locke, Adam E
    Mathieson, Iain
    Scherag, Andre
    Vedantam, Sailaja
    Wood, Andrew R
    Liang, Liming
    Steinthorsdottir, Valgerdur
    Thorleifsson, Gudmar
    Dermitzakis, Emmanouil T
    Dimas, Antigone S
    Karpe, Fredrik
    Min, Josine L
    Nicholson, George
    Clegg, Deborah J
    Person, Thomas
    Krohn, Jon P
    Bauer, Sabrina
    Buechler, Christa
    Eisinger, Kristina
    Bonnefond, Amélie
    Froguel, Philippe
    Hottenga, Jouke-Jan
    Prokopenko, Inga
    Waite, Lindsay L
    Harris, Tamara B
    Smith, Albert Vernon
    Shuldiner, Alan R
    McArdle, Wendy L
    Caulfield, Mark J
    Munroe, Patricia B
    Grönberg, Henrik
    Chen, Yii-Der Ida
    Li, Guo
    Beckmann, Jacques S
    Johnson, Toby
    Thorsteinsdottir, Unnur
    Teder-Laving, Maris
    Khaw, Kay-Tee
    Wareham, Nicholas J
    Zhao, Jing Hua
    Amin, Najaf
    Oostra, Ben A
    Kraja, Aldi T
    Province, Michael A
    Cupples, L Adrienne
    Heard-Costa, Nancy L
    Kaprio, Jaakko
    Ripatti, Samuli
    Surakka, Ida
    Collins, Francis S
    Saramies, Jouko
    Tuomilehto, Jaakko
    Jula, Antti
    Salomaa, Veikko
    Erdmann, Jeanette
    Hengstenberg, Christian
    Loley, Christina
    Schunkert, Heribert
    Lamina, Claudia
    Wichmann, H Erich
    Albrecht, Eva
    Gieger, Christian
    Hicks, Andrew A
    Johansson, Asa
    Pramstaller, Peter P
    Kathiresan, Sekar
    Speliotes, Elizabeth K
    Penninx, Brenda
    Hartikainen, Anna-Liisa
    Jarvelin, Marjo-Riitta
    Gyllensten, Ulf
    Boomsma, Dorret I
    Campbell, Harry
    Wilson, James F
    Chanock, Stephen J
    Farrall, Martin
    Goel, Anuj
    Medina-Gomez, Carolina
    Rivadeneira, Fernando
    Estrada, Karol
    Uitterlinden, André G
    Hofman, Albert
    Zillikens, M Carola
    den Heijer, Martin
    Kiemeney, Lambertus A
    Maschio, Andrea
    Hall, Per
    Tyrer, Jonathan
    Teumer, Alexander
    Völzke, Henry
    Kovacs, Peter
    Tönjes, Anke
    Mangino, Massimo
    Spector, Tim D
    Hayward, Caroline
    Rudan, Igor
    Hall, Alistair S
    Samani, Nilesh J
    Attwood, Antony Paul
    Sambrook, Jennifer G
    Hung, Joseph
    Palmer, Lyle J
    Lokki, Marja-Liisa
    Sinisalo, Juha
    Boucher, Gabrielle
    Huikuri, Heikki
    Lorentzon, Mattias
    Ohlsson, Claes
    Eklund, Niina
    Eriksson, Johan G
    Barlassina, Cristina
    Rivolta, Carlo
    Nolte, Ilja M
    Snieder, Harold
    Van der Klauw, Melanie M
    Van Vliet-Ostaptchouk, Jana V
    Gejman, Pablo V
    Shi, Jianxin
    Jacobs, Kevin B
    Wang, Zhaoming
    Bakker, Stephan J L
    Mateo Leach, Irene
    Navis, Gerjan
    van der Harst, Pim
    Martin, Nicholas G
    Medland, Sarah E
    Montgomery, Grant W
    Yang, Jian
    Chasman, Daniel I
    Ridker, Paul M
    Rose, Lynda M
    Lehtimäki, Terho
    Raitakari, Olli
    Absher, Devin
    Iribarren, Carlos
    Basart, Hanneke
    Hovingh, Kees G
    Hyppönen, Elina
    Power, Chris
    Anderson, Denise
    Beilby, John P
    Hui, Jennie
    Jolley, Jennifer
    Sager, Hendrik
    Bornstein, Stefan R
    Schwarz, Peter E H
    Kristiansson, Kati
    Perola, Markus
    Lindström, Jaana
    Swift, Amy J
    Uusitupa, Matti
    Atalay, Mustafa
    Lakka, Timo A
    Rauramaa, Rainer
    Bolton, Jennifer L
    Fowkes, Gerry
    Fraser, Ross M
    Price, Jackie F
    Fischer, Krista
    Krjutå Kov, Kaarel
    Metspalu, Andres
    Mihailov, Evelin
    Langenberg, Claudia
    Luan, Jian'an
    Ong, Ken K
    Chines, Peter S
    Keinanen-Kiukaanniemi, Sirkka M
    Saaristo, Timo E
    Edkins, Sarah
    Franks, Paul W
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Medicin.
    Hallmans, Göran
    Umeå universitet, Medicinska fakulteten, Enheten för biobanksforskning. Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Näringsforskning.
    Shungin, Dmitry
    Umeå universitet, Medicinska fakulteten, Institutionen för odontologi. Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Medicin.
    Morris, Andrew David
    Palmer, Colin N A
    Erbel, Raimund
    Moebus, Susanne
    Nöthen, Markus M
    Pechlivanis, Sonali
    Hveem, Kristian
    Narisu, Narisu
    Hamsten, Anders
    Humphries, Steve E
    Strawbridge, Rona J
    Tremoli, Elena
    Grallert, Harald
    Thorand, Barbara
    Illig, Thomas
    Koenig, Wolfgang
    Müller-Nurasyid, Martina
    Peters, Annette
    Boehm, Bernhard O
    Kleber, Marcus E
    März, Winfried
    Winkelmann, Bernhard R
    Kuusisto, Johanna
    Laakso, Markku
    Arveiler, Dominique
    Cesana, Giancarlo
    Kuulasmaa, Kari
    Virtamo, Jarmo
    Yarnell, John W G
    Kuh, Diana
    Wong, Andrew
    Lind, Lars
    de Faire, Ulf
    Gigante, Bruna
    Magnusson, Patrik K E
    Pedersen, Nancy L
    Dedoussis, George
    Dimitriou, Maria
    Kolovou, Genovefa
    Kanoni, Stavroula
    Stirrups, Kathleen
    Bonnycastle, Lori L
    Njølstad, Inger
    Wilsgaard, Tom
    Ganna, Andrea
    Rehnberg, Emil
    Hingorani, Aroon
    Kivimaki, Mika
    Kumari, Meena
    Assimes, Themistocles L
    Barroso, Inês
    Boehnke, Michael
    Borecki, Ingrid B
    Deloukas, Panos
    Fox, Caroline S
    Frayling, Timothy
    Groop, Leif C
    Haritunians, Talin
    Hunter, David
    Ingelsson, Erik
    Kaplan, Robert
    Mohlke, Karen L
    O'Connell, Jeffrey R
    Schlessinger, David
    Strachan, David P
    Stefansson, Kari
    van Duijn, Cornelia M
    Abecasis, Gonçalo R
    McCarthy, Mark I
    Hirschhorn, Joel N
    Qi, Lu
    Loos, Ruth J F
    Lindgren, Cecilia M
    North, Kari E
    Heid, Iris M
    Sex-stratified genome-wide association studies including 270,000 individuals show sexual dimorphism in genetic loci for anthropometric traits2013Ingår i: PLoS Genetics, ISSN 1553-7390, E-ISSN 1553-7404, Vol. 9, nr 6, s. e1003500-Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Given the anthropometric differences between men and women and previous evidence of sex-difference in genetic effects, we conducted a genome-wide search for sexually dimorphic associations with height, weight, body mass index, waist circumference, hip circumference, and waist-to-hip-ratio (133,723 individuals) and took forward 348 SNPs into follow-up (additional 137,052 individuals) in a total of 94 studies. Seven loci displayed significant sex-difference (FDR<5%), including four previously established (near GRB14/COBLL1, LYPLAL1/SLC30A10, VEGFA, ADAMTS9) and three novel anthropometric trait loci (near MAP3K1, HSD17B4, PPARG), all of which were genome-wide significant in women (P<5×10(-8)), but not in men. Sex-differences were apparent only for waist phenotypes, not for height, weight, BMI, or hip circumference. Moreover, we found no evidence for genetic effects with opposite directions in men versus women. The PPARG locus is of specific interest due to its role in diabetes genetics and therapy. Our results demonstrate the value of sex-specific GWAS to unravel the sexually dimorphic genetic underpinning of complex traits.

  • 186. Rauh, Simone P
    et al.
    Heymans, Martijn W
    Koopman, Anitra D M
    Nijpels, Giel
    Stehouwer, Coen D
    Thorand, Barbara
    Rathmann, Wolfgang
    Meisinger, Christa
    Peters, Annette
    de Las Heras Gala, Tonia
    Glümer, Charlotte
    Pedersen, Oluf
    Cederberg, Henna
    Kuusisto, Johanna
    Laakso, Markku
    Pearson, Ewan R
    Franks, Paul W
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Medicin. Department of Clinical Sciences, Genetic and Molecular Epidemiology Unit, Lund University; Harvard Chan School of Public Health, Boston, Massachusetts, United States of America.
    Rutters, Femke
    Dekker, Jacqueline M
    Predicting glycated hemoglobin levels in the non-diabetic general population: development and validation of the DIRECT-DETECT prediction model - a DIRECT study2017Ingår i: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 12, nr 2, artikel-id e0171816Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    AIMS/HYPOTHESIS: To develop a prediction model that can predict HbA1c levels after six years in the non-diabetic general population, including previously used readily available predictors.

    METHODS: Data from 5,762 initially non-diabetic subjects from three population-based cohorts (Hoorn Study, Inter99, KORA S4/F4) were combined to predict HbA1c levels at six year follow-up. Using backward selection, age, BMI, waist circumference, use of anti-hypertensive medication, current smoking and parental history of diabetes remained in sex-specific linear regression models. To minimize overfitting of coefficients, we performed internal validation using bootstrapping techniques. Explained variance, discrimination and calibration were assessed using R2, classification tables (comparing highest/lowest 50% HbA1c levels) and calibration graphs. The model was externally validated in 2,765 non-diabetic subjects of the population-based cohort METSIM.

    RESULTS: At baseline, mean HbA1c level was 5.6% (38 mmol/mol). After a mean follow-up of six years, mean HbA1c level was 5.7% (39 mmol/mol). Calibration graphs showed that predicted HbA1c levels were somewhat underestimated in the Inter99 cohort and overestimated in the Hoorn and KORA cohorts, indicating that the model's intercept should be adjusted for each cohort to improve predictions. Sensitivity and specificity (95% CI) were 55.7% (53.9, 57.5) and 56.9% (55.1, 58.7) respectively, for women, and 54.6% (52.7, 56.5) and 54.3% (52.4, 56.2) for men. External validation showed similar performance in the METSIM cohort.

    CONCLUSIONS/INTERPRETATION: In the non-diabetic population, our DIRECT-DETECT prediction model, including readily available predictors, has a relatively low explained variance and moderate discriminative performance, but can help to distinguish between future highest and lowest HbA1c levels. Absolute HbA1c values are cohort-dependent.

  • 187.
    Renström, Frida
    et al.
    Umeå universitet, Medicinska fakulteten, Enheten för biobanksforskning. Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Näringsforskning. Genetic and Molecular Epidemiology Unit, Department of Clinical Sciences, Lund University; Department of Nutrition, Harvard T.H. Chan School of Public Health, Boston, MA, USA.
    Koivula, Robert W.
    Varga, Tibor V.
    Hallmans, Göran
    Umeå universitet, Medicinska fakulteten, Enheten för biobanksforskning. Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Näringsforskning.
    Mulder, Hindrik
    Florez, Jose C.
    Hu, Frank B.
    Franks, Paul W.
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Medicin. Genetic and Molecular Epidemiology Unit, Department of Clinical Sciences, Lund University; Department of Nutrition, Harvard T.H. Chan School of Public Health, Boston, MA, USA.
    Season-dependent associations of circadian rhythm-regulating loci (CRY1, CRY2 and MTNR1B) and glucose homeostasis: the GLACIER Study2015Ingår i: Diabetologia, ISSN 0012-186X, E-ISSN 1432-0428, Vol. 58, nr 5, s. 997-1005Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Aims/hypothesis The association of single nucleotide polymorphisms (SNPs) proximal to CRY2 and MTNR1B with fasting glucose is well established. CRY1/2 and MTNR1B encode proteins that regulate circadian rhythmicity and influence energy metabolism. Here we tested whether season modified the relationship of these loci with blood glucose concentration. Methods SNPs rs8192440 (CRY1), rs11605924 (CRY2) and rs10830963 (MTNR1B) were genotyped in a prospective cohort study from northern Sweden (n = 16,499). The number of hours of daylight exposure during the year ranged from 4.5 to 22 h daily. Owing to the non-linear distribution of daylight throughout the year, season was dichotomised based on the vernal and autumnal equinoxes. Effect modification was assessed using linear regression models fitted with a SNP x season interaction term, marginal effect terms and putative confounding variables, with fasting or 2 h glucose concentrations as outcomes. Results The rs8192440 (CRY1) variant was only associated with fasting glucose among participants (n = 2,318) examined during the light season (beta = -0.04 mmol/l per A allele, 95% CI -0.08, -0.01, p = 0.02, p (interaction) = 0.01). In addition to the established association with fasting glucose, the rs11605924 (CRY2) and rs10830963 (MTNR1B) loci were associated with 2 h glucose concentrations (beta = 0.07 mmol/l per A allele, 95% CI 0.03, 0.12, p = 0.0008, n = 9,605, and beta = -0.11 mmol/l per G allele, 95% CI -0.15, -0.06, p < 0.0001, n = 9,517, respectively), but only in participants examined during the dark season (p (interaction) = 0.006 and 0.04, respectively). Repeated measures analyses including data collected 10 years after baseline (n = 3,500) confirmed the results for the CRY1 locus (p (interaction) = 0.01). Conclusions/interpretation In summary, these observations suggest a biologically plausible season-dependent association between SNPs at CRY1, CRY2 and MTNR1B and glucose homeostasis.

  • 188.
    Renström, Frida
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Medicin.
    Payne, Felicity
    Metabolic Disease Group, The Wellcome Trust Sanger Institute, Cambridge CB10 1SA, UK.
    Nordström, Anna
    Umeå universitet, Medicinska fakulteten, Institutionen för kirurgisk och perioperativ vetenskap, Idrottsmedicin.
    Brito, Ema C
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Medicin.
    Rolandsson, Olov
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Allmänmedicin.
    Hallmans, Göran
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Näringsforskning.
    Barroso, Ines
    Metabolic Disease Group, The Wellcome Trust Sanger Institute, Cambridge CB10 1SA, UK.
    Nordström, Peter
    Umeå universitet, Medicinska fakulteten, Institutionen för samhällsmedicin och rehabilitering, Geriatrik.
    Franks, Paul W
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Medicin.
    Replication and extension of genome-wide association study results for obesity in 4,923 adults from Northern Sweden.2009Ingår i: Human Molecular Genetics, ISSN 0964-6906, E-ISSN 1460-2083, Vol. 18, nr 8, s. 1489-1496Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Recent genome-wide association studies (GWAS) have identified multiple risk loci for common obesity (FTO, MC4R, TMEM18, GNPDA2, SH2B1, KCTD15, MTCH2, NEGR1, and PCSK1). Here we extend those studies by examining associations with adiposity and type 2 diabetes in Swedish adults. The nine single nucleotide polymorphisms (SNPs) were genotyped in 3,885 non-diabetic and 1,038 diabetic individuals with available measures of height, weight and BMI. Adipose mass and distribution was objectively assessed using dual energy X-ray absorptiometry (DEXA) in a sub-group of non-diabetics (n=2,206). In models with adipose mass traits, BMI or obesity as outcomes, the most strongly associated SNP was FTO rs1121980 (P<0.001). Five other SNPs (SH2B1 rs7498665, MTCH2 rs4752856, MC4R rs17782313, NEGR1 rs2815752, and GNPDA2 rs10938397) were significantly associated with obesity. To summarize the overall genetic burden, a weighted risk score comprising a subset of SNPs was constructed; those in the top quintile of the score were heavier (+2.6kg) and had more total (+2.4kg), gynoid (+191g), and abdominal (+136g) adipose tissue than those in the lowest quintile (all P<0.001). The genetic burden score significantly increased diabetes risk, with those in the highest quintile (n=193/594 cases/controls) being at 1.55-fold (95% CI: 1.21-1.99; P<0.0001) greater risk of type 2 diabetes than those in the lowest quintile (n=130/655 cases/controls). In summary, we have statistically replicated six of the previously associated obese-risk loci and our results suggest that the weight-inducing effects of these variants are explained largely by increased adipose accumulation.

  • 189.
    Renström, Frida
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Medicin.
    Shungin, Dmitry
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Medicin. Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Näringsforskning.
    Johansson, Ingegerd
    Umeå universitet, Medicinska fakulteten, Institutionen för odontologi, Kariologi.
    Florez, Jose C
    Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts.
    Hallmans, Göran
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Näringsforskning.
    Hu, Frank B
    Department of Nutrition, Harvard School of Public Health, Boston, Massachusetts.
    Franks, Paul W
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Medicin.
    Genetic predisposition to long-term nondiabetic deteriorations in glucose homeostasis: Ten-year follow-up of the GLACIER study.2011Ingår i: Diabetes, ISSN 0012-1797, E-ISSN 1939-327X, Vol. 60, nr 1, s. 345-54Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Our findings imply that genetic profiling might facilitate the early detection of persons who are genetically susceptible to deteriorating glucose control; studies of incident type 2 diabetes and discrete cardiovascular end points will help establish whether the magnitude of these changes is clinically relevant.

  • 190. Rockette-Wagner, Bonny
    et al.
    Edelstein, Sharon
    Venditti, Elizabeth M.
    Reddy, Deepti
    Bray, George A.
    Carrion-Petersen, Mary Lou
    Dabelea, Dana
    Delahanty, Linda M.
    Florez, Hermes
    Franks, Paul W.
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Medicin. Lund Univ, Genet & Mol Epidemiol Unit, Dept Clin Sci, Malmo, Sweden; Harvard Univ, Dept Nutr, Boston, MA 02115 USA.
    Montez, Maria G.
    Rubin, Richard
    Kriska, Andrea M.
    The impact of lifestyle intervention on sedentary time in individuals at high risk of diabetes2015Ingår i: Diabetologia, ISSN 0012-186X, E-ISSN 1432-0428, Vol. 58, nr 6, s. 1198-1202Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Aims/hypothesis The Diabetes Prevention Program (DPP) lifestyle intervention successfully achieved its goal of increasing leisure physical activity levels. This current study examines whether the lifestyle intervention also changed time spent being sedentary and the impact of sedentary time on diabetes development in this cohort.

    Methods 3,232 DPP participants provided baseline data. Sedentary behaviour was assessed via an interviewer-administered questionnaire and reported as time spent watching television specifically (or combined with sitting at work). Mean change in sedentary time was examined using repeated measures ANCOVA. The relationship between sedentary time and diabetes incidence was determined using Cox proportional hazards models.

    Results During the DPP follow-up (mean: 3.2 years), sedentary time declined more in the lifestyle than the metformin or placebo participants (p < 0.05). For the lifestyle group, the decrease in reported mean television watching time (22 [95% CI 26, 17] min/day) was greater than in the metformin or placebo groups (p < 0.001). Combining all participants together, there was a significantly increased risk of developing diabetes with increased television watching (3.4% per hour spent watching television), after controlling for age, sex, treatment arm and leisure physical activity (p < 0.01), which was attenuated when time-dependent weight was added to the model.

    Conclusions/interpretation In the DPP, the lifestyle intervention was effective at reducing sedentary time, which was not a primary goal. In addition, in all treatment arms, individuals with lower levels of sedentary time had a lower risk of developing diabetes. Future lifestyle intervention programmes should emphasise reducing television watching and other sedentary behaviours in addition to increasing physical activity.

  • 191. Rockette-Wagner, Bonny
    et al.
    Storti, Kristi L.
    Dabelea, Dana
    Edelstein, Sharon
    Florez, Hermes
    Franks, Paul W.
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Medicin. Department of Clinical Science, Genetic and Molecular Epidemiology Unit, Lund University, Malmö, Sweden; Department of Nutrition, Harvard T.H. Chan School of Public Health, Boston, Massachusetts, United States of America.
    Montez, Maria G.
    Pomeroy, Jeremy
    Kriska, Andrea M.
    Activity and Sedentary Time 10 Years After a Successful Lifestyle Intervention: The Diabetes Prevention Program2017Ingår i: American Journal of Preventive Medicine, ISSN 0749-3797, E-ISSN 1873-2607, Vol. 52, nr 3, s. 292-299Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Introduction: This study aims to determine if evidence exists for a lasting effect of the Diabetes Prevention Program (DPP) lifestyle intervention on activity levels by comparing objectively collected activity data between the DPP Outcome Study (DPPOS) cohort and adults from the National Health and Nutrition Examination Survey (NHANES; 2003-2006). Methods: Average minutes/day of light and moderate to vigorous physical activity (MVPA) and sedentary behavior from ActiGraph accelerometers (collected 2010-2012) were examined (2013-2014) for comparable DPPOS and NHANES subgroups by age, sex, and diabetes status. Longitudinal questionnaire data on leisure activity, collected yearly from DPP baseline to the time of accelerometer measurement (1996-2010; 11.9-year mean follow-up), were also examined to provide support for a long-term intervention effect. Results: Average minutes/day of accelerometer-derived MVPA was higher in all DPPOS subgroups versus NHANES subgroups of similar age/sex/diabetes status; with values as much as twice as high in some DPPOS subgroups. Longitudinal questionnaire data from DPP/DPPOS showed a maintained increase of 1.24 MET hours/week (p=0.026) of leisure activity in DPPOS participants from all original study arms between DPP baseline and accelerometer recording. There were no consistent differences between comparable DPPOS and NHANES subgroups for accelerometer derived sedentary or light-intensity activity minutes/day. Conclusions: More than 10 years after the start of DPP, DPPOS participants performed more accelerometer-measured MVPA than similar adults from NHANES. Longitudinal questionnaire data support the accelerometer-based findings by suggesting that leisure activity levels at the time of accelerometer recording remained higher than DPP baseline levels. 

  • 192. Rukh, G
    et al.
    Ahmad, S
    Ericson, U
    Hindy, G
    Stocks, Tanja
    Umeå universitet, Medicinska fakulteten, Institutionen för kirurgisk och perioperativ vetenskap, Urologi och andrologi.
    Renström, F
    Umeå universitet, Medicinska fakulteten, Enheten för biobanksforskning.
    Almgren, P
    Nilsson, P M
    Melander, O
    Franks, Paul W
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Medicin.
    Orho-Melander, M
    Inverse relationship between a genetic risk score of 31 BMI loci and weight change before and after reaching middle age2016Ingår i: International Journal of Obesity, ISSN 0307-0565, E-ISSN 1476-5497, Vol. 40, nr 2, s. 252-259Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    BACKGROUND/OBJECTIVE: Genome-wide-association studies have identified numerous body mass index (BMI)-associated variants, but it is unclear how these relate to weight gain in adults at different ages.

    METHODS: We examined the association of a genetic risk score (GRS), consisting of 31 BMI-associated variants, with an annual weight change (AWC) and a substantial weight gain (SWG) of 10% by comparing self-reported weight at 20 years (y) with baseline weight (mean: 58 y; s.d.: 8 y) in 21407 participants from the Malmö Diet and Cancer Study (MDCS), and comparing baseline weight to weight at follow-up (mean: 73 y; s.d.: 6 y) among 2673 participants. Association between GRS and AWG and SWG was replicated in 4327 GLACIER (Gene x Lifestyle interactions And Complex traits Involved in Elevated disease Risk) participants (mean: 45 y; s.d.: 7 y) with 10 y follow-up. Cohort-specific results were pooled by fixed-effect meta-analyses.

    RESULTS: In MDCS, the GRS was associated with increased AWC (β: 0.003; s.e: 0.01; P: 7 × 10(-8)) and increased odds for SWG (odds ratio (OR) 1.01 (95% confidence interval (CI): 1.00, 1.02); P: 0.013) per risk-allele from age 20y, but unexpectedly with decreased AWC (β: -0.006; s.e: 0.002; P: 0.009) and decreased odds for SWG OR 0.96 (95% CI: 0.93, 0.98); P: 0.001) between baseline and follow-up. Effect estimates from age 20 y to baseline differed significantly from those from baseline to follow-up (P: 0.0002 for AWC and P: 0.0001 for SWG). Similar to MDCS, the GRS was associated with decreased odds for SWG OR 0.98 (95% CI: 0.96, 1.00); P: 0.029) from baseline to follow-up in GLACIER. In meta-analyses (n=7000), the GRS was associated with decreased AWC (β: -0.005; s.e.m. 0.002; P: 0.002) and decreased odds for SWG OR 0.97 (95% CI: 0.96, 0.99); P: 0.001) per risk-allele.

    CONCLUSIONS: Our results provide convincing evidence for a paradoxical inversed relationship between a high number of BMI-associated risk-alleles and less weight gain during and after middle-age, in contrast to the expected increased weight gain seen in younger age.

  • 193. Sacerdote, Carlotta
    et al.
    Ricceri, Fulvio
    Rolandsson, Olov
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Allmänmedicin.
    Baldi, Ileana
    Chirlaque, Maria-Dolores
    Feskens, Edith
    Bendinelli, Benedetta
    Ardanaz, Eva
    Arriola, Larraitz
    Balkau, Beverley
    Bergmann, Manuela
    Beulens, Joline W. J.
    Boeing, Heiner
    Clavel-Chapelon, Francoise
    Crowe, Francesca
    de Lauzon-Guillain, Blandine
    Forouhi, Nita
    Franks, Paul W.
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Medicin.
    Gallo, Valentina
    Gonzalez, Carlos
    Halkjaer, Jytte
    Illner, Anne-Kathrin
    Kaaks, Rudolf
    Key, Timothy
    Khaw, Kay-Tee
    Navarro, Carmen
    Nilsson, Peter M.
    Dalton, Susanne Oksbjerg
    Overvad, Kim
    Pala, Valeria
    Palli, Domenico
    Panico, Salvatore
    Polidoro, Silvia
    Ramon Quiros, J.
    Romieu, Isabelle
    Sanchez, Maria-Jose
    Slimani, Nadia
    Sluijs, Ivonne
    Spijkerman, Annemieke
    Teucher, Birgit
    Tjonneland, Anne
    Tumino, Rosario
    van der A, Daphne
    Vergnaud, Anne-Claire
    Wennberg, Patrik
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Allmänmedicin.
    Sharp, Stephen
    Langenberg, Claudia
    Riboli, Elio
    Vineis, Paolo
    Wareham, Nicholas
    Lower educational level is a predictor of incident type 2 diabetes in European countries: The EPIC-InterAct study2012Ingår i: International Journal of Epidemiology, ISSN 0300-5771, E-ISSN 1464-3685, Vol. 41, nr 4, s. 1162-1173Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Background Type 2 diabetes mellitus ( T2DM) is one of the most common chronic diseases worldwide. In high- income countries, low socioeconomic status seems to be related to a high incidence of T2DM, but very little is known about the intermediate factors of this relationship.

    Method We performed a case-cohort study in eight Western European countries nested in the EPIC study (n = 340 234, 3.99 million person-years of follow-up). A random sub-cohort of 16 835 individuals and a total of 12 403 incident cases of T2DM were identified. Crude and multivariate-adjusted hazard ratios (HR) were estimated for each country and pooled across countries using meta-analytical methods. Age-, gender- and country-specific relative indices of inequality (RII) were used as the measure of educational level and RII tertiles were analysed.

    Results Compared with participants with a high educational level (RII tertile 1), participants with a low educational level (RII tertile 3) had a higher risk of T2DM [HR: 1.77, 95% confidence interval (CI): 1.69-1.85; P-trend < 0.01]. The HRs adjusted for physical activity, smoking status and propensity score according to macronutrient intake were very similar to the crude HR (adjusted HR: 1.67, 95% CI: 1.52-1.83 in men; HR: 1.88, 95% CI: 1.73-2.05 in women). The HRs were attenuated only when they were further adjusted for BMI (BMI-adjusted HR: 1.36, 95% CI: 1.23-1.51 in men; HR: 1.32, 95% CI: 1.20-1.45 in women).

    Conclusion This study demonstrates the inequalities in the risk of T2DM in Western European countries, with an inverse relationship between educational level and risk of T2DM that is only partially explained by variations in BMI.

  • 194. Sarwar, Nadeem
    et al.
    Butterworth, Adam S.
    Freitag, Daniel F.
    Gregson, John
    Willeit, Peter
    Gorman, Donal N.
    Gao, Pei
    Saleheen, Danish
    Rendon, Augusto
    Nelson, Christopher P.
    Braund, Peter S.
    Hall, Alistair S.
    Chasman, Daniel I.
    Tybjaerg-Hansen, Anne
    Chambers, John C.
    Benjamin, Emelia J.
    Franks, Paul W.
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Medicin.
    Clarke, Robert
    Wilde, Arthur A. M.
    Trip, Mieke D.
    Steri, Maristella
    Witteman, Jacqueline C. M.
    Qi, Lu
    van der Schoot, C. Ellen
    de Faire, Ulf
    Erdmann, Jeanette
    Stringham, Heather M.
    Koenig, Wolfgang
    Rader, Daniel J.
    Melzer, David
    Reich, David
    Psaty, Bruce M.
    Kleber, Marcus E.
    Panagiotakos, Demosthenes B.
    Willeit, Johann
    Wennberg, Patrik
    Woodward, Mark
    Adamovic, Svetlana
    Rimm, Eric B.
    Meade, Tom W.
    Gillum, Richard F.
    Shaffer, Jonathan A.
    Hofman, Albert
    Onat, Altan
    Sundstrom, Johan
    Wassertheil-Smoller, Sylvia
    Mellstrom, Dan
    Gallacher, John
    Cushman, Mary
    Tracy, Russell P.
    Kauhanen, Jussi
    Karlsson, Magnus
    Salonen, Jukka T.
    Wilhelmsen, Lars
    Amouyel, Philippe
    Cantin, Bernard
    Best, Lyle G.
    Ben-Shlomo, Yoav
    Manson, JoAnn E.
    Davey-Smith, George
    de Bakker, Paul I. W.
    O'Donnell, Christopher J.
    Wilson, James F.
    Wilson, Anthony G.
    Assimes, Themistocles L.
    Jansson, John-Olov
    Ohlsson, Claes
    Tivesten, Asa
    Ljunggren, Osten
    Reilly, Muredach P.
    Hamsten, Anders
    Ingelsson, Erik
    Cambien, Francois
    Hung, Joseph
    Thomas, G. Neil
    Boehnke, Michael
    Schunkert, Heribert
    Asselbergs, Folkert W.
    Kastelein, John J. P.
    Gudnason, Vilmundur
    Salomaa, Veikko
    Harris, Tamara B.
    Kooner, Jaspal S.
    Allin, Kristine H.
    Nordestgaard, Borge G.
    Hopewell, Jemma C.
    Goodall, Alison H.
    Ridker, Paul M.
    Holm, Hilma
    Watkins, Hugh
    Ouwehand, Willem H.
    Samani, Nilesh J.
    Kaptoge, Stephen
    Di Angelantonio, Emanuele
    Harari, Olivier
    Danesh, John
    Interleukin-6 receptor pathways in coronary heart disease: a collaborative meta-analysis of 82 studies2012Ingår i: The Lancet, ISSN 0140-6736, E-ISSN 1474-547X, Vol. 379, nr 9822, s. 1205-1213Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Background Persistent inflammation has been proposed to contribute to various stages in the pathogenesis of cardiovascular disease. Interleukin-6 receptor (IL6R) signalling propagates downstream inflammation cascades. To assess whether this pathway is causally relevant to coronary heart disease, we studied a functional genetic variant known to affect IL6R signalling. Methods In a collaborative meta-analysis, we studied Asp358Ala (rs2228145) in IL6R in relation to a panel of conventional risk factors and inflammation biomarkers in 125 222 participants. We also compared the frequency of Asp358Ala in 51 441 patients with coronary heart disease and in 136 226 controls. To gain insight into possible mechanisms, we assessed Asp358Ala in relation to localised gene expression and to postlipopolysaccharide stimulation of interleukin 6. Findings The minor allele frequency of Asp358Ala was 39%. Asp358Ala was not associated with lipid concentrations, blood pressure, adiposity, dysglycaemia, or smoking (p value for association per minor allele >= 0.04 for each). By contrast, for every copy of 358Ala inherited, mean concentration of IL6R increased by 34.3% (95% CI 30.4-38.2) and of interleukin 6 by 14.6% (10.7-18.4), and mean concentration of C-reactive protein was reduced by 7.5% (5.9-9.1) and of fibrinogen by 1.0% (0.7-1.3). For every copy of 358Ala inherited, risk of coronary heart disease was reduced by 3.4% (1.8-5.0). Asp358Ala was not related to IL6R mRNA levels or interleukin-6 production in monocytes. Interpretation Large-scale human genetic and biomarker data are consistent with a causal association between IL6R-related pathways and coronary heart disease.

  • 195. Scott, Robert A.
    et al.
    Fall, Tove
    Pasko, Dorota
    Barker, Adam
    Sharp, Stephen J.
    Arriola, Larraitz
    Balkau, Beverley
    Barricarte, Aurelio
    Barroso, Ines
    Boeing, Heiner
    Clavel-Chapelon, Francoise
    Crowe, Francesca L.
    Dekker, Jacqueline M.
    Fagherazzi, Guy
    Ferrannini, Ele
    Forouhi, Nita G.
    Franks, Paul
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Medicin.
    Gavrila, Diana
    Giedraitis, Vilmantas
    Grioni, Sara
    Groop, Leif C.
    Kaaks, Rudolf
    Key, Timothy J.
    Kuehn, Tilman
    Lotta, Luca A.
    Nilsson, Peter M.
    Overvad, Kim
    Palli, Domenico
    Panico, Salvatore
    Quiros, J. Ramon
    Rolandsson, Olov
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Allmänmedicin.
    Roswall, Nina
    Sacerdote, Carlotta
    Sala, Nuria
    Sanchez, Maria-Jose
    Schulze, Matthias B.
    Siddiq, Afshan
    Slimani, Nadia
    Sluijs, Ivonne
    Spijkerman, Annemieke M. W.
    Tjonneland, Anne
    Tumino, Rosario
    van der A, Daphne L.
    Yaghootkar, Hanieh
    McCarthy, Mark I.
    Semple, Robert K.
    Riboli, Elio
    Walker, Mark
    Ingelsson, Erik
    Frayling, Tim M.
    Savage, David B.
    Langenberg, Claudia
    Wareham, Nicholas J.
    Common Genetic Variants Highlight the Role of Insulin Resistance and Body Fat Distribution in Type 2 Diabetes, Independent of Obesity2014Ingår i: Diabetes, ISSN 0012-1797, E-ISSN 1939-327X, Vol. 63, nr 12, s. 4378-4387Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    We aimed to validate genetic variants as instruments for insulin resistance and secretion, to characterize their association with intermediate phenotypes, and to investigate their role in type 2 diabetes (T2D) risk among normal-weight, overweight, and obese individuals. We investigated the association of genetic scores with euglycemic-hyperinsulinemic clamp- and oral glucose tolerance test-based measures of insulin resistance and secretion and a range of metabolic measures in up to 18,565 individuals. We also studied their association with T2D risk among normal-weight, overweight, and obese individuals in up to 8,124 incident T2D cases. The insulin resistance score was associated with lower insulin sensitivity measured by M/I value (beta in SDs per allele [95% CI], -0.03 [-0.04, -0.01]; P = 0.004). This score was associated with lower BMI (-0.01 [-0.01, -0.0]; P = 0.02) and gluteofemoral fat mass (-0.03 [-0.05,-0.02; P = 1.4x10(-6) and with higher alanine transaminase (0.02 [0.01, 0.03]; P = 0.002) and gamma-glutamyl transferase (0.02 [0.01, 0.03]; P = 0.001). While the secretion score had a stronger association with T2D in leaner individuals (P-interaction = 0.001), we saw no difference in the association of the insulin resistance score with T2D among BMI or waist strata (P-interaction > 0.31). While insulin resistance is often considered secondary to obesity, the association of the insulin resistance score with lower BMI and adiposity and with incident T2D even among individuals of normal weight highlights the role of insulin resistance and ectopic fat distribution in T2D, independently of body size.

  • 196. Scott, Robert A.
    et al.
    Freitag, Daniel F.
    Li, Li
    Chu, Audrey Y.
    Surendran, Praveen
    Young, Robin
    Grarup, Niels
    Stancakova, Alena
    Chen, Yuning
    Varga, Tibor V.
    Yaghootkar, Hanieh
    Luan, Jian'an
    Zhao, Jing Hua
    Willems, Sara M.
    Wessel, Jennifer
    Wang, Shuai
    Maruthur, Nisa
    Michailidou, Kyriaki
    Pirie, Ailith
    van der Lee, Sven J.
    Gillson, Christopher
    Al Olama, Ali Amin
    Amouyel, Philippe
    Arriola, Larraitz
    Arveiler, Dominique
    Aviles-Olmos, Iciar
    Balkau, Beverley
    Barricarte, Aurelio
    Barroso, Ines
    Garcia, Sara Benlloch
    Bis, Joshua C.
    Blankenberg, Stefan
    Boehnke, Michael
    Boeing, Heiner
    Boerwinkle, Eric
    Borecki, Ingrid B.
    Bork-Jensen, Jette
    Bowden, Sarah
    Caldas, Carlos
    Caslake, Muriel
    Cupples, L. Adrienne
    Cruchaga, Carlos
    Czajkowski, Jacek
    den Hoed, Marcel
    Dunn, Janet A.
    Earl, Helena M.
    Ehret, Georg B.
    Ferrannini, Ele
    Ferrieres, Jean
    Foltynie, Thomas
    Ford, Ian
    Forouhi, Nita G.
    Gianfagna, Francesco
    Gonzalez, Carlos
    Grioni, Sara
    Hiller, Louise
    Jansson, Jan-Håkan
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Medicin. Research Unit, 931 41 Skellefteå, Sweden.
    Jorgensen, Marit E.
    Jukema, J. Wouter
    Kaaks, Rudolf
    Kee, Frank
    Kerrison, Nicola D.
    Key, Timothy J.
    Kontto, Jukka
    Kote-Jarai, Zsofia
    Kraja, Aldi T.
    Kuulasmaa, Kari
    Kuusisto, Johanna
    Linneberg, Allan
    Liu, Chunyu
    Marenne, Galle
    Mohlke, Karen L.
    Morris, Andrew P.
    Muir, Kenneth
    Mueller-Nurasyid, Martina
    Munroe, Patricia B.
    Navarro, Carmen
    Nielsen, Sune F.
    Nilsson, Peter M.
    Nordestgaard, Borge G.
    Packard, Chris J.
    Palli, Domenico
    Panico, Salvatore
    Peloso, Gina M.
    Perola, Markus
    Peters, Annette
    Poole, Christopher J.
    Quiros, J. Ramn
    Rolandsson, Olov
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Allmänmedicin.
    Sacerdote, Carlotta
    Salomaa, Veikko
    Sanchez, Mara-Jose
    Sattar, Naveed
    Sharp, Stephen J.
    Sims, Rebecca
    Slimani, Nadia
    Smith, Jennifer A.
    Thompson, Deborah J.
    Trompet, Stella
    Tumino, Rosario
    van der A, Daphne L.
    van der Schouw, Yvonne T.
    Virtamo, Jarmo
    Walker, Mark
    Walter, Klaudia
    Abraham, Jean E.
    Amundadottir, Laufey T.
    Aponte, Jennifer L.
    Butterworth, Adams.
    Dupuis, Josee
    Easton, Douglas F.
    Eeles, Rosalind A.
    Erdmann, Jeanette
    Franks, Paul W.
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Medicin. Department of Clinical Sciences, Genetic and Molecular Epidemiology Unit, Lund University, SE-205 Malmö, Sweden; Department of Nutrition, Harvard T. H. Chan School of Public Health, Boston, MA 02115, USA.
    Frayling, Timothy M.
    Hansen, Torben
    Howson, Joanna M. M.
    Jorgensen, Torben
    Kooner, Jaspal
    Laakso, Markku
    Langenberg, Claudia
    McCarthy, Mark I.
    Pankow, James S.
    Pedersen, Oluf
    Riboli, Elio
    Rotter, Jerome I.
    Saleheen, Danish
    Samani, Nilesh J.
    Schunkert, Heribert
    Vollenweider, Peter
    O'Rahilly, Stephen
    Deloukas, Panos
    Danesh, John
    Goodarzi, Mark O.
    Kathiresan, Sekar
    Meigs, James B.
    Ehm, Margaret G.
    Wareham, Nicholas J.
    Waterworth, Dawn M.
    A genomic approach to therapeutic target validation identifies a glucose-lowering GLP1R variant protective for coronary heart disease2016Ingår i: Science Translational Medicine, ISSN 1946-6234, E-ISSN 1946-6242, Vol. 8, nr 341, artikel-id 341ra76Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Regulatory authorities have indicated that new drugs to treat type 2 diabetes (T2D) should not be associated with an unacceptable increase in cardiovascular risk. Human genetics may be able to guide development of antidiabetic therapies by predicting cardiovascular and other health endpoints. We therefore investigated the association of variants in six genes that encode drug targets for obesity or T2D with a range of metabolic traits in up to 11,806 individuals by targeted exome sequencing and follow-up in 39,979 individuals by targeted genotyping, with additional in silico follow-up in consortia. We used these data to first compare associations of variants in genes encoding drug targets with the effects of pharmacological manipulation of those targets in clinical trials. We then tested the association of those variants with disease outcomes, including coronary heart disease, to predict cardiovascular safety of these agents. A low-frequency missense variant (Ala316Thr; rs10305492) in the gene encoding glucagon-like peptide-1 receptor (GLP1R), the target of GLP1R agonists, was associated with lower fasting glucose and T2D risk, consistent with GLP1R agonist therapies. The minor allele was also associated with protection against heart disease, thus providing evidence that GLP1R agonists are not likely to be associated with an unacceptable increase in cardiovascular risk. Our results provide an encouraging signal that these agents may be associated with benefit, a question currently being addressed in randomized controlled trials. Genetic variants associated with metabolic traits and multiple disease outcomes can be used to validate therapeutic targets at an early stage in the drug development process.

  • 197. Scott, Robert A.
    et al.
    Lagou, Vasiliki
    Welch, Ryan P.
    Wheeler, Eleanor
    Montasser, May E.
    Luan, Jian'an
    Maegi, Reedik
    Strawbridge, Rona J.
    Rehnberg, Emil
    Gustafsson, Stefan
    Kanoni, Stavroula
    Rasmussen-Torvik, Laura J.
    Yengo, Loic
    Lecoeur, Cecile
    Shungin, Dmitry
    Umeå universitet, Medicinska fakulteten, Institutionen för odontologi. Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Medicin.
    Sanna, Serena
    Sidore, Carlo
    Johnson, Paul C. D.
    Jukema, J. Wouter
    Johnson, Toby
    Mahajan, Anubha
    Verweij, Niek
    Thorleifsson, Gudmar
    Hottenga, Jouke-Jan
    Shah, Sonia
    Smith, Albert V.
    Sennblad, Bengt
    Gieger, Christian
    Salo, Perttu
    Perola, Markus
    Timpson, Nicholas J.
    Evans, David M.
    St Pourcain, Beate
    Wu, Ying
    Andrews, Jeanette S.
    Hui, Jennie
    Bielak, Lawrence F.
    Zhao, Wei
    Horikoshi, Momoko
    Navarro, Pau
    Isaacs, Aaron
    O'Connell, Jeffrey R.
    Stirrups, Kathleen
    Vitart, Veronique
    Hayward, Caroline
    Esko, Tonu
    Mihailov, Evelin
    Fraser, Ross M.
    Fall, Tove
    Voight, Benjamin F.
    Raychaudhuri, Soumya
    Chen, Han
    Lindgren, Cecilia M.
    Morris, Andrew P.
    Rayner, Nigel W.
    Robertson, Neil
    Rybin, Denis
    Liu, Ching-Ti
    Beckmann, Jacques S.
    Willems, Sara M.
    Chines, Peter S.
    Jackson, Anne U.
    Kang, Hyun Min
    Stringham, Heather M.
    Song, Kijoung
    Tanaka, Toshiko
    Peden, John F.
    Goel, Anuj
    Hicks, Andrew A.
    An, Ping
    Mueller-Nurasyid, Martina
    Franco-Cereceda, Anders
    Folkersen, Lasse
    Marullo, Letizia
    Jansen, Hanneke
    Oldehinkel, Albertine J.
    Bruinenberg, Marcel
    Pankow, James S.
    North, Kari E.
    Forouhi, Nita G.
    Loos, Ruth J. F.
    Edkins, Sarah
    Varga, Tibor V.
    Hallmans, Göran
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Näringsforskning.
    Oksa, Heikki
    Antonella, Mulas
    Nagaraja, Ramaiah
    Trompet, Stella
    Ford, Ian
    Bakker, Stephan J. L.
    Kong, Augustine
    Kumari, Meena
    Gigante, Bruna
    Herder, Christian
    Munroe, Patricia B.
    Caulfield, Mark
    Antti, Jula
    Mangino, Massimo
    Small, Kerrin
    Miljkovic, Iva
    Liu, Yongmei
    Atalay, Mustafa
    Kiess, Wieland
    James, Alan L.
    Rivadeneira, Fernando
    Uitterlinden, Andre G.
    Palmer, Colin N. A.
    Doney, Alex S. F.
    Willemsen, Gonneke
    Smit, Johannes H.
    Campbell, Susan
    Polasek, Ozren
    Bonnycastle, Lori L.
    Hercberg, Serge
    Dimitriou, Maria
    Bolton, Jennifer L.
    Fowkes, Gerard R.
    Kovacs, Peter
    Lindstrom, Jaana
    Zemunik, Tatijana
    Bandinelli, Stefania
    Wild, Sarah H.
    Basart, Hanneke V.
    Rathmann, Wolfgang
    Grallert, Harald
    Maerz, Winfried
    Kleber, Marcus E.
    Boehm, Bernhard O.
    Peters, Annette
    Pramstaller, Peter P.
    Province, Michael A.
    Borecki, Ingrid B.
    Hastie, Nicholas D.
    Rudan, Igor
    Campbell, Harry
    Watkins, Hugh
    Farrall, Martin
    Stumvoll, Michael
    Ferrucci, Luigi
    Waterworth, Dawn M.
    Bergman, Richard N.
    Collins, Francis S.
    Tuomilehto, Jaakko
    Watanabe, Richard M.
    de Geus, Eco J. C.
    Penninx, Brenda W.
    Hofman, Albert
    Oostra, Ben A.
    Psaty, Bruce M.
    Vollenweider, Peter
    Wilson, James F.
    Wright, Alan F.
    Hovingh, G. Kees
    Metspalu, Andres
    Uusitupa, Matti
    Magnusson, Patrik K. E.
    Kyvik, Kirsten O.
    Kaprio, Jaakko
    Price, Jackie F.
    Dedoussis, George V.
    Deloukas, Panos
    Meneton, Pierre
    Lind, Lars
    Boehnke, Michael
    Shuldiner, Alan R.
    van Duijn, Cornelia M.
    Morris, Andrew D.
    Toenjes, Anke
    Peyser, Patricia A.
    Beilby, John P.
    Koerner, Antje
    Kuusisto, Johanna
    Laakso, Markku
    Bornstein, Stefan R.
    Schwarz, Peter E. H.
    Lakka, Timo A.
    Rauramaa, Rainer
    Adair, Linda S.
    Smith, George Davey
    Spector, Tim D.
    Illig, Thomas
    de Faire, Ulf
    Hamsten, Anders
    Gudnason, Vilmundur
    Kivimaki, Mika
    Hingorani, Aroon
    Keinanen-Kiukaanniemi, Sirkka M.
    Saaristo, Timo E.
    Boomsma, Dorret I.
    Stefansson, Kari
    van der Harst, Pim
    Dupuis, Josee
    Pedersen, Nancy L.
    Sattar, Naveed
    Harris, Tamara B.
    Cucca, Francesco
    Ripatti, Samuli
    Salomaa, Veikko
    Mohlke, Karen L.
    Balkau, Beverley
    Froguel, Philippe
    Pouta, Anneli
    Jarvelin, Marjo-Riitta
    Wareham, Nicholas J.
    Bouatia-Naji, Nabila
    McCarthy, Mark I.
    Franks, Paul W.
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Medicin.
    Meigs, James B.
    Teslovich, Tanya M.
    Florez, Jose C.
    Langenberg, Claudia
    Ingelsson, Erik
    Prokopenko, Inga
    Barroso, Ines
    Large-scale association analyses identify new loci influencing glycemic traits and provide insight into the underlying biological pathways2012Ingår i: Nature Genetics, ISSN 1061-4036, E-ISSN 1546-1718, Vol. 44, nr 9, s. 991-1005Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Through genome-wide association meta-analyses of up to 133,010 individuals of European ancestry without diabetes, including individuals newly genotyped using the Metabochip, we have increased the number of confirmed loci influencing glycemic traits to 53, of which 33 also increase type 2 diabetes risk (q < 0.05). Loci influencing fasting insulin concentration showed association with lipid levels and fat distribution, suggesting impact on insulin resistance. Gene-based analyses identified further biologically plausible loci, suggesting that additional loci beyond those reaching genome-wide significance are likely to represent real associations. This conclusion is supported by an excess of directionally consistent and nominally significant signals between discovery and follow-up studies. Functional analysis of these newly discovered loci will further improve our understanding of glycemic control.

  • 198. Scott, Robert A.
    et al.
    Scott, Laura J.
    Maegi, Reedik
    Marullo, Letizia
    Gaulton, Kyle J.
    Kaakinen, Marika
    Pervjakova, Natalia
    Pers, Tune H.
    Johnson, Andrew D.
    Eicher, John D.
    Jackson, Anne U.
    Ferreira, Teresa
    Lee, Yeji
    Ma, Clement
    Steinthorsdottir, Valgerdur
    Thorleifsson, Gudmar
    Qi, Lu
    Van Zuydam, Natalie R.
    Mahajan, Anubha
    Chen, Han
    Almgren, Peter
    Voight, Ben F.
    Grallert, Harald
    Mueller-Nurasyid, Martina
    Ried, Janina S.
    Rayner, Nigel W.
    Robertson, Neil
    Karssen, Lennart C.
    Van Leeuwen, Elisabeth M.
    Willems, Sara M.
    Fuchsberger, Christian
    Kwan, Phoenix
    Teslovich, Tanya M.
    Chanda, Pritam
    Li, Man
    Lu, Yingchang
    Dina, Christian
    Thuillier, Dorothee
    Yengo, Loic
    Jiang, Longda
    Sparso, Thomas
    Kestler, Hans A.
    Chheda, Himanshu
    Eisele, Lewin
    Gustafsson, Stefan
    Franberg, Mattias
    Strawbridge, Rona J.
    Benediktsson, Rafn
    Hreidarsson, Astradur B.
    Kong, Augustine
    Sigurdsson, Gunnar
    Kerrison, Nicola D.
    Luan, Jian'an
    Liang, Liming
    Meitinger, Thomas
    Roden, Michael
    Thorand, Barbara
    Esko, Tonu
    Mihailov, Evelin
    Fox, Caroline
    Liu, Ching-Ti
    Rybin, Denis
    Isomaa, Bo
    Lyssenko, Valeriya
    Tuomi, Tiinamaija
    Couper, David J.
    Pankow, James S.
    Grarup, Niels
    Have, Christian T.
    Jorgensen, Marit E.
    Jorgensen, Torben
    Linneberg, Allan
    Cornelis, Marilyn C.
    Van Dam, Rob M.
    Hunter, David J.
    Kraft, Peter
    Sun, Qi
    Edkins, Sarah
    Owen, Katharine R.
    Perry, John R. B.
    Wood, Andrew R.
    Zeggini, Eleftheria
    Tajes-Fernandes, Juan
    Abecasis, Goncalo R.
    Bonnycastle, Lori L.
    Chines, Peter S.
    Stringham, Heather M.
    Koistinen, Heikki A.
    Kinnunen, Leena
    Sennblad, Bengt
    Muehleisen, Thomas W.
    Noethen, Markus M.
    Pechlivanis, Sonali
    Baldassarre, Damiano
    Gertow, Karl
    Humphries, Steve E.
    Tremoli, Elena
    Klopp, Norman
    Meyer, Julia
    Steinbach, Gerald
    Wennauer, Roman
    Eriksson, Johan G.
    Mannisto, Satu
    Peltonen, Leena
    Tikkanen, Emmi
    Charpentier, Guillaume
    Eury, Elodie
    Lobbens, Stephane
    Gigante, Bruna
    Leander, Karin
    McLeod, Olga
    Bottinger, Erwin P.
    Gottesman, Omri
    Ruderfer, Douglas
    Blueher, Matthias
    Kovacs, Peter
    Tonjes, Anke
    Maruthur, Nisa M.
    Scapoli, Chiara
    Erbel, Raimund
    Joeckel, Karl-Heinz
    Moebus, Susanne
    De Faire, Ulf
    Hamsten, Anders
    Stumvoll, Michael
    Deloukas, Panagiotis
    Donnelly, Peter J.
    Frayling, Timothy M.
    Hattersley, Andrew T.
    Ripatti, Samuli
    Salomaa, Veikko
    Pedersen, Nancy L.
    Boehm, Bernhard O.
    Bergman, Richard N.
    Collins, Francis S.
    Mohlke, Karen L.
    Tuomilehto, Jaakko
    Hansen, Torben
    Pedersen, Oluf
    Barroso, Ines
    Lannfelt, Lars
    Ingelsson, Erik
    Lind, Lars
    Lindgren, Cecilia M.
    Cauchi, Stephane
    Froguel, Philippe
    Loos, Ruth J. F.
    Balkau, Beverley
    Boeing, Heiner
    Franks, Paul W.
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Medicin. Lund University, Malmö, Sweden .
    Gurrea, Aurelio Barricarte
    Palli, Domenico
    Van der Schouw, Yvonne T.
    Altshuler, David
    Groop, Leif C.
    Langenberg, Claudia
    Wareham, Nicholas J.
    Sijbrands, Eric
    Van Duijn, Cornelia M.
    Florez, Jose C.
    Meigs, James B.
    Boerwinkle, Eric
    Gieger, Christian
    Strauch, Konstantin
    Metspalu, Andres
    Morris, Andrew D.
    Palmer, Colin N. A.
    Hu, Frank B.
    Thorsteinsdottir, Unnur
    Stefansson, Kari
    Dupuis, Josee
    Morris, Andrew P.
    Boehnke, Michael
    McCarthy, Mark I.
    Prokopenko, Inga
    An Expanded Genome-Wide Association Study of Type 2 Diabetes in Europeans2017Ingår i: Diabetes, ISSN 0012-1797, E-ISSN 1939-327X, Vol. 66, nr 11, s. 2888-2902Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    To characterize type 2 diabetes (T2D)-associated variation across the allele frequency spectrum, we conducted a meta-analysis of genome-wide association data from 26,676 T2D case and 132,532 control subjects of European ancestry after imputation using the 1000 Genomes multiethnic reference panel. Promising association signals were followed up in additional data sets (of 14,545 or 7,397 T2D case and 38,994 or 71,604 control subjects). We identified 13 novel T2D-associated loci (P < 5 x 10(-8)), including variants near the GLP2R, GIP, and HLA-DQA1 genes. Our analysis brought the total number of independent T2D associations to 128 distinct signals at 113 loci. Despite substantially increased sample size and more complete coverage of low-frequency variation, all novel associations were driven by common single nucleotide variants. Credible sets of potentially causal variants were generally larger than those based on imputation with earlier reference panels, consistent with resolution of causal signals to common risk haplotypes. Stratification of T2D-associated loci based on T2D-related quantitative trait associations revealed tissue-specific enrichment of regulatory annotations in pancreatic islet enhancers for loci influencing insulin secretion and in adipocytes, monocytes, and hepatocytes for insulin action-associated loci. These findings highlight the predominant role played by common variants of modest effect and the diversity of biological mechanisms influencing T2D pathophysiology.

  • 199.
    Shungin, Dmitry
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för odontologi. Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Medicin. Genetic and Molecular Epidemiology Unit, Department of Clinical Sciences, Skåne University Hospital, Lund University.
    Cornelis, Marilyn C.
    Divaris, Kimon
    Holtfreter, Birte
    Shaffer, John R.
    Yu, Yau-Hua
    Barros, Silvana P.
    Beck, James D.
    Biffar, Reiner
    Boerwinkle, Eric A.
    Crout, Richard J.
    Ganna, Andrea
    Hallmans, Göran
    Umeå universitet, Medicinska fakulteten, Enheten för biobanksforskning. Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Näringsforskning.
    Hindy, George
    Hu, Frank B.
    Kraft, Peter
    McNeil, Daniel W.
    Melander, Olle
    Moss, Kevin L.
    North, Kari E.
    Orho-Melander, Marju
    Pedersen, Nancy L.
    Ridker, Paul M.
    Rimm, Eric B.
    Rose, Lynda M.
    Rukh, Gull
    Teumer, Alexander
    Weyant, Robert J.
    Chasman, Daniel I.
    Joshipura, Kaumudi
    Kocher, Thomas
    Magnusson, Patrik K. E.
    Marazita, Mary L.
    Nilsson, Peter
    Offenbacher, Steve
    Smith, George Davey
    Lundberg, Pernilla
    Umeå universitet, Medicinska fakulteten, Institutionen för odontologi.
    Palmer, Tom M.
    Timpson, Nicholas J.
    Johansson, Ingegerd
    Umeå universitet, Medicinska fakulteten, Institutionen för odontologi. Umeå universitet, Medicinska fakulteten, Enheten för biobanksforskning.
    Franks, Paul W.
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Medicin. Genetic and Molecular Epidemiology Unit, Department of Clinical Sciences, Skåne University Hospital, Lund University; Department of Nutrition, Harvard School of Public Health, Boston, MA, USA.
    Using genetics to test the causal relationship of total adiposity and periodontitis: Mendelian randomization analyses in the Gene-Lifestyle Interactions and Dental Endpoints (GLIDE) Consortium2015Ingår i: International Journal of Epidemiology, ISSN 0300-5771, E-ISSN 1464-3685, Vol. 44, nr 2, s. 638-650Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Background: The observational relationship between obesity and periodontitis is widely known, yet causal evidence is lacking. Our objective was to investigate causal associations between periodontitis and body mass index (BMI). Methods: We performed Mendelian randomization analyses with BMI-associated loci combined in a genetic risk score (GRS) as the instrument for BMI. All analyses were conducted within the Gene-Lifestyle Interactions and Dental Endpoints (GLIDE) Consortium in 13 studies from Europe and the USA, including 49 066 participants with clinically assessed (seven studies, 42.1% of participants) and self-reported (six studies, 57.9% of participants) periodontitis and genotype data (17 672/31 394 with/without periodontitis); 68 761 participants with BMI and genotype data; and 57 871 participants (18 881/38 990 with/without periodontitis) with data on BMI and periodontitis. Results: In the observational meta-analysis of all participants, the pooled crude observational odds ratio (OR) for periodontitis was 1.13 [95% confidence interval (CI): 1.03, 1.24] per standard deviation increase of BMI. Controlling for potential confounders attenuated this estimate (OR = 1.08; 95% CI: 1.03, 1.12). For clinically assessed periodontitis, corresponding ORs were 1.25 (95% CI: 1.10, 1.42) and 1.13 (95% CI: 1.10, 1.17), respectively. In the genetic association meta-analysis, the OR for periodontitis was 1.01 (95% CI: 0.99, 1.03) per GRS unit (per one effect allele) in all participants and 1.00 (95% CI: 0.97, 1.03) in participants with clinically assessed periodontitis. The instrumental variable meta-analysis of all participants yielded an OR of 1.05 (95% CI: 0.80, 1.38) per BMI standard deviation, and 0.90 (95% CI: 0.56, 1.46) in participants with clinical data. Conclusions: Our study does not support total adiposity as a causal risk factor for periodontitis, as the point estimate is very close to the null in the causal inference analysis, with wide confidence intervals.

  • 200.
    Shungin, Dmitry
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för odontologi. Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Medicin. Department of Clinical Sciences, Genetic & Molecular Epidemiology Unit, Lund University Diabetes Centre, Skåne University Hospital, Malmö, Sweden; Broad Institute of the Massachusetts Institute of Technology and Harvard University, Cambridge, MA, United States of America.
    Deng, Wei Q.
    Varga, Tibor V.
    Luan, Jian'an
    Mihailov, Evelin
    Metspalu, Andres
    Morris, Andrew P.
    Forouhi, Nita G.
    Lindgren, Cecilia
    Magnusson, Patrik K. E.
    Pedersen, Nancy L.
    Hallmans, Göran
    Umeå universitet, Medicinska fakulteten, Enheten för biobanksforskning.
    Chu, Audrey Y.
    Justice, Anne E.
    Graff, Mariaelisa
    Winkler, Thomas W.
    Rose, Lynda M.
    Langenberg, Claudia
    Cupples, L. Adrienne
    Ridker, Paul M.
    Wareham, Nicholas J.
    Ong, Ken K.
    Loos, Ruth J. F.
    Chasman, Daniel I.
    Ingelsson, Erik
    Kilpeläinen, Tuomas O.
    Scott, Robert A.
    Mägi, Reedik
    Paré, Guillaume
    Franks, Paul W.
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Medicin. Department of Clinical Sciences, Genetic & Molecular Epidemiology Unit, Lund University Diabetes Centre, Skåne University Hospital, Malmö, Sweden.
    Ranking and characterization of established BMI and lipid associated loci as candidates for gene-environment interactions2017Ingår i: PLoS Genetics, ISSN 1553-7390, E-ISSN 1553-7404, Vol. 13, nr 6, artikel-id e1006812Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Phenotypic variance heterogeneity across genotypes at a single nucleotide polymorphism (SNP) may reflect underlying gene-environment (GxE) or gene-gene interactions. We modeled variance heterogeneity for blood lipids and BMI in up to 44,211 participants and investigated relationships between variance effects (P-v), GxE interaction effects (with smoking and physical activity), and marginal genetic effects (P-m). Correlations between P-v and P-m were stronger for SNPs with established marginal effects (Spearman's rho = 0.401 for triglycerides, and rho = 0.236 for BMI) compared to all SNPs. When P-v and P-m were compared for all pruned SNPs, only BMI was statistically significant (Spearman's rho = 0.010). Overall, SNPs with established marginal effects were overrepresented in the nominally significant part of the P-v distribution (P-binomial < 0.05). SNPs from the top 1% of the P-m distribution for BMI had more significant P-v values (Pmann-Whitney = 1.46x10(-5)), and the odds ratio of SNPs with nominally significant (< 0.05) P-m and P-v was 1.33 (95% CI: 1.12, 1.57) for BMI. Moreover, BMI SNPs with nominally significant GxE interaction P-values (Pint < 0.05) were enriched with nominally significant P-v values (P-binomial = 8.63x10(-9) and 8.52x10(-7) for SNP x smoking and SNP x physical activity, respectively). We conclude that some loci with strong marginal effects may be good candidates for GxE, and variance-based prioritization can be used to identify them.

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