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  • 51. Kanoni, Stavroula
    et al.
    Masca, Nicholas G D
    Stirrups, Kathleen E
    Varga, Tibor V
    Warren, Helen R
    Scott, Robert A
    Southam, Lorraine
    Zhang, Weihua
    Yaghootkar, Hanieh
    Müller-Nurasyid, Martina
    Couto Alves, Alexessander
    Strawbridge, Rona J
    Lataniotis, Lazaros
    An Hashim, Nikman
    Besse, Céline
    Boland, Anne
    Braund, Peter S
    Connell, John M
    Dominiczak, Anna
    Farmaki, Aliki-Eleni
    Franks, Stephen
    Grallert, Harald
    Jansson, Jan-Håkan
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Medicin.
    Karaleftheri, Maria
    Keinänen-Kiukaanniemi, Sirkka
    Matchan, Angela
    Pasko, Dorota
    Peters, Annette
    Poulter, Neil
    Rayner, Nigel W
    Renström, Frida
    Umeå universitet, Medicinska fakulteten, Enheten för biobanksforskning. Department of Clinical Sciences, Genetic and Molecular Epidemiology Unit, Lund University, Skåne University Hospital Malmö, Malmö , Sweden.
    Rolandsson, Olov
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Allmänmedicin.
    Sabater-Lleal, Maria
    Sennblad, Bengt
    Sever, Peter
    Shields, Denis
    Silveira, Angela
    Stanton, Alice V
    Strauch, Konstantin
    Tomaszewski, Maciej
    Tsafantakis, Emmanouil
    Waldenberger, Melanie
    Blakemore, Alexandra I F
    Dedoussis, George
    Escher, Stefan A
    Kooner, Jaspal S
    McCarthy, Mark I
    Palmer, Colin N A
    Hamsten, Anders
    Caulfield, Mark J
    Frayling, Timothy M
    Tobin, Martin D
    Jarvelin, Marjo-Riitta
    Zeggini, Eleftheria
    Gieger, Christian
    Chambers, John C
    Wareham, Nick J
    Munroe, Patricia B
    Franks, Paul W
    Samani, Nilesh J
    Deloukas, Panos
    Analysis with the exome array identifies multiple new independent variants in lipid loci2016Inngår i: Human Molecular Genetics, ISSN 0964-6906, E-ISSN 1460-2083, Vol. 25, nr 18, s. 4094-4106Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    It has been hypothesized that low frequency (1-5% minor allele frequency (MAF)) and rare (<1% MAF) variants with large effect sizes may contribute to the missing heritability in complex traits. Here, we report an association analysis of lipid traits (total cholesterol, LDL-cholesterol, HDL-cholesterol triglycerides) in up to 27 312 individuals with a comprehensive set of low frequency coding variants (ExomeChip), combined with conditional analysis in the known lipid loci. No new locus reached genome-wide significance. However, we found a new lead variant in 26 known lipid association regions of which 16 were >1000-fold more significant than the previous sentinel variant and not in close LD (six had MAF <5%). Furthermore, conditional analysis revealed multiple independent signals (ranging from 1 to 5) in a third of the 98 lipid loci tested, including rare variants. Addition of our novel associations resulted in between 1.5- and 2.5-fold increase in the proportion of heritability explained for the different lipid traits. Our findings suggest that rare coding variants contribute to the genetic architecture of lipid traits.

  • 52. Kato, Norihiro
    et al.
    Loh, Marie
    Takeuchi, Fumihiko
    Verweij, Niek
    Wang, Xu
    Zhang, Weihua
    Kelly, Tanika N.
    Saleheen, Danish
    Lehne, Benjamin
    Leach, Irene Mateo
    Drong, Alexander W.
    Abbott, James
    Wahl, Simone
    Tan, Sian-Tsung
    Scott, William R.
    Campanella, Gianluca
    Chadeau-Hyam, Marc
    Afzal, Uzma
    Ahluwalia, Tarunveer S.
    Bonder, Marc Jan
    Chen, Peng
    Dehghan, Abbas
    Edwards, Todd L.
    Esko, Tonu
    Go, Min Jin
    Harris, Sarah E.
    Hartiala, Jaana
    Kasela, Silva
    Kasturiratne, Anuradhani
    Khor, Chiea-Chuen
    Kleber, Marcus E.
    Li, Huaixing
    Mok, Zuan Yu
    Nakatochi, Masahiro
    Sapari, Nur Sabrina
    Saxena, Richa
    Stewart, Alexandre F. R.
    Stolk, Lisette
    Tabara, Yasuharu
    Teh, Ai Ling
    Wu, Ying
    Wu, Jer-Yuarn
    Zhang, Yi
    Aits, Imke
    Alves, Alexessander Da Silva Couto
    Das, Shikta
    Dorajoo, Rajkumar
    Hopewell, Jemma C.
    Kim, Yun Kyoung
    Koivula, Robert W.
    Luan, Jian'an
    Lyytikainen, Leo-Pekka
    Nguyen, Quang N.
    Pereira, Mark A.
    Postmus, Iris
    Raitakari, Olli T.
    Bryan, Molly Scannell
    Scott, Robert A.
    Sorice, Rossella
    Tragante, Vinicius
    Traglia, Michela
    White, Jon
    Yamamoto, Ken
    Zhang, Yonghong
    Adair, Linda S.
    Ahmed, Alauddin
    Akiyama, Koichi
    Asif, Rasheed
    Aung, Tin
    Barroso, Ines
    Bjonnes, Andrew
    Braun, Timothy R.
    Cai, Hui
    Chang, Li-Ching
    Chen, Chien-Hsiun
    Cheng, Ching-Yu
    Chong, Yap-Seng
    Collins, Rory
    Courtney, Regina
    Davies, Gail
    Delgado, Graciela
    Do, Loi D.
    Doevendans, Pieter A.
    Gansevoort, Ron T.
    Gao, Yu-Tang
    Grammer, Tanja B.
    Grarup, Niels
    Grewal, Jagvir
    Gu, Dongfeng
    Wander, Gurpreet S.
    Hartikainen, Anna-Liisa
    Hazen, Stanley L.
    He, Jing
    Heng, Chew-Kiat
    Hixson, James E.
    Hofman, Albert
    Hsu, Chris
    Huang, Wei
    Husemoen, Lise L. N.
    Hwang, Joo-Yeon
    Ichihara, Sahoko
    Igase, Michiya
    Isono, Masato
    Justesen, Johanne M.
    Katsuy, Tomohiro
    Kibriya, Muhammad G.
    Kim, Young Jin
    Kishimoto, Miyako
    Koh, Woon-Puay
    Kohara, Katsuhiko
    Kumari, Meena
    Kwek, Kenneth
    Lee, Nanette R.
    Lee, Jeannette
    Liao, Jiemin
    Lieb, Wolfgang
    Liewald, David C. M.
    Matsubara, Tatsuaki
    Matsushita, Yumi
    Meitinger, Thomas
    Mihailov, Evelin
    Milani, Lili
    Mills, Rebecca
    Mononen, Nina
    Mueller-Nurasyid, Martina
    Nabika, Toru
    Nakashima, Eitaro
    Ng, Hong Kiat
    Nikus, Kjell
    Nutile, Teresa
    Ohkubo, Takayoshi
    Ohnaka, Keizo
    Parish, Sarah
    Paternoster, Lavinia
    Peng, Hao
    Peters, Annette
    Pham, Son T.
    Pinidiyapathirage, Mohitha J.
    Rahman, Mahfuzar
    Rakugi, Hiromi
    Rolandsson, Olov
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Allmänmedicin.
    Rozario, Michelle Ann
    Ruggiero, Daniela
    Sala, Cinzia F.
    Sarju, Ralhan
    Shimokawa, Kazuro
    Snieder, Harold
    Sparso, Thomas
    Spiering, Wilko
    Starr, John M.
    Stott, David J.
    Stram, Daniel O.
    Sugiyama, Takao
    Szymczak, Silke
    Tang, W. H. Wilson
    Tong, Lin
    Trompet, Stella
    Turjanmaa, Vaino
    Ueshima, Hirotsugu
    Uitterlinden, Andre G.
    Umemura, Satoshi
    Vaarasmaki, Marja
    van Dam, Rob M.
    van Gilst, Wiek H.
    van Veldhuisen, Dirk J.
    Viikari, Jorma S.
    Waldenberger, Melanie
    Wang, Yiqin
    Wang, Aili
    Wilson, Rory
    Wong, Tien-Yin
    Xiang, Yong-Bing
    Yamaguchi, Shuhei
    Ye, Xingwang
    Young, Robin D.
    Young, Terri L.
    Yuan, Jian-Min
    Zhou, Xueya
    Asselbergs, Folkert W.
    Ciullo, Marina
    Clarke, Robert
    Deloukas, Panos
    Franke, Andre
    Franks, Paul W
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Allmänmedicin. Department of Nutrition, Harvard School of Public Health, Boston, Massachusetts, USA; Department of Clinical Sciences, Genetic and Molecular Epidemiology Unit, Skåne University Hospital Malmö, Malmö, Sweden.
    Franks, Steve
    Friedlander, Yechiel
    Gross, Myron D.
    Guo, Zhirong
    Hansen, Torben
    Jarvelin, Marjo-Riitta
    Jorgensen, Torben
    Jukema, J. Wouter
    Kahonen, Mika
    Kajio, Hiroshi
    Kivimaki, Mika
    Lee, Jong-Young
    Lehtimaki, Terho
    Linneberg, Allan
    Miki, Tetsuro
    Pedersen, Oluf
    Samani, Nilesh J.
    Sorensen, Thorkild I. A.
    Takayanagi, Ryoichi
    Toniolo, Daniela
    Ahsan, Habibul
    Allayee, Hooman
    Chen, Yuan-Tsong
    Danesh, John
    Deary, Ian J.
    Franco, Oscar H.
    Franke, Lude
    Heijman, Bastiaan T.
    Holbrook, Joanna D.
    Isaacs, Aaron
    Kim, Bong-Jo
    Lin, Xu
    Liu, Jianjun
    Maerz, Winfried
    Metspalu, Andres
    Mohlke, Karen L.
    Sanghera, Dharambir K.
    Shu, Xiao-Ou
    van Meurs, Joyce B. J.
    Vithana, Eranga
    Wickremasinghe, Ananda R.
    Wijmenga, Cisca
    Wolffenbuttel, Bruce H. W.
    Yokota, Mitsuhiro
    Zheng, Wei
    Zhu, Dingliang
    Vineis, Paolo
    Kyrtopoulos, Soterios A.
    Kleinjans, Jos C. S.
    McCarthy, Mark I.
    Soong, Richie
    Gieger, Christian
    Scott, James
    Teo, Yik-Ying
    He, Jiang
    Elliott, Paul
    Tai, E. Shyong
    van der Harst, Pim
    Kooner, Jaspal S.
    Chambers, John C.
    Trans-ancestry genome-wide association study identifies 12 genetic loci influencing blood pressure and implicates a role for DNA methylation2015Inngår i: Nature Genetics, ISSN 1061-4036, E-ISSN 1546-1718, Vol. 47, nr 11, s. 1282-1293Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    We carried out a trans-ancestry genome-wide association and replication study of blood pressure phenotypes among up to 320,251 individuals of East Asian, European and South Asian ancestry. We find genetic variants at 12 new loci to be associated with blood pressure (P = 3.9 × 10−11 to 5.0 × 10−21). The sentinel blood pressure SNPs are enriched for association with DNA methylation at multiple nearby CpG sites, suggesting that, at some of the loci identified, DNA methylation may lie on the regulatory pathway linking sequence variation to blood pressure. The sentinel SNPs at the 12 new loci point to genes involved in vascular smooth muscle (IGFBP3, KCNK3, PDE3A and PRDM6) and renal (ARHGAP24, OSR1, SLC22A7 and TBX2) function. The new and known genetic variants predict increased left ventricular mass, circulating levels of NT-proBNP, and cardiovascular and all-cause mortality (P = 0.04 to 8.6 × 10−6). Our results provide new evidence for the role of DNA methylation in blood pressure regulation.

  • 53. Kengne, Andre Pascal
    et al.
    Beulens, Joline W. J.
    Peelen, Linda M.
    Moons, Karel G. M.
    van der Schouw, Yvonne T.
    Schulze, Matthias B.
    Spijkerman, Annemieke M. W.
    Griffin, Simon J.
    Grobbee, Diederick E.
    Palla, Luigi
    Tormo, Maria-Jose
    Arriola, Larraitz
    Barengo, Noel C.
    Barricarte, Aurelio
    Boeing, Heiner
    Bonet, Catalina
    Clavel-Chapelon, Francoise
    Dartois, Laureen
    Fagherazzi, Guy
    Franks, Paul W.
    Maria Huerta, Jose
    Kaaks, Rudolf
    Key, Timothy J.
    Khaw, Kay Tee
    Li, Kuanrong
    Muehlenbruch, Kristin
    Nilsson, Peter M.
    Overvad, Kim
    Overvad, Thure F.
    Palli, Domenico
    Panico, Salvatore
    Ramon Quiros, J.
    Rolandsson, Olov
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Allmänmedicin.
    Roswall, Nina
    Sacerdote, Carlotta
    Sanchez, Maria-Jose
    Slimani, Nadia
    Tagliabue, Giovanna
    Tjonneland, Anne
    Tumino, Rosario
    van der A, Daphne L.
    Forouhi, Nita G.
    Sharp, Stephen J.
    Langenberg, Claudia
    Riboli, Elio
    Wareham, Nicholas J.
    Non-invasive risk scores for prediction of type 2 diabetes (EPIC-InterAct): a validation of existing models2014Inngår i: Lancet Diabetes & Endocrinology, ISSN 2213-8587, Vol. 2, nr 1, s. 19-29Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Background The comparative performance of existing models for prediction of type 2 diabetes across populations has not been investigated. We validated existing non-laboratory-based models and assessed variability in predictive performance in European populations. Methods We selected non-invasive prediction models for incident diabetes developed in populations of European ancestry and validated them using data from the EPIC-InterAct case-cohort sample (27 779 individuals from eight European countries, of whom 12 403 had incident diabetes). We assessed model discrimination and calibration for the first 10 years of follow-up. The models were first adjusted to the country-specific diabetes incidence. We did the main analyses for each country and for subgroups defined by sex, age (<60 years vs >= 60 years), BMI (<25 kg/m(2) vs >= 25 kg/m(2)), and waist circumference (men <102 cm vs >= 102 cm; women <88 cm vs >= 88 cm). Findings We validated 12 prediction models. Discrimination was acceptable to good: C statistics ranged from 0.76 (95% CI 0.72-0.80) to 0.81 (0.77-0.84) overall, from 0.73 (0.70-0.76) to 0.79 (0.74-0.83) in men, and from 0.78 (0.74-0.82) to 0.81 (0.80-0.82) in women. We noted significant heterogeneity in discrimination (p(heterogeneity) <0.0001) in all but one model. Calibration was good for most models, and consistent across countries (p(heterogeneity) >0.05) except for three models. However, two models overestimated risk, DPoRT by 34% (95% CI 29-39%) and Cambridge by 40% (28-52%). Discrimination was always better in individuals younger than 60 years or with a low waist circumference than in those aged at least 60 years or with a large waist circumference. Patterns were inconsistent for BMI. All models overestimated risks for individuals with a BMI of <25 kg/m(2). Calibration patterns were inconsistent for age and waist-circumference subgroups. Interpretation Existing diabetes prediction models can be used to identify individuals at high risk of type 2 diabetes in the general population. However, the performance of each model varies with country, age, sex, and adiposity.

  • 54. Kroeger, Janine
    et al.
    Meidtner, Karina
    Stefan, Norbert
    Guevara, Marcela
    Kerrison, Nicola D.
    Ardanaz, Eva
    Aune, Dagfinn
    Boeing, Heiner
    Dorronsoro, Miren
    Dow, Courtney
    Fagherazzi, Guy
    Franks, Paul W.
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Medicin. Lund University, Malmö, Sweden .
    Freisling, Heinz
    Gunter, Marc J.
    Huerta, José Maria
    Kaaks, Rudolf
    Key, Timothy J.
    Khaw, Kay Tee
    Krogh, Vittorio
    Kuehn, Tilman
    Mancini, Francesca Romana
    Mattiello, Amalia
    Nilsson, Peter M.
    Olsen, Anja
    Overvad, Kim
    Palli, Domenico
    Quiros, J. Ramon
    Rolandsson, Olov
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Allmänmedicin.
    Sacerdote, Carlotta
    Sala, Nuria
    Salamanca-Fernandez, Elena
    Sluijs, Ivonne
    Spijkerman, Annemieke M. W.
    Tjonneland, Anne
    Tsilidis, Konstantinos K.
    Tumino, Rosario
    van der Schouw, Yvonne T.
    Forouhi, Nita G.
    Sharp, Stephen J.
    Langenberg, Claudia
    Riboli, Elio
    Schulze, Matthias B.
    Wareham, Nicholas J.
    Circulating Fetuin-A and Risk of Type 2 Diabetes: A Mendelian Randomization Analysis2018Inngår i: Diabetes, ISSN 0012-1797, E-ISSN 1939-327X, Vol. 67, nr 6, s. 1200-1205Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Fetuin-A, a hepatic-origin protein, is strongly positively associated with risk of type 2 diabetes in human observational studies, but it is unknown whether this association is causal. Weaimed to study the potential causal relation of circulating fetuin-A to risk of type 2 diabetes in a Mendelian randomization study with single nucleotide polymorphisms located in the fetuin-A-encoding AHSG gene. We used data from eight European countries of the European Prospective Investigation into Cancer and Nutrition (EPIC)-InterAct case-cohort study including 10,020 incident cases. Plasma fetuin-A concentration was measured in a subset of 965 subcohort participants and 654 case subjects. A genetic score of the AHSG single nucleotide polymorphisms was strongly associated with fetuin-A (28% explained variation). Using the genetic score as instrumental variable of fetuin-A, we observed no significant association of a 50 mu g/mL higher fetuin-A concentration with diabetes risk (hazard ratio 1.02 [95% CI 0.97, 1.07]). Combining our results with those from the DIAbetes Genetics Replication And Meta-analysis (DIAGRAM) consortium (12,171 case subjects) also did not suggest a clear significant relation of fetuin-A with diabetes risk. In conclusion, although there is mechanistic evidence for an effect of fetuin-A on insulin sensitivity and secretion, this study does not support a strong, relevant relationship between circulating fetuin-A and diabetes risk in the general population.

  • 55. Kroeger, Janine
    et al.
    Schulze, Matthias B
    Romaguera, Dora
    Guevara, Marcela
    Buijsse, Brian
    Boeing, Heiner
    Beulens, Joline WJ
    Feskens, Edith JM
    Amiano, Pilar
    Ardanaz, Eva
    Agnoli, Claudia
    Buckland, Genevieve
    Clavel-Chapelon, Francoise
    Dahm, Christina C
    Fagherazzi, Guy
    Franks, Paul W
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Medicin.
    Kaaks, Rudolf
    Key, Timothy J
    Khaw, Kay Tee
    Lajous, Martin
    Mattiello, Amalia
    Menendez Garcia, Virginia
    Navarro, Carmen
    Nilsson, Peter M
    Overvad, Kim
    Palli, Domenico
    Ricceri, Fulvio
    Rolandsson, Olov
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Allmänmedicin.
    Sanchez, Maria-Jose
    Slimani, Nadia
    Spijkerman, Annemieke MW
    Tjonneland, Anne
    Tumino, Rosario
    van der A, Daphne L
    Langenberg, Claudia
    Sharp, Stephen J
    Forouhi, Nita G
    Riboli, Elio
    Wareham, Nicholas J
    Adherence to predefined dietary patterns and incident type 2 diabetes in European populations: EPIC-InterAct Study2014Inngår i: Diabetologia, ISSN 0012-186X, E-ISSN 1432-0428, Vol. 57, nr 2, s. 321-333Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Few studies have investigated the relationship between predefined dietary patterns and type 2 diabetes incidence; little is known about the generalisability of these associations. We aimed to assess the association between predefined dietary patterns and type 2 diabetes risk in European populations. From among a case-cohort of 12,403 incident diabetes cases and 16,154 subcohort members nested within the prospective European Prospective Investigation into Cancer and Nutrition study, we used data on 9,682 cases and 12,595 subcohort participants from seven countries. Habitual dietary intake was assessed at baseline with country-specific dietary questionnaires. Two diet-quality scores (alternative Healthy Eating Index [aHEI], Dietary Approaches to Stop Hypertension [DASH] score) and three reduced rank regression (RRR)-derived dietary-pattern scores were constructed. Country-specific HRs were calculated and combined using a random-effects meta-analysis. After multivariable adjustment, including body size, the aHEI and DASH scores were not significantly associated with diabetes, although for the aHEI there was a tendency towards an inverse association in countries with higher mean age. We observed inverse associations of the three RRR-derived dietary-pattern scores with diabetes: HRs (95% CIs) for a 1-SD difference were 0.91 (0.86, 0.96), 0.92 (0.84, 1.01) and 0.87 (0.82, 0.92). Random-effects meta-analyses revealed heterogeneity between countries that was explainable by differences in the age of participants or the distribution of dietary intake. Adherence to specific RRR-derived dietary patterns, commonly characterised by high intake of fruits or vegetables and low intake of processed meat, sugar-sweetened beverages and refined grains, may lower type 2 diabetes risk.

  • 56. Lagali, Neil S.
    et al.
    Allgeier, Stephan
    Guimaraes, Pedro
    Badian, Reza A.
    Ruggeri, Alfredo
    Koehler, Bernd
    Utheim, Tor Paaske
    Peebo, Beatrice Bourghardt
    Peterson, Magnus
    Dahlin, Lars
    Rolandsson, Olov
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Allmänmedicin.
    Analysis of corneal subbasal nerve plexus from wide-area mosaics in healthy subjects and in type 2 diabetics2016Inngår i: Investigative Ophthalmology and Visual Science, ISSN 0146-0404, E-ISSN 1552-5783, Vol. 57, nr 12Artikkel i tidsskrift (Fagfellevurdert)
  • 57. Lagali, Neil S.
    et al.
    Allgeier, Stephan
    Guimaraes, Pedro
    Badian, Reza A.
    Ruggeri, Alfredo
    Koehler, Bernd
    Utheim, Tor Paaske
    Peebo, Beatrice
    Peterson, Magnus
    Dahlin, Lars B.
    Rolandsson, Olov
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Allmänmedicin.
    Reduced Corneal Nerve Fiber Density in Type 2 Diabetes by Wide-Area Mosaic Analysis2017Inngår i: Investigative Ophthalmology and Visual Science, ISSN 0146-0404, E-ISSN 1552-5783, Vol. 58, nr 14, s. 6318-6327Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    PURPOSE. To determine if corneal subbasal nerve plexus (SBP) parameters derived from wide-area depth-corrected mosaic images are associated with type 2 diabetes.

    METHODS. One hundred sixty-three mosaics were produced from eyes of 82 subjects by laser-scanning in vivo confocal microscopy (IVCM). Subjects were of the same age, without (43 subjects) or with type 2 diabetes (39 subjects). Mosaic corneal nerve fiber length density (mCNFL) and apical whorl corneal nerve fiber length density (wCNFL) were quantified and related to the presence and duration of diabetes (short duration < 10 years and long duration ≥10 years).

    RESULTS. In mosaics with a mean size of 6 mm2 in subjects aged 69.1 ± 1.2 years, mCNFL in type 2 diabetes was reduced relative to nondiabetic subjects (13.1 ± 4.2 vs. 15.0 ± 3.2 mm/mm2, P = 0.018). Also reduced relative to nondiabetic subjects was mCNFL in both short-duration (14.0 ± 4.0 mm/mm2, 3.2 ± 3.9 years since diagnosis) and long-duration diabetes (12.7 ± 4.2 mm/mm2, 15.4 ± 4.2 years since diagnosis; ANOVA P =0.023). Lower mCNFL was associated with presence of diabetes (=0.032) and increased hemoglobin A1c (HbA1c) levels (P = 0.047). By contrast, wCNFL was unaffected by diabetes or HbA1c (P > 0.05). Global SBP patterns revealed marked degeneration of secondary nerve fiber branches outside the whorl region in long-duration diabetes.

    CONCLUSIONS. Wide-area mosaic images provide reference values for mCNFL and wCNFL and reveal a progressive degeneration of the SBP with increasing duration of type 2 diabetes.

  • 58. Lagali, Neil S.
    et al.
    Allgeier, Stephan
    Guimaraes, Pedro
    Badian, Reza A.
    Ruggeri, Alfredo
    Koehler, Bernd
    Utheim, Tor Paaske
    Peebo, Beatrice
    Peterson, Magnus
    Dahlin, Lars B.
    Rolandsson, Olov
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Allmänmedicin.
    Wide-field corneal subbasal nerve plexus mosaics in age-controlled healthy and type 2 diabetes populations2018Inngår i: Scientific Data, E-ISSN 2052-4463, Vol. 5, artikkel-id 180075Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    A dense nerve plexus in the clear outer window of the eye, the cornea, can be imaged in vivo to enable non-invasive monitoring of peripheral nerve degeneration in diabetes. However, a limited field of view of corneal nerves, operator-dependent image quality, and subjective image sampling methods have led to difficulty in establishing robust diagnostic measures relating to the progression of diabetes and its complications. Here, we use machine-based algorithms to provide wide-area mosaics of the cornea's subbasal nerve plexus (SBP) also accounting for depth (axial) fluctuation of the plexus. Degradation of the SBP with age has been mitigated as a confounding factor by providing a dataset comprising healthy and type 2 diabetes subjects of the same age. To maximize reuse, the dataset includes bilateral eye data, associated clinical parameters, and machine-generated SBP nerve density values obtained through automatic segmentation and nerve tracing algorithms. The dataset can be used to examine nerve degradation patterns to develop tools to non-invasively monitor diabetes progression while avoiding narrow-field imaging and image selection biases.

  • 59. Lagali, Neil S.
    et al.
    Badian, Reza A.
    Liu, Xu
    Feldreich, Tobias R.
    Arnlov, Johan
    Utheim, Tor Paaske
    Dahlin, Lars B.
    Rolandsson, Olov
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Allmänmedicin.
    Dendritic cell maturation in the corneal epithelium with onset of type 2 diabetes is associated with tumor necrosis factor receptor superfamily member 92018Inngår i: Scientific Reports, ISSN 2045-2322, E-ISSN 2045-2322, Vol. 8, artikkel-id 14248Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Type 2 diabetes mellitus is characterized by a low-grade inflammation; however, mechanisms leading to this inflammation in specific tissues are not well understood. The eye can be affected by diabetes; thus, we hypothesized that inflammatory changes in the eye may parallel the inflammation that develops with diabetes. Here, we developed a non-invasive means to monitor the status of inflammatory dendritic cell (DC) subsets in the corneal epithelium as a potential biomarker for the onset of inflammation in type 2 diabetes. In an age-matched cohort of 81 individuals with normal and impaired glucose tolerance and type 2 diabetes, DCs were quantified from wide-area maps of the corneal epithelial sub-basal plexus, obtained using clinical in vivo confocal microscopy (IVCM). With the onset of diabetes, the proportion of mature, antigen-presenting DCs increased and became organized in clusters. Out of 92 plasma proteins analysed in the cohort, tumor necrosis factor receptor super family member 9 (TNFRSF9) was associated with the observed maturation of DCs from an immature to mature antigen-presenting phenotype. A low-grade ocular surface inflammation observed in this study, where resident immature dendritic cells are transformed into mature antigen-presenting cells in the corneal epithelium, is a process putatively associated with TNFRSF9 signalling and may occur early in the development of type 2 diabetes. IVCM enables this process to be monitored non-invasively in the eye.

  • 60. Langenberg, C.
    et al.
    Sharp, S.
    Forouhi, N. G.
    Franks, Paul
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Medicin.
    Schulze, M. B.
    Kerrison, N.
    Ekelund, U.
    Barroso, I.
    Panico, S.
    Tormo, M. J.
    Spranger, J.
    Griffin, S.
    van der Schouw, Y. T.
    Amiano, P.
    Ardanaz, E.
    Arriola, L.
    Balkau, B.
    Barricarte, A.
    Beulens, J. W. J.
    Boeing, H.
    Bueno-de-Mesquita, H. B.
    Buijsse, B.
    Chirlaque Lopez, M. D.
    Clavel-Chapelon, F.
    Crowe, F. L.
    de Lauzon-Guillan, B.
    Deloukas, P.
    Dorronsoro, M.
    Drogan, D.
    Froguel, P.
    Gonzalez, C.
    Grioni, S.
    Groop, L.
    Groves, C.
    Hainaut, P.
    Halkjaer, J.
    Hallmans, Göran
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Näringsforskning.
    Hansen, T.
    Huerta Castano, J. M.
    Kaaks, R.
    Key, T. J.
    Khaw, K. T.
    Koulman, A.
    Mattiello, A.
    Navarro, C.
    Nilsson, P.
    Norat, T.
    Overvad, K.
    Palla, L.
    Palli, D.
    Pedersen, O.
    Peeters, P. H.
    Quiros, J. R.
    Ramachandran, A.
    Rodriguez-Suarez, L.
    Rolandsson, Olov
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Allmänmedicin.
    Romaguera, D.
    Romieu, I.
    Sacerdote, C.
    Sanchez, M. J.
    Sandbaek, A.
    Slimani, N.
    Sluijs, I.
    Spijkerman, A. M. W.
    Teucher, B.
    Tjonneland, A.
    Tumino, R.
    van der A, D. L.
    Verschuren, W. M. M.
    Tuomilehto, J.
    Feskens, E.
    McCarthy, M.
    Riboli, E.
    Wareham, N. J.
    Design and cohort description of the InterAct Project: an examination of the interaction of genetic and lifestyle factors on the incidence of type 2 diabetes in the EPIC Study2011Inngår i: Diabetologia, ISSN 0012-186X, E-ISSN 1432-0428, Vol. 54, nr 9, s. 2272-2282Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Studying gene-lifestyle interaction may help to identify lifestyle factors that modify genetic susceptibility and uncover genetic loci exerting important subgroup effects. Adequately powered studies with prospective, unbiased, standardised assessment of key behavioural factors for gene-lifestyle studies are lacking. This case-cohort study aims to investigate how genetic and potentially modifiable lifestyle and behavioural factors, particularly diet and physical activity, interact in their influence on the risk of developing type 2 diabetes. Incident cases of type 2 diabetes occurring in European Prospective Investigation into Cancer and Nutrition (EPIC) cohorts between 1991 and 2007 from eight of the ten EPIC countries were ascertained and verified. Prentice-weighted Cox regression and random-effects meta-analyses were used to investigate differences in diabetes incidence by age and sex. A total of 12,403 verified incident cases of type 2 diabetes occurred during 3.99 million person-years of follow-up of 340,234 EPIC participants eligible for InterAct. We defined a centre-stratified subcohort of 16,154 individuals for comparative analyses. Individuals with incident diabetes who were randomly selected into the subcohort (n = 778) were included as cases in the analyses. All prevalent diabetes cases were excluded from the study. InterAct cases were followed-up for an average of 6.9 years; 49.7% were men. Mean baseline age and age at diagnosis were 55.6 and 62.5 years, mean BMI and waist circumference values were 29.4 kg/m(2) and 102.7 cm in men, and 30.1 kg/m(2) and 92.8 cm in women, respectively. Risk of type 2 diabetes increased linearly with age, with an overall HR of 1.56 (95% CI 1.48-1.64) for a 10 year age difference, adjusted for sex. A male excess in the risk of incident diabetes was consistently observed across all countries, with a pooled HR of 1.51 (95% CI 1.39-1.64), adjusted for age. InterAct is a large, well-powered, prospective study that will inform our understanding of the interplay between genes and lifestyle factors on the risk of type 2 diabetes development.

  • 61. Langenberg, Claudia
    et al.
    Sharp, Stephen J.
    Franks, Paul W.
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Medicin. Lund University, Malmö, Sweden.
    Scott, Robert A.
    Deloukas, Panos
    Forouhi, Nita G.
    Froguel, Philippe
    Groop, Leif C.
    Hansen, Torben
    Palla, Luigi
    Pedersen, Oluf
    Schulze, Matthias B.
    Tormo, Maria-Jose
    Wheeler, Eleanor
    Agnoli, Claudia
    Arriola, Larraitz
    Barricarte, Aurelio
    Boeing, Heiner
    Clarke, Geraldine M.
    Clavel-Chapelon, Francoise
    Duell, Eric J.
    Fagherazzi, Guy
    Kaaks, Rudolf
    Kerrison, Nicola D.
    Key, Timothy J.
    Khaw, Kay Tee
    Kroeger, Janine
    Lajous, Martin
    Morris, Andrew P.
    Navarro, Carmen
    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.
    Sacerdote, Carlotta
    Sanchez, Maria-Jose
    Slimani, Nadia
    Spijkerman, Annemieke M. W.
    Tumino, Rosario
    van der A, Daphne L.
    van der Schouw, Yvonne T.
    Barroso, Ines
    McCarthy, Mark I.
    Riboli, Elio
    Wareham, Nicholas J.
    Gene-Lifestyle Interaction and Type 2 Diabetes: the EPIC InterAct Case-Cohort Study2014Inngår i: PLoS Medicine, ISSN 1549-1277, E-ISSN 1549-1676, Vol. 11, nr 5, artikkel-id e1001647Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Background: Understanding of the genetic basis of type 2 diabetes (T2D) has progressed rapidly, but the interactions between common genetic variants and lifestyle risk factors have not been systematically investigated in studies with adequate statistical power. Therefore, we aimed to quantify the combined effects of genetic and lifestyle factors on risk of T2D in order to inform strategies for prevention. Methods and Findings: The InterAct study includes 12,403 incident T2D cases and a representative sub-cohort of 16,154 individuals from a cohort of 340,234 European participants with 3.99 million person-years of follow-up. We studied the combined effects of an additive genetic T2D risk score and modifiable and non-modifiable risk factors using Prentice-weighted Cox regression and random effects meta-analysis methods. The effect of the genetic score was significantly greater in younger individuals (p for interaction = 1.20x10(-4)). Relative genetic risk (per standard deviation [4.4 risk alleles]) was also larger in participants who were leaner, both in terms of body mass index (p for interaction = 1.50x10(-3)) and waist circumference (p for interaction = 7.49x10(-9)). Examination of absolute risks by strata showed the importance of obesity for T2D risk. The 10-y cumulative incidence of T2D rose from 0.25% to 0.89% across extreme quartiles of the genetic score in normal weight individuals, compared to 4.22% to 7.99% in obese individuals. We detected no significant interactions between the genetic score and sex, diabetes family history, physical activity, or dietary habits assessed by a Mediterranean diet score. Conclusions: The relative effect of a T2D genetic risk score is greater in younger and leaner participants. However, this subgroup is at low absolute risk and would not be a logical target for preventive interventions. The high absolute risk associated with obesity at any level of genetic risk highlights the importance of universal rather than targeted approaches to lifestyle intervention.

  • 62. Langenberg, Claudia
    et al.
    Sharp, Stephen J.
    Schulze, Matthias B
    Rolandsson, Olov
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Allmänmedicin.
    Overvad, Kim
    Forouhi, Nita G
    Spranger, Joachim
    Drogan, Dagmar
    Maria Huerta, Jose
    Arriola, Larraitz
    de Lauzon-Guillan, Blandine
    Tormo, Maria-Jose
    Ardanaz, Eva
    Balkau, Beverley
    Beulens, Joline WJ
    Boeing, Heiner
    Bueno-de-Mesquita, H Bas
    Clavel-Chapelon, Francoise
    Crowe, Francesca L
    Franks, Paul W
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Medicin.
    Gonzalez, Carlos A
    Grioni, Sara
    Halkjaer, Jytte
    Hallmans, Göran
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Näringsforskning.
    Kaaks, Rudolf
    Kerrison, Nicola D
    Key, Timothy J
    Khaw, Kay Tee
    Mattiello, Amalia
    Nilsson, Peter
    Norat, Teresa
    Palla, Luigi
    Palli, Domenico
    Panico, Salvatore
    Ramon Quiros, J
    Romaguera, Dora
    Romieu, Isabelle
    Sacerdote, Carlotta
    Sanchez, Maria-Jose
    Slimani, Nadia
    Sluijs, Ivonne
    Spijkerman, Annemieke MW
    Teucher, Birgit
    Tjonneland, Anne
    Tumino, Rosario
    Daphne, L van der A
    van der Schouw, Yvonne T
    Feskens, Edith JM
    Riboli, Elio
    Wareham, Nicholas J
    Long-term risk of incident type 2 diabetes and measures of overall and regional obesity: the EPIC-interact case-cohort study2012Inngår i: PLoS Medicine, ISSN 1549-1277, E-ISSN 1549-1676, Vol. 9, nr 6, s. e1001230-Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Background: Waist circumference (WC) is a simple and reliable measure of fat distribution that may add to the prediction of type 2 diabetes (T2D), but previous studies have been too small to reliably quantify the relative and absolute risk of future diabetes by WC at different levels of body mass index (BMI).

    Methods and Findings: The prospective InterAct case-cohort study was conducted in 26 centres in eight European countries and consists of 12,403 incident T2D cases and a stratified subcohort of 16,154 individuals from a total cohort of 340,234 participants with 3.99 million person-years of follow-up. We used Prentice-weighted Cox regression and random effects meta-analysis methods to estimate hazard ratios for T2D. Kaplan-Meier estimates of the cumulative incidence of T2D were calculated. BMI and WC were each independently associated with T2D, with WC being a stronger risk factor in women than in men. Risk increased across groups defined by BMI and WC; compared to low normal weight individuals (BMI 18.5-22.4 kg/m(2)) with a low WC (< 94/80 cm in men/women), the hazard ratio of T2D was 22.0 (95% confidence interval 14.3; 33.8) in men and 31.8 (25.2; 40.2) in women with grade 2 obesity (BMI >= 35 kg/m(2)) and a high WC (> 102/88 cm). Among the large group of overweight individuals, WC measurement was highly informative and facilitated the identification of a subgroup of overweight people with high WC whose 10-y T2D cumulative incidence (men, 70 per 1,000 person-years; women, 44 per 1,000 person-years) was comparable to that of the obese group (50-103 per 1,000 person-years in men and 28-74 per 1,000 person-years in women).

    Conclusions: WC is independently and strongly associated with T2D, particularly in women, and should be more widely measured for risk stratification. If targeted measurement is necessary for reasons of resource scarcity, measuring WC in overweight individuals may be an effective strategy, since it identifies a high-risk subgroup of individuals who could benefit from individualised preventive action.

  • 63. Li, Sherly X.
    et al.
    Imamura, Fumiaki
    Ye, Zheng
    Schulze, Matthias B.
    Zheng, Jusheng
    Ardanaz, Eva
    Arriola, Larraitz
    Boeing, Heiner
    Dow, Courtney
    Fagherazzi, Guy
    Franks, Paul W.
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Medicin. Lund Univ, Sweden.
    Agudo, Antonio
    Grioni, Sara
    Kaaks, Rudolf
    Katzke, Verena A.
    Key, Timothy J.
    Khaw, Kay Tee
    Mancini, Francesca R.
    Navarro, Carmen
    Nilsson, Peter M.
    Onland-Moret, N. Charlotte
    Overvad, Kim
    Palli, Domenico
    Panico, Salvatore
    Quiros, J. Ramon
    Rolandsson, Olov
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Allmänmedicin.
    Sacerdote, Carlotta
    Sanchez, Maria-Jose
    Slimani, Nadia
    Sluijs, Ivonne
    Spijkerman, Annemieke M. W.
    Tjonneland, Anne
    Tumino, Rosario
    Sharp, Stephen J.
    Riboli, Elio
    Langenberg, Claudia
    Scott, Robert A.
    Forouhi, Nita G.
    Wareham, Nicholas J.
    Interaction between genes and macronutrient intake on the risk of developing type 2 diabetes: systematic review and findings from European Prospective Investigation into Cancer (EPIC)-InterAct2017Inngår i: American Journal of Clinical Nutrition, ISSN 0002-9165, E-ISSN 1938-3207, Vol. 106, nr 1, s. 263-275Artikkel, forskningsoversikt (Fagfellevurdert)
    Abstract [en]

    Background: Gene-diet interactions have been reported to contribute to the development of type 2 diabetes (T2D). However, to our knowledge, few examples have been consistently replicated to date. Objective: We aimed to identify existing evidence for genemacronutrient interactions and T2D and to examine the reported interactions in a large-scale study. Design: We systematically reviewed studies reporting genemacronutrient interactions and T2D. We searched the MEDLINE, Human Genome Epidemiology Network, and WHO International Clinical Trials Registry Platform electronic databases to identify studies published up to October 2015. Eligibility criteria included assessment of macronutrient quantity (e.g., total carbohydrate) or indicators of quality (e. g., dietary fiber) by use of self-report or objective biomarkers of intake. Interactions identified in the review were subsequently examined in the EPIC (European Prospective Investigation into Cancer)-InterAct case-cohort study (n = 21,148, with 9403 T2D cases; 8 European countries). Prentice-weighted Cox regression was used to estimate countryspecific HRs, 95% CIs, and P-interaction values, which were then pooled by random-effects meta-analysis. A primary model was fitted by using the same covariates as reported in the published studies, and a second model adjusted for additional covariates and estimated the effects of isocaloric macronutrient substitution. Results: Thirteen observational studies met the eligibility criteria (n < 1700 cases). Eight unique interactions were reported to be significant between macronutrients [carbohydrate, fat, saturated fat, dietary fiber, and glycemic load derived from self-report of dietary intake and circulating n-3 (v-3) polyunsaturated fatty acids] and genetic variants in or near transcription factor 7-like 2 (TCF7L2), gastric inhibitory polypeptide receptor (GIPR), caveolin 2 (CAV2), and peptidase D (PEPD) (P-interaction, 0.05). We found no evidence of interaction when we tried to replicate previously reported interactions. In addition, no interactions were detected in models with additional covariates. Conclusions: Eight gene-macronutrient interactions were identified for the risk of T2D from the literature. These interactions were not replicated in the EPIC-InterAct study, which mirrored the analyses undertaken in the original reports. Our findings highlight the importance of independent replication of reported interactions.

  • 64.
    Lilja, Mikael
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Allmänmedicin.
    Rolandsson, Olov
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Allmänmedicin.
    Norberg, Margareta
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Epidemiologi och global hälsa.
    Söderberg, Stefan
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Kardiologi.
    The iImpact of Leptin and Adiponectin on incident type 2 Diabetes is modified by sex and insulin resistance2012Inngår i: Metabolic Syndrome and Related Disorders, ISSN 1540-4196, E-ISSN 1557-8518, Vol. 10, nr 2, s. 143-151Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Background: Adiponectin and leptin and their ratio have been associated with incident type 2 diabetes (T2DM), although the data presented are conflicting and the populations studied have been small. In this large, prospective, nested, case referent study, we hypothesized that these associations are sex specific and may be modified by insulin resistance. Methods: Men and women aged 30-60 years with incident T2DM (n = 640) and a prior health survey within the Vasterbotten Intervention Programme (VIP) and matched referents (n = 1564) were identified. Using conditional logistic regression analyses, we tested whether baseline plasma adiponectin and leptin levels and their ratio independently predicted incident T2DM, stratified for gender and insulin resistance. Results: Adjusted for traditional risk factors, fourth-quartile levels of adiponectin were associated with a reduced risk of T2DM in men [odds ratio (OR) 0.55 (0.36-0.86)] and women [OR 0.47 (0.27-0.83)]. Quartile four of the leptin/adiponectin ratio predicted T2DM in both men [OR 3.08 (1.68-5.67)] and women [OR 3.31 (1.56-7.03)], whereas quartile-four levels of leptin predicted T2DM only in men [OR 2.30 (1.32-4.02)]. When stratified for insulin sensitivity and adjusted for body mass index (BMI), loge-transformed leptin predicted T2DM in insulin-sensitive men [OR 1.56 (1.13-2.17)] but not in insulin-resistant men [OR 1.03 (0.76-1.39)]. The effect of adiponectin and the leptin/adiponectin ratio was not influenced by the insulin sensitivity status. Conclusions: Leptin in men and adiponectin in both sexes were independent predictors of T2DM. The association was modified by the degree of insulin sensitivity. The leptin/adiponectin ratio may add predictive information beyond the separate hormones.

  • 65.
    Lilja, Mikael
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Allmänmedicin.
    Rolandsson, Olov
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Allmänmedicin.
    Norberg, Margareta
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Epidemiologi och global hälsa.
    Söderberg, Stefan
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Medicin.
    The impact of leptin and adiponectin on incident type 2 diabetes is modified by sex and insulin resistanceManuskript (preprint) (Annet vitenskapelig)
    Abstract [en]

    Background Adiponectin and leptin and their ratio have been associated with incident type 2 diabetes (T2DM), although presented data are conflicting and populations studied have been small. In this large prospective nested case referent study, we hypothesised that these associations are sex-specific and may be modified by insulin resistance.

    Methods Men and women aged 30–60 years with incident T2DM (n=640) and a prior health survey within the Västerbotten Intervention Programme (VIP), and matched referents (n=1564) were identified. Using conditional logistic regression analyses, we tested whether baseline plasma adiponectin and leptin levels and their ratio independently predicted incident T2DM, stratified for gender and insulin resistance.

    Results Adjusted for traditional risk factors, fourth-quartile levels of adiponectin were associated with a reduced risk of T2DM in men (OR 0.55 [0.36–0.86]) and women (OR 0.47 [0.27–0.83]). Quartile four of the leptin/adiponectin ratio predicted T2DM in both men (OR 3.08 [1.68–5.67]) and women (OR 3.31 [1.56–7.03]), while quartile-four levels of leptin predicted T2DM only in men (OR 2.30 [1.32–4.02]). When stratified for insulin sensitivity and adjusted for BMI, loge-transformed leptin predicted T2DM in insulin-sensitive men (OR 1.56 [1.13–2.17]) but not in insulin-resistant men (OR 1.03 [0.76–1.39]). The effect of adiponectin and the leptin/adiponectin ratio was not influenced by the insulin sensitivity status.

    Conclusions Leptin in men and adiponectin in both sexes were independent predictors of T2DM. The association was modified by the degree of insulin sensitivity. The leptin/adiponectin ratio may add predictive information beyond the separate hormones

  • 66.
    Lilja, Mikael
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Allmänmedicin.
    Rolandsson, Olov
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Allmänmedicin.
    Shaw, JE
    Baker IDI Heart and diabetes institute, Melbourne.
    Pauvaday, Vassen
    Ministry of Health and Quality of Life, Port Louis, Mauritiu.
    Cameron, Adrian
    Baker IDI, Heart and diabetes institute, Melbourne.
    Tuomilehto, J
    Department of Public Health, University of Helsinki.
    Alberti, KGMM
    Department of Endocrinology and Metabolic Medicine, Imperial College, London.
    Zimmet, Paul
    Baker IDI, Heart and diabetes institute, Melbourne.
    Söderberg, Stefan
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Medicin.
    Higher leptin levels in Asian Indians than Creoles and Europids:  a potential explanation for increased metabolic risk2010Inngår i: International Journal of Obesity, ISSN 0307-0565, E-ISSN 1476-5497, Vol. 34, nr 5, s. 878-885Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    BACKGROUND AND PURPOSE:

    Leptin predicts cardiovascular diseases and type 2 diabetes, diseases to which Asian Indians are highly susceptible. As a risk marker, leptin's intra-individual and seasonal stability is unstudied and only small studies have compared leptin levels in Asian Indians with other populations. The aim of this study was to explore ethnicity related differences in leptin levels and its intra-individual and seasonal stability.

    METHODS:

    Leptin and anthropometric data from the northern Sweden MONICA (3513 Europids) and the Mauritius Non-communicable Disease (2480 Asian Indians and Creoles) studies were used. In both studies men and women, 25- to 74-year old, participated in both an initial population survey and a follow-up after 5-13 years. For the analysis of seasonal leptin variation, a subset of 1780 participants, 30- to 60-year old, in the Västerbotten Intervention Project was used.

    RESULTS:

    Asian Indian men and women had higher levels of leptin, leptin per body mass index (BMI) unit (leptin/BMI) or per cm in waist circumference (WC; leptin/waist) than Creoles and Europids when adjusted for BMI (all P<0.0005) or WC (all P<0.005). In men, Creoles had higher leptin, leptin/BMI and leptin/waist than Europids when adjusted for BMI or WC (all P<0.0005). In women, Creoles had higher leptin/BMI and leptin/waist than Europids only when adjusted for WC (P<0.0005). Asian Indian ethnicity in both sexes, and Creole ethnicity in men, was independently associated with high leptin levels. The intra-class correlation for leptin was similar (0.6-0.7), independently of sex, ethnicity or follow-up time. No seasonal variation in leptin levels was seen.

    CONCLUSION:

    Asian Indians have higher levels of leptin, leptin/BMI and leptin/waist than Creoles and Europids. Leptin has a high intra-individual stability and seasonal leptin variation does not appear to explain the ethnic differences observed here

  • 67. Long, G H
    et al.
    Johansson, Ingegerd
    Umeå universitet, Medicinska fakulteten, Institutionen för odontologi.
    Rolandsson, Olov
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Allmänmedicin.
    Wennberg, Patrik
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Allmänmedicin.
    Fhärm, Eva
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Allmänmedicin.
    Weinehall, Lars
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Epidemiologi och global hälsa.
    Griffin, S J
    Simmons, R K
    Norberg, Margareta
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Epidemiologi och global hälsa. Umeå universitet, Samhällsvetenskapliga fakulteten, Centrum för befolkningsstudier (CBS).
    Healthy behaviours and 10-year incidence of diabetes: a population cohort study2015Inngår i: Preventive Medicine, ISSN 0091-7435, E-ISSN 1096-0260, Vol. 71, s. 121-127Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    OBJECTIVE: To examine the association between meeting behavioural goals and diabetes incidence over 10years in a large, representative Swedish population.

    METHODS: Population-based prospective cohort study of 32,120 individuals aged 35 to 55years participating in a health promotion intervention in Västerbotten County, Sweden (1990 to 2013). Participants underwent an oral glucose tolerance test, clinical measures, and completed diet and activity questionnaires. Poisson regression quantified the association between achieving six behavioural goals at baseline - body mass index (BMI) <25kg/m(2), moderate physical activity, non-smoker, fat intake <30% of energy, fibre intake ≥15g/4184kJ and alcohol intake ≤20g/day - and diabetes incidence over 10years.

    RESULTS: Median interquartile range (IQR) follow-up time was 9.9 (0.3) years; 2211 individuals (7%) developed diabetes. Only 4.4% of participants met all 6 goals (n=1245) and compared to these individuals, participants meeting 0/1 goals had a 3.74 times higher diabetes incidence (95% confidence interval (CI)=2.50 to 5.59), adjusting for sex, age, calendar period, education, family history of diabetes, history of myocardial infarction and long-term illness. If everyone achieved at least four behavioural goals, 14.1% (95% CI: 11.7 to 16.5%) of incident diabetes cases might be avoided.

    CONCLUSION: Interventions promoting the achievement of behavioural goals in the general population could significantly reduce diabetes incidence.

  • 68. Long, Gráinne H.
    et al.
    Simmons, Rebecca K.
    Norberg, Margareta
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Epidemiologi och global hälsa. Umeå universitet, Samhällsvetenskapliga fakulteten, Centrum för befolkningsstudier (CBS). Ageing and Living Conditions Programme.
    Wennberg, Patrik
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Allmänmedicin.
    Lindahl, Bernt
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Yrkes- och miljömedicin.
    Rolandsson, Olov
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Allmänmedicin.
    Griffin, Simon J.
    Weinehall, Lars
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Epidemiologi och global hälsa.
    Temporal shifts in cardiovascular risk factor distribution2014Inngår i: American Journal of Preventive Medicine, ISSN 0749-3797, E-ISSN 1873-2607, Vol. 46, nr 2, s. 112-121Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    BACKGROUND: Complementary strategies to shift risk factor population distributions and target high-risk individuals are required to reduce the burden of type 2 diabetes and cardiovascular disease (CVD).

    PURPOSE: To examine secular changes in glucose and CVD risk factors over 20 years during an individual and population-based CVD prevention program in Västerbotten County, Sweden.

    METHODS: Population-based health promotion intervention was conducted and annual invitation for individuals turning 40, 50, and 60 years to attend a health assessment, including an oral glucose tolerance test, biochemical measures, and a questionnaire. Data were collected between 1991 and 2010, analyzed in 2012 and available for 120,929 individuals. Linear regression modeling examined age-adjusted differences in CVD risk factor means over time. Data were direct-age-standardized to compare disease prevalence.

    RESULTS: Between 1991-1995 and 2006-2010, mean age-adjusted cholesterol (men=-0.53, 95% CI=-0.55, -0.50 mmol/L; women=-0.48, 95% CI=-0.50, -0.45 mmol/L) and systolic blood pressure declined (men=-3.06, 95% CI=-3.43, -2.70 mm Hg; women=-5.27, 95% CI=-5.64, -4.90 mm Hg), with corresponding decreases in the age-standardized prevalence of hypertension and hyperlipidemia. Mean age-adjusted 2-hour plasma glucose (men=0.19, 95% CI=0.15, 0.23 mmol/L; women=0.08, 95% CI=0.04, 0.11 mmol/L) and BMI increased (men=1.12, 95% CI=1.04, 1.21; women=0.65, 95% CI=0.55, 0.75), with increases in the age-standardized prevalence of diabetes and obesity.

    CONCLUSIONS: These data demonstrate the potential of combined individual- and population-based approaches to CVD risk factor control and highlight the need for additional strategies addressing hyperglycemia and obesity.

  • 69. Lotta, Luca A
    et al.
    Gulati, Pawan
    Day, Felix R
    Payne, Felicity
    Ongen, Halit
    van de Bunt, Martijn
    Gaulton, Kyle J
    Eicher, John D
    Sharp, Stephen J
    Luan, Jian'an
    De Lucia Rolfe, Emanuella
    Stewart, Isobel D
    Wheeler, Eleanor
    Willems, Sara M
    Adams, Claire
    Yaghootkar, Hanieh
    Forouhi, Nita G
    Khaw, Kay-Tee
    Johnson, Andrew D
    Semple, Robert K
    Frayling, Timothy
    Perry, John R B
    Dermitzakis, Emmanouil
    McCarthy, Mark I
    Barroso, Inês
    Wareham, Nicholas J
    Savage, David B
    Langenberg, Claudia
    O'Rahilly, Stephen
    Scott, Robert A
    Integrative genomic analysis implicates limited peripheral adipose storage capacity in the pathogenesis of human insulin resistance.2016Inngår i: Nature Genetics, ISSN 1061-4036, E-ISSN 1546-1718Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Insulin resistance is a key mediator of obesity-related cardiometabolic disease, yet the mechanisms underlying this link remain obscure. Using an integrative genomic approach, we identify 53 genomic regions associated with insulin resistance phenotypes (higher fasting insulin levels adjusted for BMI, lower HDL cholesterol levels and higher triglyceride levels) and provide evidence that their link with higher cardiometabolic risk is underpinned by an association with lower adipose mass in peripheral compartments. Using these 53 loci, we show a polygenic contribution to familial partial lipodystrophy type 1, a severe form of insulin resistance, and highlight shared molecular mechanisms in common/mild and rare/severe insulin resistance. Population-level genetic analyses combined with experiments in cellular models implicate CCDC92, DNAH10 and L3MBTL3 as previously unrecognized molecules influencing adipocyte differentiation. Our findings support the notion that limited storage capacity of peripheral adipose tissue is an important etiological component in insulin-resistant cardiometabolic disease and highlight genes and mechanisms underpinning this link.

  • 70. 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-analysis2016Inngår i: Journal of the American Medical Association (JAMA), ISSN 0098-7484, E-ISSN 1538-3598, Vol. 316, nr 13, s. 1383-1391Artikkel i tidsskrift (Fagfellevurdert)
    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.

  • 71. 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 menarche2015Inngår i: Nature Communications, ISSN 2041-1723, E-ISSN 2041-1723, Vol. 6, artikkel-id 7756Artikkel i tidsskrift (Fagfellevurdert)
    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.

  • 72. Luo, D
    et al.
    Gilliam, L K
    Greenbaum, C
    Bekris, L
    Hampe, C S
    Daniels, T
    Richter, W
    Marcovina, S M
    Rolandsson, Olov
    Umeå universitet, Medicinsk fakultet, Folkhälsa och klinisk medicin, Allmänmedicin.
    Landin-Olsson, M
    Kockum, I
    Lernmark, A
    Conformation-dependent GAD65 autoantibodies in diabetes.2004Inngår i: Diabetologia, ISSN 0012-186X, Vol. 47, nr 9, s. 1581-91Artikkel i tidsskrift (Fagfellevurdert)
  • 73. 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 diabetes2018Inngår i: Nature Genetics, ISSN 1061-4036, E-ISSN 1546-1718, Vol. 50, nr 4, s. 559-571Artikkel i tidsskrift (Fagfellevurdert)
    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.

  • 74. 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 Risk2017Inngår i: Diabetes, ISSN 0012-1797, E-ISSN 1939-327X, Vol. 66, nr 7, s. 2019-2032Artikkel i tidsskrift (Fagfellevurdert)
    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.

  • 75. Marouli, Eirini
    et al.
    Graff, Mariaelisa
    Medina-Gomez, Carolina
    Lo, Ken Sin
    Wood, Andrew R.
    Kjaer, Troels R.
    Fine, Rebecca S.
    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
    Burt, Amber A.
    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.
    Toenjes, Anke
    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 height2017Inngår i: Nature, ISSN 0028-0836, E-ISSN 1476-4687, Vol. 542, nr 7640, s. 186-190Artikkel i tidsskrift (Fagfellevurdert)
    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.

  • 76. 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 cohorts2013Inngår i: American Journal of Epidemiology, ISSN 0002-9262, E-ISSN 1476-6256, Vol. 177, nr 2, s. 103-115Artikkel, forskningsoversikt (Fagfellevurdert)
    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.

  • 77. 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 studies2010Inngår i: Diabetes Care, ISSN 0149-5992, E-ISSN 1935-5548, Vol. 33, nr 12, s. 2684-2691Artikkel i tidsskrift (Fagfellevurdert)
    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.

  • 78.
    Nilsson, Anna-Lena
    et al.
    Department of Pediatrics, Östersund Hospital, Östersund, Sweden.
    Lagerquist, E
    Department of Medicine, University of Washington, Seattle, WA, USA.
    Lynch, KF
    Department of Clinical Sciences, Lund University/CRC, University Hospital MAS, Malmö, Sweden.
    Lernmark, Å
    Department of Clinical Sciences, Lund University/CRC, University Hospital MAS, Malmö, Sweden.
    Rolandsson, Olov
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Allmänmedicin.
    Temporal variation of Ljungan Virus antibody levels in relation to islet autoantibodies and possible correlation to childhood type 1 diabetes2009Inngår i: The Open Pediatric Medicine Journal, Vol. 3, s. 61-66Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Viral infection may trigger islet autoimmunity, type 1diabetes (T1D), or both. Fluctuating population density of bank voles as a putative reservoir of Ljungan virus has been claimed to be associated with variations in T1D incidence rate (IR). We tested the hypothesis that Ljungan virus antibodies reflecting prior exposure(s) to the virus may be associated with islet autoimmunity, childhood diabetes or both. Incident, 0-18y, T1D patients (n = 63) were studied along with age and sample time matched controls (n = 126). The younger children (< 9 years) tended to have a higher incidence rate during winter (IR = 67.6, 95%CI 41.9-103.5) compared to summer (IR = 33.6, 95%CI 15.3-63.9) months. The proportion of children with high level antibodies against Ljungan virus (LVAb) were both younger compared to the rest of the children (p < 0.002) and correlated with half yearly T1D IR (r = 0.78, p = 0.005). High level LVAb fluctuating with season and correlating with T1D IR indicates that past exposure to Ljungan virus may be associated with T1D.

  • 79. Nilsson, Mats
    et al.
    Rasmark, Ulf
    Nordgren, Helena
    Hallberg, Per
    Umeå universitet, Medicinska fakulteten, Institutionen för strålningsvetenskaper. Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Centrum för medicinsk teknik och fysik (CMTF).
    Skönevik, Johan
    Umeå universitet, Medicinska fakulteten, Institutionen för strålningsvetenskaper, Radiofysik.
    Westman, Göran
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Allmänmedicin.
    Rolandsson, Olov
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Allmänmedicin.
    The physician at a distance: the use of videoconferencing in the treatment of patients with hypertension2009Inngår i: Journal of Telemedicine and Telecare, ISSN 1357-633X, E-ISSN 1758-1109, Vol. 15, nr 8, s. 397-403Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    We evaluated the feasibility and quality of uncomplicated hypertension care based on telemedicine in a rural area of northern Sweden. The intervention subjects were 91 consecutive patients with primary hypertension. For comparison, 182 age- and sex-matched patients with hypertension were randomly selected from a similar health centre. The telemedicine equipment consisted of a video link between the physician and the patients, supported by a system for accessing medical data via the Internet. During a 21-month study period, telemedicine was used in 270 (91%) of the 297 consultations in the intervention group. All health personnel involved in the telemedicine treatment rated the method as feasible. Both systolic and diastolic blood pressure improved in the two groups during the study period. In the intervention group, a higher proportion had their blood pressure within treatment goals (systolic blood pressure <140 mmHg, diastolic blood pressure <90 mmHg) both at baseline and at follow-up than in the comparison group. An adjusted multivariate model (adjustment for sex, age, time between visits, change in number of drugs between first and last visit, blood pressure at first visit) showed that the intervention group had a higher probability (OR 2.7, 95% CI 1.4-5.2) of reaching the target blood pressure levels than the reference group. Treatment of hypertension by means of telemedicine was quite feasible and at least as effective as face-to-face consultations with a physician.

  • 80.
    Norberg, Margareta
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Epidemiologi och folkhälsovetenskap.
    Eriksson, Jan
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Medicin.
    Lindahl, B
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Yrkes- och miljömedicin.
    Andersson, Christer
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Allmänmedicin.
    Rolandsson, Olov
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Allmänmedicin.
    Stenlund, Hans
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Epidemiologi och folkhälsovetenskap.
    Weinehall, Lars
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Epidemiologi och folkhälsovetenskap.
    A combination of HbA1c, fasting glucose and BMI is effective in screening for individuals at risk of future type 2 diabetes: OGTT is not needed.2006Inngår i: Journal of Internal Medicine, ISSN 0954-6820, E-ISSN 1365-2796, Vol. 260, nr 3, s. 263-71Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    OBJECTIVE: To identify a screening model that predicts high risk of future type 2 diabetes and is useful in clinical practice. DESIGN AND METHODS: Incident case-referent study nested within a population-based health survey. We compared screening models with three risk criteria and calculated sensitivity, specificity, positive (PPV) and negative (NPV) predictive values and attributable proportion. We used fasting plasma glucose (FPG) alone or with an oral glucose tolerance test (OGTT), glycosylated haemoglobin A (HbA1c) (normal range 3.6-5.3%), body mass index (BMI), triglycerides and family history of diabetes (FHD). SETTING: Participants in a health survey at all primary care centres (n=33,336) and subjects with diagnosed type 2 diabetes in primary and hospital care (n=6088) in Umeå during 1989-2001. SUBJECTS: Each of the 164 subjects who developed clinically diagnosed type 2 diabetes (median time to diagnosis of 5.4 years) and 304 sex- and age-matched referents without diabetes diagnosis. RESULTS: Screening models with at least one criterion present had sensitivities of 0.90-0.96, specificities of 0.43-0.57 and PPVs of 8-9%. Combinations of the criteria, FPG>or=6.1 mmol L-1 (capillary plasma), HbA1c>or=4.7% and BMI>or=27 in men and BMI>or=30 in women, had sensitivities, specificities and PPVs of 0.66%, 0.93% and 32%, and 0.52%, 0.97% and 46% respectively. Using FHD as one of three risk criteria showed comparable results. Addition of triglycerides or OGTT did not improve the prediction. CONCLUSIONS: The combination of HbA1c, FPG and BMI are effective in screening for individuals at risk of future clinical diagnosis of type 2 diabetes. OGTT or FHD is not necessary.

  • 81.
    Nygren, Karina
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin.
    Hammarstrom, Anne
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Socialmedicin. Uppsala Univ, Dept Publ Hlth & Caring Sci, Uppsala, Sweden.
    Rolandsson, Olov
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Allmänmedicin.
    Binge drinking and total alcohol consumption from 16 to 43 years of age are associated with elevated fasting plasma glucose in women: results from the northern Swedish cohort study2017Inngår i: BMC Public Health, ISSN 1471-2458, E-ISSN 1471-2458, Vol. 17, artikkel-id 509Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Background: Studies have indicated that moderate alcohol consumption is associated with lower incidence of diabetes in women. However, not only the amount but also the drinking pattern could be of importance when assessing the longitudinal relation between alcohol and glucose. Also, there is a lack of studies on alcohol use beginning in adolescence on adult glucose levels. The aim was to examine the association between total alcohol consumption and binge drinking between ages 16 and 43 and fasting plasma glucose at age 43. Methods: Data were retrieved from a 27-year prospective cohort study, the Northern Swedish Cohort. In 1981, all 9th grade students (n = 1083) within a municipality in Sweden were invited to participate. There were re-assessments at ages 18, 21, 30 and 43. This particular study sample consisted of 897 participants (82.8%). Fasting plasma glucose (mmol/L) was measured at a health examination at age 43. Total alcohol consumption (in grams) and binge drinking were calculated from alcohol consumption data obtained from questionnaires. Results: Descriptive analyses showed that men had higher levels of fasting plasma glucose as compared to women. Men also reported higher levels of alcohol consumption and binge drinking behavior. Linear regressions showed that total alcohol consumption in combination with binge drinking between ages 16 and 43 was associated with elevated fasting plasma glucose at age 43 in women (beta = 0.14, p = 0.003) but not in men after adjustment for BMI, hypertension and smoking at age 43. Conclusions: Our findings indicate that reducing binge drinking and alcohol consumption among young and middle-aged women with the highest consumption might be metabolically favorable for their future glucose metabolism.

  • 82. 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.2011Inngår i: European Journal of Clinical Nutrition, ISSN 0954-3007, E-ISSN 1476-5640, Vol. 65, nr 5, s. 635-41Artikkel i tidsskrift (Fagfellevurdert)
    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.

  • 83. 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.2012Inngår i: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 7, nr 1, s. e29202-Artikkel i tidsskrift (Fagfellevurdert)
    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.

  • 84. 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 Study2012Inngår i: American Journal of Clinical Nutrition, ISSN 0002-9165, E-ISSN 1938-3207, Vol. 95, nr 6, s. 1445-1453Artikkel i tidsskrift (Fagfellevurdert)
    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,

  • 85. Peterson, M.
    et al.
    Pingel, R.
    Lagali, N.
    Dahlin, L. B.
    Rolandsson, Olov
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Allmänmedicin.
    Association between HbA1c and peripheral neuropathy in a 10-year follow-up study of people with normal glucose tolerance, impaired glucose tolerance and Type 2 diabetes2017Inngår i: Diabetic Medicine, ISSN 0742-3071, E-ISSN 1464-5491, Vol. 34, nr 12, s. 1756-1764Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Aims: To explore the association between HbA1c and sural nerve function in a group of people with normal glucose tolerance, impaired glucose tolerance or Type 2 diabetes.

    Methods: We conducted a 10-year follow-up study in 87 out of an original 119 participants. At study commencement (2004), 64 men and 55 women (mean age 61.1 years) with normal glucose tolerance (n=39), impaired glucose tolerance (n=29), or Type 2 diabetes (n=51) were enrolled. At the 2014 follow-up (men, n=46, women, n=41; mean age 71.1 years), 36, nine and 42 participants in the normal glucose tolerance, impaired glucose tolerance and Type 2 diabetes categories, respectively, were re-tested. Biometric data and blood samples were collected, with an electrophysiological examination performed on both occasions.

    Results: At follow-up, we measured the amplitude of the sural nerve in 74 of the 87 participants. The mean amplitude had decreased from 10.9 μV (2004) to 7.0 μV (2014; P<0.001). A 1% increase in HbA1c was associated with a ~1% average decrease in the amplitude of the sural nerve, irrespective of group classification. Crude and adjusted estimates ranged from –0.84 (95% CI –1.32, –0.37) to –1.25 (95% CI –2.31, –0.18). Although the mean conduction velocity of those measured at both occasions (n=73) decreased from 47.6 m/s to 45.8 m/s (P=0.009), any association with HbA1c level was weak. Results were robust with regard to potential confounders and missing data.

    Conclusions: Our data suggest an association between sural nerve amplitude and HbA1c at all levels of HbA1c. Decreased amplitude was more pronounced than was diminished conduction velocity, supporting the notion that axonal degeneration is an earlier and more prominent effect of hyperglycaemia than demyelination.

  • 86. 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 Study2016Inngår i: Diabetes Care, ISSN 0149-5992, E-ISSN 1935-5548, Vol. 39, nr 4, s. 572-581Artikkel i tidsskrift (Fagfellevurdert)
    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.

  • 87.
    Pourhamidi, Kaveh
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Allmänmedicin.
    Dahlin, Lars B
    Boman, Kurt
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Medicin.
    Rolandsson, Olov
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Allmänmedicin.
    Heat shock protein 27 is associated with better nerve function and fewer signs of neuropathy2011Inngår i: Diabetologia, ISSN 0012-186X, E-ISSN 1432-0428, Vol. 54, nr 12, s. 3143-3149Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Aims/hypothesis High levels of serum heat shock protein 27 (sHSP27) have been associated with distal symmetric polyneuropathy in patients with type 1 diabetes. Our objective was to investigate the association between sHSP27, neuropathic signs and nerve function in individuals with normal glucose tolerance (NGT), impaired glucose tolerance (IGT) and type 2 diabetes.

    Methods Participants were recruited consecutively from the population-based Vasterbotten Intervention Program (NGT, n=39, IGT, n=29, and type 2 diabetes, n=51) and were matched for age and sex. sHSP27 levels were measured and nerve conduction studies were performed (peroneal and sural nerves). z Scores for each nerve conduction measure were calculated and compiled into a composite z score for the leg. Neuropathy disability score (NDS) was used to assess neuropathic signs.

    Results Patients with diabetes had significantly lower sHSP27 levels (geometric mean sHSP27 206 pg/ml, 95% CI 142, 299) than those with IGT (geometric mean sHSP27 455 pg/ml, 95% CI 319, 650, p<0.05) and controls (geometric mean sHSP27 361 pg/ml, 95% CI 282, 461, p<0.05). Participants with few signs of neuropathy (first tertile, NDS <= 2) had significantly higher sHSP27 levels (geometric mean sHSP27 401 pg/ml, 95% CI 310, 520) than participants with many signs (third tertile, NDS >= 7) (geometric mean sHSP27 192 pg/ml, 95% CI 128, 288, p=0.007). The highest sHSP27 tertile was associated with better nerve function, adjusted for age, sex, statin medication and HbA(1c) (OR 2.51, 95% CI 1.25, 5.05, p<0.05).

    Conclusions/interpretation High sHSP27 levels were associated with better nerve function and fewer neuropathic signs in NGT, IGT and type 2 diabetes.

  • 88.
    Pourhamidi, Kaveh
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Allmänmedicin.
    Dahlin, Lars B
    Englund, Elisabet
    Rolandsson, Olov
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Allmänmedicin.
    Evaluation of clinical tools and their diagnostic use in distal symmetric polyneuropathy2014Inngår i: Primary care diabetes, ISSN 1878-0210, Vol. 8, nr 1, s. 77-84Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    AIMS: To compare the diagnostic usefulness of tuning fork, monofilament, biothesiometer and skin biopsies in peripheral neuropathy in individuals with varying glucose metabolism.

    METHODS: Normoglycaemic, impaired glucose tolerance (IGT) and type 2 diabetes (T2DM) individuals were recruited. Nerve conduction studies (NCS) and thermal threshold tests were performed. Vibrotactile sense was tested with a biothesiometer and a 128-Hz tuning fork. Touch/pressure perception was examined with a 10-g monofilament. Skin biopsies were performed and intraepidermal nerve fibres were quantified. Distal symmetric polyneuropathy (DSPN) was defined as neuropathy disability score ≥2 and abnormal NCS. Thermal threshold tests were used to define small nerve fibre neuropathy (sDSPN) in cases where NCS (large nerve fibres) were normal.

    RESULTS: The prevalence of DSPN and sDSPN in the whole group (n=119) was 18% and 23%, respectively. For the biothesiometer, a cut-off of ≥24.5V had a sensitivity of 82% and specificity of 70% (AUC=0.81, 95% CI 0.71-0.91) when evaluating DSPN. An intraepidermal nerve fibre density cut-off of ≤3.39fibres/mm showed a sensitivity of 74% and specificity of 70% in the detection of sDSPN, whereas the sensitivity of the tuning fork and the biothesiometer were relatively low, 46% and 67%, respectively. When combining skin biopsies with the tuning fork, 10 more sDSPN cases were identified. Adding skin biopsy to the combination of the tuning fork and biothesiometer increased the sensitivity of finding sDSPN cases, but not DSPN, from 81% to 93%.

    CONCLUSION: Using a biothesiometer in clinical routine might be a sensitive method to detect large nerve fibre dysfunction in the lower extremity, whereas skin biopsies in combination with methods measuring vibrotactile sense could increase the diagnostic sensitivity of detecting peripheral neuropathy at an early stage.

  • 89.
    Pourhamidi, Kaveh
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Allmänmedicin.
    Dahlin, Lars B
    Englund, Elisabet
    Rolandsson, Olov
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Allmänmedicin.
    Intraepidermal nerve fibre density is associated with weight2011Konferansepaper (Annet vitenskapelig)
    Abstract [en]

    Background and aims: Intraepidermal nerve fibre density (IENFD) quantification is regarded to be a sensitive and specific measure of small nerve fibre dysfunction and IENFD loss is an early feature in glucose dysregulation. Our aims were to study IENFD in individuals with normal glucose tolerance (NGT), impaired glucose tolerance (IGT) and type 2 diabetes (T2D) and to study if IENFD was associated to metabolic traits, e.g. obesity and dyslipidemia, and to neurophysiologic assessments of nerve function.

    Materials and methods: Participants were consecutively recruited from the population-based Västerbotten Intervention Program; NGT (n=22), IGT (n=14), T2D (n=24), at the age of 60±1 years. The individuals’ height and weight were measured. Blood glucose and lipids were measured. Nerve conduction studies (NCS) were performed (sural and peroneal nerves) and the results were standardized to z-scores and compiled into a composite Z-score representing the nerve function in the leg. Neuropathy disability score (NDS) was used to evaluate neuropathic signs. In addition, thermal threshold tests (TTT) were performed to assess small nerve fibre function. Skin biopsies were performed using a 3-mm punch taken 10 cm proximal to the lateral malleolus. The intraepidermal nerve fibres were evaluated by routine immunohistochemistry and stained with anti-PGP9.5 (ubiquitin carboxyl-terminal hydrolase) antibodies. Light microscopy was used to identify nerve fibres in thin sections (5 µm) according to a standardized protocol. The IENFD was given as the mean of counts in 3 sections per millimeter of epidermal length. The assessors were blinded to the identity of the samples.

    Results: Patients with diabetes had lower IENFD (median 2.9 nerves mm-1, IQR 1.2-4.8) than controls (median 4.4 nerves mm-1, IQR 3.5-6.3; Mann-Whitney U test p=0.007). IGT individuals did not differ in IENFD (median 3.2 nerves mm-1, IQR 1.4-5.5) compared to controls (p=0.12) or diabetic patients (p=0.53). IENFD was positively correlated to NCS (r=0.39, p=0.002), but not to TTT and NDS. Individuals in the 3rd tertile of composite Z-score (i.e. better nerve conduction) had higher IENFD (median 4.1 nerves mm-1, IQR 2.7-5.8) than individuals in the 1st tertile (median 2.4 nerves mm-1, IQR 0.7-3.9; p=0.009). Triglycerides and cholesterols were not associated with IENFD. However, a stepwise multiple linear regression analysis revealed that weight was independently associated to IENFD, after adjustment for age, sex, height, and diabetic status (β=-0.419, p<0.001).

    Conclusion: We conclude that skin biopsies for IENFD quantification in thin sections is a simple useful method for assessing small nerve fibre neuropathy in individuals with diabetes. The association between weight and IENFD indicates that metabolic traits other than glucose dysmetabolism might play a role in the development small nerve fibre neuropathy.

  • 90.
    Pourhamidi, Kaveh
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Allmänmedicin.
    Dahlin, Lars B
    Department of Clinical Sciences Malmö, Hand Surgery, Skåne University Hospital, Lund University, Malmö, Sweden.
    Englund, Elisabet
    Division of Neuropathology, Department of Pathology, Lund University, Lund, Sweden.
    Rolandsson, Olov
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Allmänmedicin.
    No difference in small or large nerve fiber function between individuals with normal glucose tolerance and impaired glucose tolerance2013Inngår i: Diabetes Care, ISSN 0149-5992, E-ISSN 1935-5548, Vol. 36, nr 4, s. 962-964Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    OBJECTIVE To assess small and large nerve fiber function in people with normal glucose tolerance (NGT), impaired glucose tolerance (IGT), and type 2 diabetes (T2D).

    RESEARCH DESIGN AND METHODS Participants were recruited consecutively from a population-based cohort: NGT (n = 39), IGT (n = 29), and T2D (n = 51). Electrophysiological measures included nerve conduction studies and thermal thresholds. Intraepidermal nerve fiber density (IENFD) in skin biopsies was calculated.

    RESULTS There was no difference between IGT and NGT in sural nerve conduction, IENFD, and thermal thresholds. IENFD was significantly lower in T2D (median = 2.8 fibers/mm [Interquartile range 1.1–4.7 fibers/mm]) than NGT individuals (4.5 fibers/mm [3.4–6.1 fibers/mm]; P < 0.05). T2D participants had poorer nerve conduction and higher heat thresholds than NGT and IGT.

    CONCLUSIONS Large and small nerve function in people with IGT did not differ from those with NGT. Our finding does not support the existence of neuropathy in a prediabetic stage.

  • 91.
    Pourhamidi, Kaveh
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Allmänmedicin.
    Dahlin, Lars
    Department of Clinical Sciences Malmö – Hand Surgery, Skåne University Hospital, Lund University, Malmö, Sweden. .
    Rolandsson, Olov
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Allmänmedicin.
    Association between symptoms of neuropathy, nerve conduction and levels of heat shock protein 27 in type 2 diabetes2010Konferansepaper (Fagfellevurdert)
    Abstract [en]

    Background and aims: Increased levels of serum HSP27 (sHSP27) are associated with distal symmetric polyneuropathy (DSPN) in type 1 diabetic patients. However, the association between nerve function and sHSP27 has not been studied in subjects with type 2 diabetes (T2D) and impaired glucose tolerance (IGT). Thus, our objectives were to investigate the association between nerve conduction in the legs, symptoms of distal polyneuropathy and sHSP27 levels. Methods: Subjects were consecutively recruited from the population-based Västerbotten Intervention Program; controls (n=39, m/f=19/20, mean age=61± 0.6 years), IGT (n=29, m/f=15/14, mean age=61± 0.8 years), T2D (n=51, m/f=30/21, mean age=61± 1.3 years). Nerve conduction studies were performed. Z-scores for motor conduction velocity (CV) of the peroneal nerve, and the sensory CV and amplitude of the sural nerve were measured and compiled into a composite Z-score of the right leg (Z-score leg). Neurological Disability Score (NDS), including examination of sensory perception, reflexes and muscle strength, were used to evaluate symptoms of neuropathy in the leg. NDS and Z-score leg were categorized into tertiles, respectively. sHSP27 levels were measured and divided into low and high levels. Results: Subjects in the highest NDS tertile had lower sHSP27 levels (328 ± 287 pg/mL) compared to subjects in the lowest NDS tertile (558 ± 404 pg/mL, p=0.04). Subjects in the lowest tertile of Z-score leg were in the lowest sHSP27 group (63%) compared to the subjects in the highest group (38%, p=0.034). The highest tertile of Z-score leg was associated with high levels of sHSP27 (OR 3.8, 95% CI 1.2; 11.5, p=0.02); adjusted for age and sex. However, this association was attenuated when adjusted for T2D status (OR 3.1, 95% CI 0.9; 9.9, p=0.06). Conclusion: In summary, increased sHSP27 levels were associated with an increasing Z-score of the leg; thus, a better nerve conduction, and fewer symptoms using the whole study population. The attenuation of the association when including diabetic status indicates an altered HSP27 production in T2D patients compared to controls and subjects with IGT.

  • 92.
    Pourhamidi, Kaveh
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Allmänmedicin. Malmö.
    Skarstrand, H.
    Dahlin, L. B.
    Rolandsson, Olov
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Allmänmedicin. Malmö.
    Function of large nerve fibres and levels of HSP27 in type 1 diabetes: a longitudinal follow-up2013Inngår i: Diabetologia, ISSN 0012-186X, E-ISSN 1432-0428, Vol. 56, nr Supplement: 1, s. S498-S499, Meeting Abstract: 1245Artikkel i tidsskrift (Annet vitenskapelig)
  • 93.
    Pourhamidi, Kaveh
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Allmänmedicin.
    Skärstrand, Hanna
    Department of Clinical Sciences, Malmö, Lund University, Skåne University Hospital, Sweden.
    Dahlin, Lars B
    Department of Clinical Sciences, Malmö, Hand Surgery, Skåne University Hospital, Lund University, Malmö, Sweden.
    Rolandsson, Olov
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Allmänmedicin.
    Heat shock protein 27 concentrations are lower in patientswith type 1 diabetes mellitus than in healthy controls andcorrelates with large nerve fibre dysfunctionManuskript (preprint) (Annet vitenskapelig)
    Abstract [en]

    Objective Heat shock protein 27 (HSP27) may contribute to the survival of neurons. Our aims were to study whether HSP27 concentrations differ between individuals with and without type 1 diabetes, and evaluate the relationship between the progression of peripheral nerve dysfunction and HSP27 concentrations.

    Research Design and Methods Type 1 diabetes patients (n=27, 41% women; mean age 41±8 years) were recruited in 1992 with a follow-up in 2005; serum HSP27 concentrations were determined in baseline and follow-up samples and compared to non-diabetic controls (n=397, 34% women; mean age 43±14 years). The type 1 diabetes patients underwent nerve conduction studies and thermal and vibration perception threshold tests at baseline and at follow-up. Reference data was used to standardise results for age, height and sex by calculating the Z-scores. Delta changes in HSP27 (follow-up HSP27 – baseline HSP27) and small and large nerve fibre function were used for correlation analyses.

    Results Type 1 diabetes patients had lower HSP27 concentrations at baseline (mean HSP27547 pg/ml, 95% CI 421, 711) and at follow-up (mean HSP27 538 pg/ml, 95% CI 417,693) compared to healthy controls (mean HSP27 785 pg/ml, 95% CI 732, 842; p<0.05 for both comparisons). Deteriorating large nerve fibre function correlated with delta HSP27 concentrations in type 1 diabetes (r=0.50, p=0.01).

    Conclusions Patients with type 1 diabetes had lower HSP27 concentrations than non-diabetic controls and progression of large nerve fibre dysfunction correlated with decreasing HSP27 concentrations during the follow-up period. This could be indicative ofinsufficient neuroprotection in type 1 diabetes.

  • 94.
    Pourhamidi, Kaveh
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Allmänmedicin.
    Skärstrand, Hanna
    Department of Clinical Sciences, Malmö, Lund University, Skåne University Hospital, Sweden .
    Dahlin, Lars B.
    Department of Clinical Sciences, Malmö, Hand Surgery, Skåne University Hospital, Lund University, Malmö, Sweden .
    Rolandsson, Olov
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Allmänmedicin.
    HSP27 concentrations are lower in patients with type 1 diabetes and correlate with large nerve fiber dysfunction2014Inngår i: Diabetes Care, ISSN 0149-5992, E-ISSN 1935-5548, Vol. 37, nr 3, s. E49-E50Artikkel i tidsskrift (Annet vitenskapelig)
  • 95.
    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.2009Inngår i: Human Molecular Genetics, ISSN 0964-6906, E-ISSN 1460-2083, Vol. 18, nr 8, s. 1489-1496Artikkel i tidsskrift (Fagfellevurdert)
    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.

  • 96.
    Rolandsson, Olov
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Allmänmedicin.
    News from the Nordic countries2011Inngår i: Scandinavian Journal of Primary Health Care, ISSN 0281-3432, E-ISSN 1502-7724, Vol. 29, nr 1, s. 2-3Artikkel i tidsskrift (Annet vitenskapelig)
  • 97.
    Rolandsson, Olov
    Umeå universitet, Medicinsk fakultet, Folkhälsa och klinisk medicin, Allmänmedicin.
    What is the mechanism behind the association between autoantibodies against GAD65 and high body mass index?2004Inngår i: J Intern Med, ISSN 0954-6820, Vol. 256, nr 3, s. 262-3; author reply 264Artikkel i tidsskrift (Annet vitenskapelig)
  • 98.
    Rolandsson, Olov
    et al.
    Allmänmedicin.
    Backeström, Anna
    Eriksson, Sture
    Hallmans, Göran
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Näringsforskning.
    Nilsson, Lars-Göran
    Increased glucose levels are associated with episodic memory in nondiabetic women.2008Inngår i: Diabetes, ISSN 1939-327X, Vol. 57, nr 2, s. 440-3Artikkel i tidsskrift (Fagfellevurdert)
  • 99.
    Rolandsson, Olov
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin.
    Hampe, C. S.
    Sharp, S. J.
    Langenberg, C.
    Wareham, N.
    GAD65 autoantibodies are associated with incident diabetes in mid-life: the EPIC-InterAct study2018Inngår i: Diabetologia, ISSN 0012-186X, E-ISSN 1432-0428, Vol. 61, s. S211-S211Artikkel i tidsskrift (Annet vitenskapelig)
  • 100.
    Rolandsson, Olov
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Allmänmedicin.
    Hampe, Christiane S
    Wennberg, Patrik
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Allmänmedicin.
    Radtke, Jared
    Langenberg, Claudia
    Wareham, Nicholas
    Prevalence and Regional Distribution of Autoantibodies Against GAD65Ab in a European Population Without Diabetes: The EPIC-InterAct Study2015Inngår i: Diabetes Care, ISSN 0149-5992, E-ISSN 1935-5548, Vol. 38, nr 8, s. E114-E115Artikkel i tidsskrift (Fagfellevurdert)
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