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  • 151.
    Lövheim, Hugo
    et al.
    Umeå University, Faculty of Medicine, Department of Community Medicine and Rehabilitation, Geriatric Medicine.
    Elgh, Fredrik
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Virology.
    Johansson, Anders
    Umeå University, Faculty of Medicine, Department of Odontology. Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Nutritional Research.
    Zetterberg, Henrik
    Blennow, Kaj
    Hallmans, Göran
    Umeå University, Faculty of Medicine, Department of Biobank Research. Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Nutritional Research.
    Eriksson, Sture
    Umeå University, Faculty of Medicine, Department of Community Medicine and Rehabilitation, Geriatric Medicine. Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Nutritional Research.
    Plasma concentrations of free amyloid β cannot predict the development of Alzheimer's disease2017In: Alzheimer's & Dementia, ISSN 1552-5260, E-ISSN 1552-5279, Vol. 13, no 7, p. 778-782Article in journal (Refereed)
    Abstract [en]

    Introduction: Biomarkers that identify individuals at risk of Alzheimer's disease (AD) development would be highly valuable. Plasma concentration of amyloid β (Aβ)—central in the pathogenesis of AD—is a logical candidate, but studies to date have produced conflicting results on its utility.

    Methods: Plasma samples from 339 preclinical AD cases (76.4% women, mean age 61.3 years) and 339 age- and sex-matched dementia-free controls, taken an average of 9.4 years before AD diagnosis, were analyzed using Luminex xMAP technology and INNO-BIA plasma Aβ form assays to determine concentrations of free plasma Aβ40 and Aβ42.

    Results: Plasma concentrations of free Aβ40 and Aβ42 did not differ between preclinical AD cases and dementia-free controls, in the full sample or in subgroups defined according to sex and age group (<60 and ≥ 60 years). The interval between sampling and AD diagnosis did not affect the results. Aβ concentrations did not change in the years preceding AD diagnosis among individuals for whom longitudinal samples were available.

    Discussion: Plasma concentrations of free Aβ could not predict the development of clinical AD, and Aβ concentrations did not change in the years preceding AD diagnosis in this sample. These results indicate that free plasma Aβ is not a useful biomarker for the identification of individuals at risk of developing clinical AD.

  • 152.
    Lövheim, Hugo
    et al.
    Umeå University, Faculty of Medicine, Department of Community Medicine and Rehabilitation, Geriatric Medicine.
    Gilthorpe, Jonathan
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Clinical Neuroscience.
    Johansson, Anders
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Nutritional Research. Umeå University, Faculty of Medicine, Department of Odontology, School of Dentistry.
    Eriksson, Sture
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Nutritional Research. Umeå University, Faculty of Medicine, Department of Community Medicine and Rehabilitation, Geriatric Medicine.
    Hallmans, Göran
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Nutritional Research. Umeå University, Faculty of Medicine, Department of Biobank Research.
    Elgh, Fredrik
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Virology.
    Herpes simplex infection and the risk of Alzheimer's disease: a nested case-control study2015In: Alzheimer's & Dementia, ISSN 1552-5260, E-ISSN 1552-5279, Vol. 11, no 6, p. 587-592Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: Herpes simplex virus (HSV) is thought to play an etiological role in the development of Alzheimer's disease (AD).

    METHODS: Plasma samples from 360 AD cases (75.3% women, mean age 61.2 years) and 360 age- and sex-matched dementia-free controls, taken on average 9.6 years before AD diagnosis, were analyzed for anti-HSV antibodies (immunoglobulin G, IgG, and immunoglobulin M, IgM) by enzyme-linked immunosorbent assays.

    RESULTS: In the complete sample group, the presence of anti-HSV IgG and IgM antibodies did not increase the risk of AD significantly (odds ratio (OR) 1.636, P = .069 and OR 1.368, P = .299, respectively). In cases with 6.6 years or more between plasma sampling and AD diagnosis (n = 270), there was a significant association between presence of anti-HSV IgG antibodies and AD (OR 2.250, P = .019).

    CONCLUSION: Among persons with a follow-up time of 6.6 years or more, HSV infection was significantly associated with AD.

  • 153. Machiela, Mitchell J.
    et al.
    Zhou, Weiyin
    Sampson, Joshua N.
    Dean, Michael C.
    Jacobs, Kevin B.
    Black, Amanda
    Brinton, Louise A.
    Chang, I-Shou
    Chen, Chu
    Chen, Constance
    Chen, Kexin
    Cook, Linda S.
    Bou, Marta Crous
    De Vivo, Immaculata
    Doherty, Jennifer
    Friedenreich, Christine M.
    Gaudet, Mia M.
    Haiman, Christopher A.
    Hankinson, Susan E.
    Hartge, Patricia
    Henderson, Brian E.
    Hong, Yun-Chul
    Hosgood, H. Dean, III
    Hsiung, Chao A.
    Hu, Wei
    Hunter, David J.
    Jessop, Lea
    Kim, Hee Nam
    Kim, Yeul Hong
    Kim, Young Tae
    Klein, Robert
    Kraft, Peter
    Lan, Qing
    Lin, Dongxin
    Liu, Jianjun
    Le Marchand, Loic
    Liang, Xiaolin
    Lissowska, Jolanta
    Lu, Lingeng
    Magliocco, Anthony M.
    Matsuo, Keitaro
    Olson, Sara H.
    Orlow, Irene
    Park, Jae Yong
    Pooler, Loreall
    Prescott, Jennifer
    Rastogi, Radhai
    Risch, Harvey A.
    Schumacher, Fredrick
    Seow, Adeline
    Setiawan, Veronica Wendy
    Shen, Hongbing
    Sheng, Xin
    Shin, Min-Ho
    Shu, Xiao-Ou
    VanDen Berg, David
    Wang, Jiu-Cun
    Wentzensen, Nicolas
    Wong, Maria Pik
    Wu, Chen
    Wu, Tangchun
    Wu, Yi-Long
    Xia, Lucy
    Yang, Hannah P.
    Yang, Pan-Chyr
    Zheng, Wei
    Zhou, Baosen
    Abnet, Christian C.
    Albanes, Demetrius
    Aldrich, Melinda C.
    Amos, Christopher
    Amundadottir, Laufey T.
    Berndt, Sonja I.
    Blot, William J.
    Bock, Cathryn H.
    Bracci, Paige M.
    Burdett, Laurie
    Buring, Julie E.
    Butler, Mary A.
    Carreon, Tania
    Chatterjee, Nilanjan
    Chung, Charles C.
    Cook, Michael B.
    Cullen, Michael
    Davis, Faith G.
    Ding, Ti
    Duell, Eric J.
    Epstein, Caroline G.
    Fan, Jin-Hu
    Figueroa, Jonine D.
    Fraumeni, Joseph F., Jr.
    Freedman, Neal D.
    Fuchs, Charles S.
    Gao, Yu-Tang
    Gapstur, Susan M.
    Patino-Garcia, Ana
    Garcia-Closas, Montserrat
    Gaziano, J. Michael
    Giles, Graham G.
    Gillanders, Elizabeth M.
    Giovannucci, Edward L.
    Goldin, Lynn
    Goldstein, Alisa M.
    Greene, Mark H.
    Hallmans, Göran
    Umeå University, Faculty of Medicine, Department of Biobank Research. Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Nutritional Research.
    Harris, Curtis C.
    Henriksson, Roger
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Holly, Elizabeth A.
    Hoover, Robert N.
    Hu, Nan
    Hutchinson, Amy
    Jenab, Mazda
    Johansen, Christoffer
    Khaw, Kay-Tee
    Koh, Woon-Puay
    Kolonel, Laurence N.
    Kooperberg, Charles
    Krogh, Vittorio
    Kurtz, Robert C.
    LaCroix, Andrea
    Landgren, Annelie
    Landi, Maria Teresa
    Li, Donghui
    Liao, Linda M.
    Malats, Nuria
    McGlynn, Katherine A.
    McNeill, Lorna H.
    McWilliams, Robert R.
    Melin, Beatrice S.
    Mirabello, Lisa
    Peplonska, Beata
    Peters, Ulrike
    Petersen, Gloria M.
    Prokunina-Olsson, Ludmila
    Purdue, Mark
    Qiao, You-Lin
    Rabe, Kari G.
    Rajaraman, Preetha
    Real, Francisco X.
    Riboli, Elio
    Rodriguez-Santiago, Benjamin
    Rothman, Nathaniel
    Ruder, Avima M.
    Savage, Sharon A.
    Schwartz, Ann G.
    Schwartz, Kendra L.
    Sesso, Howard D.
    Severi, Gianluca
    Silverman, Debra T.
    Spitz, Margaret R.
    Stevens, Victoria L.
    Stolzenberg-Solomon, Rachael
    Stram, Daniel
    Tang, Ze-Zhong
    Taylor, Philip R.
    Teras, Lauren R.
    Tobias, Geoffrey S.
    Viswanathan, Kala
    Wacholder, Sholom
    Wang, Zhaoming
    Weinstein, Stephanie J.
    Wheeler, William
    White, Emily
    Wiencke, John K.
    Wolpin, Brian M.
    Wu, Xifeng
    Wunder, Jay S.
    Yu, Kai
    Zanetti, Krista A.
    Zeleniuch-Jacquotte, Anne
    Umeå University, Faculty of Medicine, Department of Biobank Research.
    Ziegler, Regina G.
    De Andrade, Mariza
    Barnes, Kathleen C.
    Beaty, Terri H.
    Bierut, Laura J.
    Desch, Karl C.
    Doheny, Kimberly F.
    Feenstra, Bjarke
    Ginsburg, David
    Heit, John A.
    Kang, Jae H.
    Laurie, Cecilia A.
    Li, Jun Z.
    Lowe, William L.
    Marazita, Mary L.
    Melbye, Mads
    Mirel, Daniel B.
    Murray, Jeffrey C.
    Nelson, Sarah C.
    Pasquale, Louis R.
    Rice, Kenneth
    Wiggs, Janey L.
    Wise, Anastasia
    Tucker, Margaret
    Perez-Jurado, Luis A.
    Laurie, Cathy C.
    Caporaso, Neil E.
    Yeager, Meredith
    Chanock, Stephen J.
    Characterization of Large Structural Genetic Mosaicism in Human Autosomes2015In: American Journal of Human Genetics, ISSN 0002-9297, E-ISSN 1537-6605, Vol. 96, no 3, p. 487-497Article in journal (Refereed)
    Abstract [en]

    Analyses of genome-wide association study (GWAS) data have revealed that detectable genetic mosaicism involving large (>2 Mb) structural autosomal alterations occurs in a fraction of individuals. We present results for a set of 24,849 genotyped individuals (total GWAS set II [TGSII]) in whom 341 large autosomal abnormalities were observed in 168 (0.68%) individuals. Merging data from the new TGSII set with data from two prior reports (the Gene-Environment Association Studies and the total GWAS set I) generated a large dataset of 127,179 individuals; we then conducted a meta-analysis to investigate the patterns of detectable autosomal mosaicism (n = 1,315 events in 925 [0.73%] individuals). Restricting to events >2 Mb in size, we observed an increase in event frequency as event size decreased. The combined results underscore that the rate of detectable mosaicism increases with age (p value = 5.5 x 3 10(-31)) and is higher in men (p value = 0.002) but lower in participants of African ancestry (p value = 0.003). In a subset of 47 individuals from whom serial samples were collected up to 6 years apart, complex changes were noted over time and showed an overall increase in the proportion of mosaic cells as age increased. Our large combined sample allowed for a unique ability to characterize detectable genetic mosaicism involving large structural events and strengthens the emerging evidence of non-random erosion of the genome in the aging population.

  • 154. 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 University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine.
    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 University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine.
    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 University, Faculty of Medicine, Department of Biobank Research.
    Ridker, Paul M.
    Rioux, John D.
    Robertson, Neil
    Robino, Antonietta
    Rolandsson, Olov
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Family Medicine.
    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 height2017In: Nature, ISSN 0028-0836, E-ISSN 1476-4687, Vol. 542, no 7640, p. 186-190Article in journal (Refereed)
    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.

  • 155. Matejcic, M.
    et al.
    Lesueur, F.
    Biessy, C.
    Renault, A. L.
    Mebirouk, N.
    Yammine, S.
    Keski-Rahkonen, P.
    Li, K.
    Hemon, B.
    Weiderpass, E.
    Rebours, V.
    Boutron-Ruault, M. C.
    Carbonnel, F.
    Kaaks, R.
    Katzke, V.
    Kuhn, T.
    Boeing, H.
    Trichopoulou, A.
    Palli, D.
    Agnoli, C.
    Panico, S.
    Tumino, R.
    Sacerdote, C.
    Quiros, J. R.
    Duell, E. J.
    Porta, M.
    Sanchez, M. J.
    Chirlaque, M. D.
    Barricarte, A.
    Amiano, P.
    Ye, Weimin
    Umeå University, Faculty of Medicine, Department of Biobank Research. Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.
    Peeters, P. H.
    Khaw, K. T.
    Perez-Cornago, A.
    Key, T. J.
    Bueno-de-Mesquita, H. B.
    Riboli, E.
    Vineis, P.
    Romieu, I.
    Gunter, M. J.
    Chajes, V.
    Circulating plasma phospholipid fatty acids and risk of pancreatic cancer in a large European cohort2018In: International Journal of Cancer, ISSN 0020-7136, E-ISSN 1097-0215, Vol. 143, no 10, p. 2437-2448Article in journal (Refereed)
    Abstract [en]

    There are both limited and conflicting data on the role of dietary fat and specific fatty acids in the development of pancreatic cancer. In this study, we investigated the association between plasma phospholipid fatty acids and pancreatic cancer risk in the European Prospective Investigation into Cancer and Nutrition (EPIC) cohort. The fatty acid composition was measured by gas chromatography in plasma samples collected at recruitment from375 incident pancreatic cancer cases and375 matched controls. Associations of specific fatty acids with pancreatic cancer risk were evaluated using multivariable conditional logistic regression models with adjustment for established pancreatic cancer risk factors. Statistically significant inverse associations were found between pancreatic cancer incidence and levels of heptadecanoic acid (ORT3‐T1[odds ratio for highest versus lowest tertile] =0.63; 95%CI[confidence interval] = 0.41–0.98; ptrend = 0.036), n‐3 polyunsaturated α‐linolenic acid (ORT3‐T1 = 0.60; 95%CI = 0.39–0.92; ptrend = 0.02) and docosapentaenoic acid (ORT3‐T1 = 0.52; 95%CI = 0.32–0.85; ptrend = 0.008). Industrial trans‐fatty acids were positively associated with pancreatic cancer risk among men (ORT3‐T1 = 3.00; 95%CI = 1.13–7.99; ptrend = 0.029), while conjugated linoleic acids were inversely related to pancreatic cancer among women only (ORT3‐T1 = 0.37; 95%CI = 0.17–0.81; ptrend = 0.008). Among current smokers, the long‐chain n‐6/n‐3 polyunsaturated fatty acids ratio was positively associated with pancreatic cancer risk (ORT3‐T1 = 3.40; 95%CI = 1.39–8.34; ptrend = 0.007). Results were robust to a range of sensitivity analyses. Our findings suggest that higher circulating levels of saturated fatty acids with an odd number of carbon atoms and n‐3 polyunsaturated fatty acids may be related to lower risk of pancreatic cancer. The influence of some fatty acids on the development of pancreatic cancer may be sex‐specific and modulated by smoking.

  • 156.
    Mayans, Sofia
    et al.
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Medical and Clinical Genetics.
    Lackovic, Kurt
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Medical and Clinical Genetics.
    Lindgren, Petter
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Medical and Clinical Genetics.
    Ruikka, Karin
    Department of Medicine, Sunderby Hospital, Luleå.
    Ågren, Åsa
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Nutritional Research. Umeå University, Faculty of Medicine, Department of Biobank Research.
    Eliasson, Mats
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine. Department of Medicine, Sunderby Hospital, Luleå.
    Holmberg, Dan
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Medical and Clinical Genetics. Umeå University, Faculty of Medicine, Umeå Centre for Molecular Medicine (UCMM).
    TCF7L2 polymorphisms are associated with type 2 diabetes in northern Sweden2007In: European Journal of Human Genetics, ISSN 1018-4813, E-ISSN 1476-5438, Vol. 15, no 3, p. 342-346Article in journal (Refereed)
    Abstract [en]

    A recent study found association of one microsatellite and five single nucleotide polymorphisms (SNPs) in intron 3 of the TCF7L2 gene with type 2 diabetes (T2D) in the Icelandic, Danish and American populations. The aim of the present study was to investigate if those SNPs were associated to T2D in two (family- and population-based) cohorts from northern Sweden. We genotyped four of the associated SNPs in a case-control cohort consisting of 872 T2D cases and 857 controls matched with respect to age, sex and geographical origin and in a sample of 59 extended families (148 affected and 83 unaffected individuals). Here, we report replication of association between T2D and three SNPs in the case-control (rs7901695, P=0.003; rs7901346, P=0.00002; and rs12255372, P=0.000004) and two SNPs in the family-based (rs7901695, P=0.01 and rs7901346, P=0.04) samples from northern Sweden. This replication strengthens the evidence for involvement of TCF7L2 in T2D.

  • 157. McKay, James D.
    et al.
    Truong, Therese
    Gaborieau, Valerie
    Chabrier, Amelie
    Chuang, Shu-Chun
    Byrnes, Graham
    Zaridze, David
    Shangina, Oxana
    Szeszenia-Dabrowska, Neonila
    Lissowska, Jolanta
    Rudnai, Peter
    Fabianova, Eleonora
    Bucur, Alexandru
    Bencko, Vladimir
    Holcatova, Ivana
    Janout, Vladimir
    Foretova, Lenka
    Lagiou, Pagona
    Trichopoulos, Dimitrios
    Benhamou, Simone
    Bouchardy, Christine
    Ahrens, Wolfgang
    Merletti, Franco
    Richiardi, Lorenzo
    Talamini, Renato
    Barzan, Luigi
    Kjaerheim, Kristina
    Macfarlane, Gary J.
    Macfarlane, Tatiana V.
    Simonato, Lorenzo
    Canova, Cristina
    Agudo, Antonio
    Castellsague, Xavier
    Lowry, Ray
    Conway, David I.
    McKinney, Patricia A.
    Healy, Claire M.
    Toner, Mary E.
    Znaor, Ariana
    Curado, Maria Paula
    Koifman, Sergio
    Menezes, Ana
    Wuensch-Filho, Victor
    Neto, Jose Eluf
    Fernandez Garrote, Leticia
    Boccia, Stefania
    Cadoni, Gabriella
    Arzani, Dario
    Olshan, Andrew F.
    Weissler, Mark C.
    Funkhouser, William K.
    Luo, Jingchun
    Lubinski, Jan
    Trubicka, Joanna
    Lener, Marcin
    Oszutowska, Dorota
    Schwartz, Stephen M.
    Chen, Chu
    Fish, Sherianne
    Doody, David R.
    Muscat, Joshua E.
    Lazarus, Philip
    Gallagher, Carla J.
    Chang, Shen-Chih
    Zhang, Zuo-Feng
    Wei, Qingyi
    Sturgis, Erich M.
    Wang, Li-E
    Franceschi, Silvia
    Herrero, Rolando
    Kelsey, Karl T.
    McClean, Michael D.
    Marsit, Carmen J.
    Nelson, Heather H.
    Romkes, Marjorie
    Buch, Shama
    Nukui, Tomoko
    Zhong, Shilong
    Lacko, Martin
    Manni, Johannes J.
    Peters, Wilbert H. M.
    Hung, Rayjean J.
    McLaughlin, John
    Vatten, Lars
    Njolstad, Inger
    Goodman, Gary E.
    Field, John K.
    Liloglou, Triantafillos
    Vineis, Paolo
    Clavel-Chapelon, Francoise
    Palli, Domenico
    Tumino, Rosario
    Krogh, Vittorio
    Panico, Salvatore
    Gonzalez, Carlos A.
    Ramon Quiros, J.
    Martinez, Carmen
    Navarro, Carmen
    Ardanaz, Eva
    Larranaga, Nerea
    Khaw, Kay-Tee
    Key, Timothy
    Bueno-de-Mesquita, H. Bas
    Peeters, Petra H. M.
    Trichopoulou, Antonia
    Linseisen, Jakob
    Boeing, Heiner
    Hallmans, Göran
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Nutritional Research. Umeå University, Faculty of Medicine, Department of Biobank Research.
    Overvad, Kim
    Tjonneland, Anne
    Kumle, Merethe
    Riboli, Elio
    Vaelk, Kristjan
    Voodern, Tonu
    Metspalu, Andres
    Zelenika, Diana
    Boland, Anne
    Delepine, Marc
    Foglio, Mario
    Lechner, Doris
    Blanche, Helene
    Gut, Ivo G.
    Galan, Pilar
    Heath, Simon
    Hashibe, Mia
    Hayes, Richard B.
    Boffetta, Paolo
    Lathrop, Mark
    Brennan, Paul
    A Genome-Wide Association Study of Upper Aerodigestive Tract Cancers Conducted within the INHANCE Consortium2011In: PLOS Genetics, ISSN 1553-7390, E-ISSN 1553-7404, Vol. 7, no 3, article id e1001333Article in journal (Refereed)
    Abstract [en]

    Genome-wide association studies (GWAS) have been successful in identifying common genetic variation involved in susceptibility to etiologically complex disease. We conducted a GWAS to identify common genetic variation involved in susceptibility to upper aero-digestive tract (UADT) cancers. Genome-wide genotyping was carried out using the Illumina HumanHap300 beadchips in 2,091 UADT cancer cases and 3,513 controls from two large European multi-centre UADT cancer studies, as well as 4,821 generic controls. The 19 top-ranked variants were investigated further in an additional 6,514 UADT cancer cases and 7,892 controls of European descent from an additional 13 UADT cancer studies participating in the INHANCE consortium. Five common variants presented evidence for significant association in the combined analysis (p <= 5 x 10(-7)). Two novel variants were identified, a 4q21 variant (rs1494961, p = 1 x 10(-8)) located near DNA repair related genes HEL308 and FAM175A (or Abraxas) and a 12q24 variant (rs4767364, p = 2 x 10(-8)) located in an extended linkage disequilibrium region that contains multiple genes including the aldehyde dehydrogenase 2 (ALDH2) gene. Three remaining variants are located in the ADH gene cluster and were identified previously in a candidate gene study involving some of these samples. The association between these three variants and UADT cancers was independently replicated in 5,092 UADT cancer cases and 6,794 controls non-overlapping samples presented here (rs1573496-ADH7, p = 5 x 10(-8); rs1229984-ADH1B, p = 7 x 10(-9); and rs698-ADH1C, p = 0.02). These results implicate two variants at 4q21 and 12q24 and further highlight three ADH variants in UADT cancer susceptibility.

  • 158.
    Melin, Beatrice
    et al.
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Dahlin, Anna M
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Andersson, Ulrika
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Wang, Zhaoming
    Henriksson, Roger
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Hallmans, Göran
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Nutritional Research. Umeå University, Faculty of Medicine, Department of Biobank Research.
    Bondy, Melissa L
    Johansen, Christoffer
    Feychting, Maria
    Ahlbom, Anders
    Kitahara, Cari M
    Wang, Sophia S
    Ruder, Avima M
    Carreon, Tania
    Butler, Mary Ann
    Inskip, Peter D
    Purdue, Mark
    Hsing, Ann W
    Mechanic, Leah
    Gillanders, Elizabeth
    Yeager, Meredith
    Linet, Martha
    Chanock, Stephen J
    Hartge, Patricia
    Rajaraman, Preetha
    Known glioma risk loci are associated with glioma with a family history of brain tumours: a case-control gene association study2013In: International Journal of Cancer, ISSN 0020-7136, E-ISSN 1097-0215, Vol. 132, no 10, p. 2464-2468Article in journal (Refereed)
    Abstract [en]

    Familial cancer can be used to leverage genetic association studies. Recent genome-wide association studies have reported independent associations between seven single nucleotide polymorphisms (SNPs) and risk of glioma. The aim of this study was to investigate whether glioma cases with a positive family history of brain tumours, defined as having at least one first- or second-degree relative with a history of brain tumour, are associated with known glioma risk loci. One thousand four hundred and thirty-one glioma cases and 2,868 cancer-free controls were identified from four casecontrol studies and two prospective cohorts from USA, Sweden and Denmark and genotyped for seven SNPs previously reported to be associated with glioma risk in casecontrol designed studies. Odds ratios were calculated by unconditional logistic regression. In analyses including glioma cases with a family history of brain tumours (n = 104) and control subjects free of glioma at baseline, three of seven SNPs were associated with glioma risk: rs2736100 (5p15.33, TERT), rs4977756 (9p21.3, CDKN2A-CDKN2B) and rs6010620 (20q13.33, RTEL1). After Bonferroni correction for multiple comparisons, only one marker was statistically significantly associated with glioma risk, rs6010620 (ORtrend for the minor (A) allele, 0.39; 95% CI: 0.250.61; Bonferroni adjusted ptrend, 1.7 x 104). In conclusion, as previously shown for glioma regardless of family history of brain tumours, rs6010620 (RTEL1) was associated with an increased risk of glioma when restricting to cases with family history of brain tumours. These findings require confirmation in further studies with a larger number of glioma cases with a family history of brain tumours.

  • 159. Michaud, Dominique S
    et al.
    Izard, Jacques
    Wilhelm-Benartzi, Charlotte S
    You, Doo-Ho
    Grote, Verena A
    Tjønneland, Anne
    Dahm, Christina C
    Overvad, Kim
    Jenab, Mazda
    Fedirko, Veronika
    Boutron-Ruault, Marie Christine
    Clavel-Chapelon, Françoise
    Racine, Antoine
    Kaaks, Rudolf
    Boeing, Heiner
    Foerster, Jana
    Trichopoulou, Antonia
    Lagiou, Pagona
    Trichopoulos, Dimitrios
    Sacerdote, Carlotta
    Sieri, Sabina
    Palli, Domenico
    Tumino, Rosario
    Panico, Salvatore
    Siersema, Peter D
    Peeters, Petra Hm
    Lund, Eiliv
    Barricarte, Aurelio
    Huerta, José-María
    Molina-Montes, Esther
    Dorronsoro, Miren
    Quirós, J Ramón
    Duell, Eric J
    Ye, Weimin
    Umeå University, Faculty of Medicine, Department of Biobank Research.
    Sund, Malin
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Surgery. Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Nutritional Research.
    Lindkvist, Björn
    Johansen, Dorthe
    Khaw, Kay-Tee
    Wareham, Nick
    Travis, Ruth C
    Vineis, Paolo
    Bueno-de-Mesquita, H Bas
    Riboli, Elio
    Plasma antibodies to oral bacteria and risk of pancreatic cancer in a large European prospective cohort study2013In: Gut, ISSN 0017-5749, E-ISSN 1468-3288, Vol. 62, no 12, p. 1764-1770Article in journal (Refereed)
    Abstract [en]

    OBJECTIVE: Examine the relationship between antibodies to 25 oral bacteria and pancreatic cancer risk in a prospective cohort study. DESIGN: We measured antibodies to oral bacteria in prediagnosis blood samples from 405 pancreatic cancer cases and 416 matched controls, nested within the European Prospective Investigation into Cancer and Nutrition study. Analyses were conducted using conditional logistic regression and additionally adjusted for smoking status and body mass index. RESULTS: Individuals with high levels of antibodies against Porphyromonas gingivalis ATTC 53978, a pathogenic periodontal bacteria, had a twofold higher risk of pancreatic cancer than individuals with lower levels of these antibodies (OR 2.14; 95% CI 1.05 to 4.36; >200 ng/ml vs ≤200 ng/ml). To explore the association with commensal (non-pathogenic) oral bacteria, we performed a cluster analysis and identified two groups of individuals, based on their antibody profiles. A cluster with overall higher levels of antibodies had a 45% lower risk of pancreatic cancer than a cluster with overall lower levels of antibodies (OR 0.55; 95% CI 0.36 to 0.83). CONCLUSIONS: Periodontal disease might increase the risk for pancreatic cancer. Moreover, increased levels of antibodies against specific commensal oral bacteria, which can inhibit growth of pathogenic bacteria, might reduce the risk of pancreatic cancer. Studies are needed to determine whether oral bacteria have direct effects on pancreatic cancer pathogenesis or serve as markers of the immune response.

  • 160. Molina-Montes, Esther
    et al.
    Sanchez, Maria-Jose
    Buckland, Genevieve
    Bueno-de-Mesquita, H. B(as)
    Weiderpass, Elisabete
    Amiano, Pilar
    Wark, Petra A.
    Kuehn, Tilman
    Katzke, Verena
    Maria Huerta, Jose
    Ardanaz, Eva
    Ramon Quiros, Jose
    Affret, Aurelie
    His, Mathilde
    Boutron-Ruault, Marie-Christine
    Peeters, Petra H.
    Ye, Weimin
    Umeå University, Faculty of Medicine, Department of Biobank Research. Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.
    Sund, Malin
    Umeå University, Faculty of Medicine, Department of Biobank Research. Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.
    Boeing, Heiner
    Iqbal, Khalid
    Ohlsson, Bodil
    Sonestedt, Emily
    Tjonneland, Anne
    Petersen, Kristina E. N.
    Travis, Ruth C.
    Skeie, Guri
    Agnoli, Claudia
    Panico, Salvatore
    Palli, Domenico
    Tumino, Rosario
    Sacerdote, Carlotta
    Freisling, Heinz
    Huybrechts, Inge
    Overvad, Kim
    Trichopoulou, Antonia
    Bamia, Christina
    Vasilopoulou, Effie
    Wareham, Nick
    Khaw, Kay-Tee
    Cross, Amanda J.
    Ward, Heather A.
    Riboli, Elio
    Duell, Eric J.
    Mediterranean diet and risk of pancreatic cancer in the European Prospective Investigation into Cancer and Nutrition cohort2017In: British Journal of Cancer, ISSN 0007-0920, E-ISSN 1532-1827, Vol. 116, no 6, p. 811-820Article in journal (Refereed)
    Abstract [en]

    Background: The Mediterranean diet (MD) has been proposed as a means for cancer prevention, but little evidence has been accrued regarding its potential to prevent pancreatic cancer. We investigated the association between the adherence to the MD and pancreatic cancer risk within the European Prospective Investigation into Cancer and Nutrition (EPIC) cohort.

    Methods: Over half a million participants from 10 European countries were followed up for over 11 years, after which 865 newly diagnosed exocrine pancreatic cancer cases were identified. Adherence to the MD was estimated through an adapted score without the alcohol component (arMED) to discount alcohol-related harmful effects. Cox proportional hazards regression models, stratified by age, sex and centre, and adjusted for energy intake, body mass index, smoking status, alcohol intake and diabetes status at recruitment, were used to estimate hazard ratios (HRs) associated with pancreatic cancer and their corresponding 95% confidence intervals (CIs).

    Results: Adherence to the arMED score was not associated with risk of pancreatic cancer (HR highvs low adherence=0.99; 95% CI: 0.77–1.26, and HR per increments of two units in adherence to arMED=1.00; 95% CI: 0.94–1.06). There was no convincing evidence for heterogeneity by smoking status, body mass index, diabetes or European region. There was also no evidence of significant associations in analyses involving microscopically confirmed cases, plausible reporters of energy intake or other definitions of the MD pattern.

    Conclusions: A high adherence to the MD is not associated with pancreatic cancer risk in the EPIC study.

  • 161. Molina-Montes, Esther
    et al.
    Sanchez, Maria-Jose
    Zamora-Ros, Raul
    Bueno-de-Mesquita, H. B(as)
    Wark, Petra A.
    Obon-Santacana, Mireia
    Kuehn, Tilman
    Katzke, Verena
    Travis, Ruth C.
    Ye, Weimin
    Umeå University, Faculty of Medicine, Department of Biobank Research. Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.
    Sund, Malin
    Umeå University, Faculty of Medicine, Department of Biobank Research. Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.
    Naccarati, Alessio
    Mattiello, Amalia
    Krogh, Vittorio
    Martorana, Caterina
    Masala, Giovanna
    Amiano, Pilar
    Huerta, Jose-Maria
    Barricarte, Aurelio
    Quiros, Jose-Ramon
    Weiderpass, Elisabete
    Asli, Lene Angell
    Skeie, Guri
    Ericson, Ulrika
    Sonestedt, Emily
    Peeters, Petra H.
    Romieu, Isabelle
    Scalbert, Augustin
    Overvad, Kim
    Clemens, Matthias
    Boeing, Heiner
    Trichopoulou, Antonia
    Peppa, Eleni
    Vidalis, Pavlos
    Khaw, Kay-Tee
    Wareham, Nick
    Olsen, Anja
    Tjonneland, Anne
    Boutroun-Rualt, Marie-Christine
    Clavel-Chapelon, Francoise
    Cross, Amanda J.
    Lu, Yunxia
    Riboli, Elio
    Duell, Eric J.
    Flavonoid and lignan intake and pancreatic cancer risk in the European prospective investigation into cancer and nutrition cohort2016In: International Journal of Cancer, ISSN 0020-7136, E-ISSN 1097-0215, Vol. 139, no 7, p. 1480-1492Article in journal (Refereed)
    Abstract [en]

    Despite the potential cancer preventive effects of flavonoids and lignans, their ability to reduce pancreatic cancer risk has not been demonstrated in epidemiological studies. Our aim was to examine the association between dietary intakes of flavonoids and lignans and pancreatic cancer risk in the European Prospective Investigation into Cancer and Nutrition (EPIC) cohort. A total of 865 exocrine pancreatic cancer cases occurred after 11.3 years of follow-up of 477,309 cohort members. Dietary flavonoid and lignan intake was estimated through validated dietary questionnaires and the US Department of Agriculture (USDA) and Phenol Explorer databases. Hazard ratios (HR) and 95% confidence intervals (CIs) were calculated using age, sex and center-stratified Cox proportional hazards models, adjusted for energy intake, body mass index (BMI), smoking, alcohol and diabetes status. Our results showed that neither overall dietary intake of flavonoids nor of lignans were associated with pancreatic cancer risk (multivariable-adjusted HR for a doubling of intake=1.03, 95% CI: 0.95-1.11 and 1.02; 95% CI: 0.89-1.17, respectively). Statistically significant associations were also not observed by flavonoid subclasses. An inverse association between intake of flavanones and pancreatic cancer risk was apparent, without reaching statistical significance, in microscopically confirmed cases (HR for a doubling of intake=0.96, 95% CI: 0.91-1.00). In conclusion, we did not observe an association between intake of flavonoids, flavonoid subclasses or lignans and pancreatic cancer risk in the EPIC cohort. What's new? Flavonoids and lignans found in plant-based foods are potent cancer chemopreventive agents but little is known about their effects on pancreatic cancer risk. Here the authors address this question in a large prospective epidemiological study using comprehensively derived dietary data. Their results support growing evidence that there is no association between food-based consumption of both substances with pancreatic cancer risk.

  • 162. Moore, Steven C.
    et al.
    Lee, I-Min
    Weiderpass, Elisabete
    Campbell, Peter T.
    Sampson, Joshua N.
    Kitahara, Cari M.
    Keadle, Sarah K.
    Arem, Hannah
    de Gonzalez, Amy Berrington
    Hartge, Patricia
    Adami, Hans-Olov
    Blair, Cindy K.
    Borch, Kristin B.
    Boyd, Eric
    Check, David P.
    Fournier, Agness
    Freedman, Neal D.
    Gunter, Marc
    Johannson, Mattias
    Umeå University, Faculty of Medicine, Department of Biobank Research. Genetic Epidemiology Group, International Agency for Research on Cancer (IARC), Lyon, France.
    Khaw, Kay-Tee
    Linet, Martha S.
    Orsini, Nicola
    Park, Yikyung
    Riboli, Elio
    Robien, Kim
    Schairer, Catherine
    Sesso, Howard
    Spriggs, Michael
    Van Dusen, Roy
    Wolk, Alicja
    Matthews, Charles E.
    Patel, Alpa V.
    Association of Leisure-Time Physical Activity With Risk of 26 Types of Cancer in 1.44 Million Adults2016In: JAMA Internal Medicine, ISSN 2168-6106, E-ISSN 2168-6114, Vol. 176, no 6, p. 816-825Article in journal (Refereed)
    Abstract [en]

    Importance: Leisure-time physical activity has been associated with lower risk of heart-disease and all-cause mortality, but its association with risk of cancer is not well understood.

    Objective: To determine the association of leisure-time physical activity with incidence of common types of cancer and whether associations vary by body size and/or smoking.

    Design, Setting, and Participants: We pooled data from 12 prospective US and European cohorts with self-reported physical activity (baseline, 1987-2004). We used multivariable Cox regression to estimate hazard ratios (HRs) and 95% confidence intervals for associations of leisure-time physical activity with incidence of 26 types of cancer. Leisure-time physical activity levels were modeled as cohort-specific percentiles on a continuous basis and cohort-specific results were synthesized by random-effects meta-analysis. Hazard ratios for high vs low levels of activity are based on a comparison of risk at the 90th vs 10th percentiles of activity. The data analysis was performed from January 1, 2014, to June 1, 2015.

    Exposures: Leisure-time physical activity of a moderate to vigorous intensity.

    Main Outcomes and Measures: Incident cancer during follow-up.

    Results: A total of 1.44 million participants (median [range] age, 59 [19-98] years; 57% female) and 186 932 cancers were included. High vs low levels of leisure-time physical activity were associated with lower risks of 13 cancers: esophageal adenocarcinoma (HR, 0.58; 95% CI, 0.37-0.89), liver (HR, 0.73; 95% CI, 0.55-0.98), lung (HR, 0.74; 95% CI, 0.71-0.77), kidney (HR, 0.77; 95% CI, 0.70-0.85), gastric cardia (HR, 0.78; 95% CI, 0.64-0.95), endometrial (HR, 0.79; 95% CI, 0.68-0.92), myeloid leukemia (HR, 0.80; 95% CI, 0.70-0.92), myeloma (HR, 0.83; 95% CI, 0.72-0.95), colon (HR, 0.84; 95% CI, 0.77-0.91), head and neck (HR, 0.85; 95% CI, 0.78-0.93), rectal (HR, 0.87; 95% CI, 0.80-0.95), bladder (HR, 0.87; 95% CI, 0.82-0.92), and breast (HR, 0.90; 95% CI, 0.87-0.93). Body mass index adjustment modestly attenuated associations for several cancers, but 10 of 13 inverse associations remained statistically significant after this adjustment. Leisure-time physical activity was associated with higher risks of malignant melanoma (HR, 1.27; 95% CI, 1.16-1.40) and prostate cancer (HR, 1.05; 95% CI, 1.03-1.08). Associations were generally similar between overweight/obese and normal-weight individuals. Smoking status modified the association for lung cancer but not other smoking-related cancers.

    Conclusions and Relevance: Leisure-time physical activity was associated with lower risks of many cancer types. Health care professionals counseling inactive adults should emphasize that most of these associations were evident regardless of body size or smoking history, supporting broad generalizability of findings.

  • 163. Mostafavi, Nahid
    et al.
    Vlaanderen, Jelle
    Chadeau-Hyam, Marc
    Beelen, Rob
    Modig, Lars
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Occupational and Environmental Medicine.
    Palli, Domenico
    Bergdahl, Ingvar A.
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Occupational and Environmental Medicine. Umeå University, Faculty of Medicine, Department of Biobank Research.
    Vineis, Paolo
    Hoek, Gerard
    Kyrtopoulos, Soterios A.
    Vermeulen, Roel
    Inflammatory markers in relation to long-term air pollution2015In: Environment International, ISSN 0160-4120, E-ISSN 1873-6750, Vol. 81, p. 1-7Article in journal (Refereed)
    Abstract [en]

    Long-term exposure to ambient air pollution can lead to chronic health effects such as cancer, cardiovascular and respiratory disease. Systemic inflammation has been hypothesized as a putative biological mechanism contributing to these adverse health effects. We evaluated the effect of long-term exposure to air pollution on blood markers of systemic inflammation. We measured a panel of 28 inflammatory markers in peripheral blood samples from 587 individuals that were biobanked as part of a prospective study. Participants were from Varese and Turin (Italy) and Umea (Sweden). Long-term air pollution estimates of nitrogen oxides (NOx) were available from the European Study of Cohorts for Air Pollution Effects (ESCAPE). Linear mixed models adjusted for potential confounders were applied to assess the association between NOx and the markers of inflammation. Long-term exposure to NO was associated with decreased levels of interleukin (IL)-2, IL-8, IL-10 and tumor necrosis factor-alpha in Italy, but not in Sweden. NOx exposure levels were considerably lower in Sweden than in Italy (Sweden: median (5th, 95th percentiles) 6.65 mu g/m(3) (4.8, 19.7); Italy: median (5th, 95th percentiles) 94.2 mu g/m(3) (7.8, 124.5)). Combining data from Italy and Sweden we only observed a significant association between long-term exposure to NOx and decreased levels of circulating IL-8. We observed some indication for perturbations in the inflammatory markers due to long-term exposure to NOx. Effects were stronger in Italy than in Sweden, potentially reflecting the difference in air pollution levels between the two cohorts.

  • 164. Mostafavi, Nahid
    et al.
    Vlaanderen, Jelle
    Portengen, Lutzen
    Chadeau-Hyam, Marc
    Modig, Lars
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Occupational and Environmental Medicine.
    Palli, Domenico
    Bergdahl, Ingvar A
    Umeå University, Faculty of Medicine, Department of Biobank Research. Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Occupational and Environmental Medicine.
    Brunekreef, Bert
    Vineis, Paolo
    Hebels, Dennie G A J
    Kleinjans, Jos C S
    Krogh, Vittorio
    Hoek, Gerard
    Georgiadis, Panagiotis
    Kyrtopoulos, Soterios A
    Vermeulen, Roel
    Associations between genome-wide gene expression and ambient nitrogen oxides (NOx)2017In: Epidemiology, ISSN 1044-3983, E-ISSN 1531-5487, Vol. 28, no 3, p. 320-328Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: We hypothesize that biological perturbations due to exposure to ambient air pollution are reflected in gene-expression levels in peripheral blood mononuclear cells.

    METHODS: We assessed the association between exposure to ambient air pollution and genome-wide gene-expression levels in peripheral blood mononuclear cells collected from 550 healthy subjects participating in cohorts from Italy and Sweden. Annual air pollution estimates of nitrogen oxides (NOx) at time of blood collection (1990 to 2006) were available from the ESCAPE study. In addition to univariate analysis and two variable selection methods to investigate the association between expression and exposure to NOx, we applied gene set enrichment analysis to assess overlap between our most perturbed genes and gene sets hypothesized to be related to air pollution and cigarette smoking. Finally, we assessed associations between NOx and CpG island methylation at the identified genes.

    RESULTS: Annual average NOx exposure in the Italian and Swedish cohorts was 94.2 µg/m3, and 6.7 µg/m3, respectively. Long-term exposure to NOx was associated with seven probes in the Italian cohort and one probe in the Swedish (and combined) cohorts. For genes AHCYL2 and MTMR2 changes were also seen in the methylome. Genes hypothesized to be downregulated due to cigarette smoking were enriched among the most strongly downregulated genes from our study.

    CONCLUSION: This study provides evidence of subtle changes in gene expression related to exposure to long-term NOx. On a global level the observed changes in the transcriptome may indicate similarities between air pollution and tobacco induced changes in the transcriptome.

  • 165.
    Myte, Robin
    et al.
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Gylling, Björn
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Häggström, Jenny
    Umeå University, Faculty of Social Sciences, Umeå School of Business and Economics (USBE), Statistics.
    Häggström, Christel
    Umeå University, Faculty of Medicine, Department of Biobank Research. Department of Surgical Sciences, Uppsala University, Uppsala, Sweden..
    Zingmark, Carl
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Löfgren Burström, Anna
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Palmqvist, Richard
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    van Guelpen, Bethany
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology. Umeå University, Faculty of Medicine, Wallenberg Centre for Molecular Medicine at Umeå University (WCMM).
    Metabolic factors and the risk of colorectal cancer by KRAS and BRAF mutation status2019In: International Journal of Cancer, ISSN 0020-7136, E-ISSN 1097-0215, Vol. 145, no 2, p. 327-337Article in journal (Refereed)
    Abstract [en]

    Factors related to energy metabolism and the metabolic syndrome, such as higher body mass index (BMI), blood glucose, or blood lipids, and blood pressure, are associated with an increased risk of colorectal cancer (CRC). However, CRC is a heterogeneous disease, developing through distinct pathways with differences in molecular characteristics and prognosis, and possibly also in risk factors. For subtypes defined by KRAS and BRAF mutation status, BMI is the only metabolic factor previously studied, with inconsistent findings. We investigated whether associations between BMI, blood glucose, blood lipids, and blood pressure and CRC risk differed by tumor KRAS and BRAF mutation status in 117,687 participants from two population-based cohorts within the Northern Sweden Health and Disease Study (NSHDS). Hazard ratios (HRs) for overall CRC and CRC subtypes by metabolic factors were estimated with Cox proportional hazards regression, using multiple imputation to handle missing exposure and tumor data. During a median follow-up of 15.6 years, we acquired 1,250 prospective CRC cases, of which 766 cases had complete baseline and molecular tumor data. Consistent with previous evidence, higher BMI, total cholesterol, triglyceride levels, and blood pressure were associated with an increased risk of overall CRC (HRs per 1 standard deviation increase: 1.07 to 1.12). These associations were similar regardless of CRC subtype by KRAS and BRAF mutation status (all pheterogeneity > 0.05). The same was true for subtypes based on microsatellite instability status. Poor metabolic health may therefore be a universal mechanism for colorectal cancer, acting across multiple developmental pathways.

  • 166.
    Myte, Robin
    et al.
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Gylling, Björn
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Häggström, Jenny
    Umeå University, Faculty of Social Sciences, Umeå School of Business and Economics (USBE), Statistics.
    Schneede, Jörn
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Pharmacology.
    Löfgren-Burström, Anna
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Huyghe, Jeroen R.
    Hallmans, Göran
    Umeå University, Faculty of Medicine, Department of Biobank Research. Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Nutritional Research.
    Meyer, Klaus
    Johansson, Ingegerd
    Umeå University, Faculty of Medicine, Department of Odontology.
    Ueland, Per Magne
    Palmqvist, Richard
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Van Guelpen, Bethany
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    One-carbon metabolism biomarkers and genetic variants in relation to colorectal cancer risk by KRAS and BRAF mutation status2018In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 13, no 4, article id e0196233Article in journal (Refereed)
    Abstract [en]

    Disturbances in one-carbon metabolism, intracellular reactions involved in nucleotide synthesis and methylation, likely increase the risk of colorectal cancer (CRC). However, results have been inconsistent. To explore whether this inconsistency could be explained by intertumoral heterogeneity, we evaluated a comprehensive panel of one-carbon metabolism biomarkers and some single nucleotide polymorphisms (SNPs) in relation to the risk of molecular subtypes of CRC defined by mutations in the KRAS and BRAF oncogenes. This nested case-control study included 488 CRC cases and 947 matched controls from two population-based cohorts in the Northern Sweden Health and Disease Study. We analyzed 14 biomarkers and 17 SNPs in prediagnostic blood and determined KRAS and BRAF mutation status in tumor tissue. In a multivariate network analysis, no variable displayed a strong association with the risk of specific CRC subtypes. A non-synonymous SNP in the CTH gene, rs1021737, had a stronger association compared with other variables. In subsequent univariate analyses, participants with variant rs1021737 genotype had a decreased risk of KRAS-mutated CRC (OR per allele = 0.72, 95% CI = 0.50, 1.05), and an increased risk of BRAF-mutated CRC (OR per allele = 1.56, 95% CI = 1.07, 2.30), with weak evidence for heterogeneity (Pheterogeneity = 0.01). This subtype-specific SNP association was not replicated in a case-case analysis of 533 CRC cases from The Cancer Genome Atlas (P = 0.85). In conclusion, we found no support for clear subtype-specific roles of one-carbon metabolism biomarkers and SNPs in CRC development, making differences in CRC molecular subtype distributions an unlikely explanation for the varying results on the role of one-carbon metabolism in CRC development across previous studies. Further investigation of the CTH gene in colorectal carcinogenesis with regards to KRAS and BRAF mutations or other molecular characteristics of the tumor may be warranted.

  • 167.
    Myte, Robin
    et al.
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Gylling, Björn
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Häggström, Jenny
    Umeå University, Faculty of Social Sciences, Umeå School of Business and Economics (USBE), Statistics.
    Schneede, Jörn
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Pharmacology.
    Ueland, Per Magne
    Hallmans, Göran
    Umeå University, Faculty of Medicine, Department of Biobank Research. Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Nutritional Research.
    Johansson, Ingegerd
    Umeå University, Faculty of Medicine, Department of Odontology.
    Palmqvist, Richard
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Van Guelpen, Bethany
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Untangling the role of one-carbon metabolism in colorectal cancer risk: a comprehensive Bayesian network analysis2017In: Scientific Reports, ISSN 2045-2322, E-ISSN 2045-2322, Vol. 7, article id 43434Article in journal (Refereed)
    Abstract [en]

    The role of one-carbon metabolism (1CM), particularly folate, in colorectal cancer (CRC) development has been extensively studied, but with inconclusive results. Given the complexity of 1CM, the conventional approach, investigating components individually, may be insufficient. We used a machine learning-based Bayesian network approach to study, simultaneously, 14 circulating one-carbon metabolites, 17 related single nucleotide polymorphisms (SNPs), and several environmental factors in relation to CRC risk in 613 cases and 1190 controls from the prospective Northern Sweden Health and Disease Study. The estimated networks corresponded largely to known biochemical relationships. Plasma concentrations of folate (direct), vitamin B6 (pyridoxal 5-phosphate) (inverse), and vitamin B2 (riboflavin) (inverse) had the strongest independent associations with CRC risk. Our study demonstrates the importance of incorporating B-vitamins in future studies of 1CM and CRC development, and the usefulness of Bayesian network learning for investigating complex biological systems in relation to disease.

  • 168.
    Myte, Robin
    et al.
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Gylling, Björn
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Schneede, Jörn
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Pharmacology.
    Ueland, Per Magne
    Häggström, Jenny
    Umeå University, Faculty of Social Sciences, Umeå School of Business and Economics (USBE), Statistics.
    Hultdin, Johan
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Clinical chemistry.
    Hallmans, Göran
    Umeå University, Faculty of Medicine, Department of Biobank Research. Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Nutritional Research.
    Johansson, Ingegerd
    Umeå University, Faculty of Medicine, Department of Odontology.
    Palmqvist, Richard
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Van Guelpen, Bethany
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Components of One-carbon Metabolism Other than Folate and Colorectal Cancer Risk2016In: Epidemiology, ISSN 1044-3983, E-ISSN 1531-5487, Vol. 27, no 6, p. 787-796Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: Despite extensive study, the role of folate in colorectal cancer remains unclear. Research has therefore begun to address the role of other elements of the folate-methionine metabolic cycles. This study investigated factors other than folate involved in one-carbon metabolism, i.e., choline, betaine, dimethylglycine, sarcosine, and methionine and relevant polymorphisms, in relation to the risk of colorectal cancer in a population with low intakes and circulating levels of folate.

    METHODS: This was a prospective case-control study of 613 case subjects and 1,190 matched control subjects nested within the population-based Northern Sweden Health and Disease Study. We estimated odds ratios (OR) by conditional logistic regression, and marginal risk differences with weighted maximum likelihood estimation using incidence data from the study cohort.

    RESULTS: Higher plasma concentrations of methionine and betaine were associated with modest colorectal cancer risk reductions (OR [95% confidence interval {CI}] for highest versus lowest tertile: 0.76 [0.57, 0.99] and 0.72 [0.55, 0.94], respectively). Estimated marginal risk differences corresponded to approximately 200 fewer colorectal cancer cases per 100,000 individuals on average. We observed no clear associations between choline, dimethylglycine, or sarcosine and colorectal cancer risk. The inverse association of methionine was modified by plasma folate concentrations (OR [95% CI] for highest/lowest versus lowest/lowest tertile of plasma methionine/folate concentrations 0.39 [0.24, 0.64], Pinteraction = 0.06).

    CONCLUSIONS: In this population-based, nested case-control study with a long follow-up time from baseline to diagnosis (median: 8.2 years), higher plasma concentrations of methionine and betaine were associated with lower colorectal cancer risk. See Video Abstract at http://links.lww.com/EDE/B83.

  • 169. Nead, Kevin T.
    et al.
    Li, Aihua
    Wehner, Mackenzie R.
    Neupane, Binod
    Gustafsson, Stefan
    Butterworth, Adam
    Engert, James C.
    Davis, A. Darlene
    Hegele, Robert A.
    Miller, Ruby
    den Hoed, Marcel
    Khaw, Kay-Tee
    Kilpelaeinen, Tuomas O.
    Wareham, Nick
    Edwards, Todd L.
    Hallmans, Goeran
    Umeå University, Faculty of Medicine, Department of Biobank Research. Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Nutritional Research.
    Varga, Tibor V.
    Kardia, Sharon L. R.
    Smith, Jennifer A.
    Zhao, Wei
    Faul, Jessica D.
    Weir, David
    Mi, Jie
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine.
    Xi, Bo
    Quinteros, Samuel Canizales
    Cooper, Cyrus
    Sayer, Avan Aihie
    Jameson, Karen
    Grontved, Anders
    Fornage, Myriam
    Sidney, Stephen
    Hanis, Craig L.
    Highland, Heather M.
    Haering, Hans-Ulrich
    Heni, Martin
    Lasky-Su, Jessica
    Weiss, Scott T.
    Gerhard, Glenn S.
    Still, Christopher
    Melka, Melkaey M.
    Pausova, Zdenka
    Paus, Tomas
    Grant, Struan F. A.
    Hakonarson, Hakon
    Price, R. Arlen
    Wang, Kai
    Scherag, Andre
    Hebebrand, Johannes
    Hinney, Anke
    Franks, Paul W.
    Frayling, Timothy M.
    McCarthy, Mark I.
    Hirschhorn, Joel N.
    Loos, Ruth J.
    Ingelsson, Erik
    Gerstein, Hertzel C.
    Yusuf, Salim
    Beyene, Joseph
    Anand, Sonia S.
    Meyre, David
    Contribution of common non-synonymous variants in PCSK1 to body mass index variation and risk of obesity: a systematic review and meta-analysis with evidence from up to 331 175 individuals2015In: Human Molecular Genetics, ISSN 0964-6906, E-ISSN 1460-2083, Vol. 24, no 12, p. 3582-3594Article in journal (Refereed)
    Abstract [en]

    Polymorphisms rs6232 and rs6234/rs6235 in PCSK1 have been associated with extreme obesity [e.g. body mass index (BMI) a parts per thousand yen 40 kg/m(2)], but their contribution to common obesity (BMI a parts per thousand yen 30 kg/m(2)) and BMI variation in a multi-ethnic context is unclear. To fill this gap, we collected phenotypic and genetic data in up to 331 175 individuals from diverse ethnic groups. This process involved a systematic review of the literature in PubMed, Web of Science, Embase and the NIH GWAS catalog complemented by data extraction from pre-existing GWAS or custom-arrays in consortia and single studies. We employed recently developed global meta-analytic random-effects methods to calculate summary odds ratios (OR) and 95% confidence intervals (CIs) or beta estimates and standard errors (SE) for the obesity status and BMI analyses, respectively. Significant associations were found with binary obesity status for rs6232 (OR = 1.15, 95% CI 1.06-1.24, P = 6.08 x 10(-6)) and rs6234/rs6235 (OR = 1.07, 95% CI 1.04-1.10, P = 3.00 x 10(-7)). Similarly, significant associations were found with continuous BMI for rs6232 (beta = 0.03, 95% CI 0.00-0.07; P = 0.047) and rs6234/rs6235 (beta = 0.02, 95% CI 0.00-0.03; P = 5.57 x 10(-4)). Ethnicity, age and study ascertainment significantly modulated the association of PCSK1 polymorphisms with obesity. In summary, we demonstrate evidence that common gene variation in PCSK1 contributes to BMI variation and susceptibility to common obesity in the largest known meta-analysis published to date in genetic epidemiology.

  • 170. Nelson, C. P.
    et al.
    Hamby, S. E.
    Saleheen, D.
    Hopewell, J. C.
    Zeng, L.
    Assimes, T. L.
    Kanoni, S.
    Willenborg, C.
    Burgess, S.
    Amouyel, P.
    Anand, S.
    Blankenberg, S.
    Boehm, B. O.
    Clarke, R. J.
    Collins, R.
    Dedoussis, G.
    Farrall, M.
    Franks, Paul W.
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine. Department of Clinical Sciences, Lund University Diabetes Center, Skåne University Hospital; Department of Nutrition, Harvard School of Public Health, USA.
    Groop, L.
    Hall, A. S.
    Hamsten, A.
    Hengstenberg, C.
    Hovingh, G. Kees
    Ingelsson, E.
    Kathiresan, S.
    Kee, F.
    Koenig, I. R.
    Kooner, J.
    Lehtimaeki, T.
    Maerz, W.
    McPherson, R.
    Metspalu, A.
    Nieminen, M. S.
    O'Donnell, C. J.
    Palmer, C. N. A.
    Peters, A.
    Perola, M.
    Reilly, M. P.
    Ripatti, S.
    Roberts, R.
    Salomaa, V.
    Shah, S. H.
    Schreiber, S.
    Siegbahn, A.
    Thorsteinsdottir, U.
    Veronesi, G.
    Wareham, N.
    Willer, C. J.
    Zalloua, P. A.
    Erdmann, J.
    Deloukas, P.
    Watkins, H.
    Schunkert, H.
    Danesh, J.
    Thompson, J. R.
    Samani, N. J.
    Hallmans, Göran
    Umeå University, Faculty of Medicine, Department of Biobank Research. Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Nutritional Research.
    Genetically Determined Height and Coronary Artery Disease2015In: New England Journal of Medicine, ISSN 0028-4793, E-ISSN 1533-4406, Vol. 372, no 17, p. 1608-1618Article in journal (Refereed)
    Abstract [en]

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

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

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

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

  • 171. Nettleton, Jennifer A
    et al.
    Follis, Jack L
    Ngwa, Julius S
    Smith, Caren E
    Ahmad, Shafqat
    Tanaka, Toshiko
    Wojczynski, Mary K
    Voortman, Trudy
    Lemaitre, Rozenn N
    Kristiansson, Kati
    Nuotio, Marja-Liisa
    Houston, Denise K
    Perälä, Mia-Maria
    Qi, Qibin
    Sonestedt, Emily
    Manichaikul, Ani
    Kanoni, Stavroula
    Ganna, Andrea
    Mikkilä, Vera
    North, Kari E
    Siscovick, David S
    Harald, Kennet
    Mckeown, Nicola M
    Johansson, Ingegerd
    Umeå University, Faculty of Medicine, Department of Odontology. Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Nutritional Research.
    Rissanen, Harri
    Liu, Yongmei
    Lahti, Jari
    Hu, Frank B
    Bandinelli, Stefania
    Rukh, Gull
    Rich, Stephen
    Booij, Lisanne
    Dmitriou, Maria
    Ax, Erika
    Raitakari, Olli
    Mukamal, Kenneth
    Männistö, Satu
    Hallmans, Göran
    Umeå University, Faculty of Medicine, Department of Biobank Research. Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Nutritional Research.
    Jula, Antti
    Ericson, Ulrika
    Jacobs, David R, Jr
    Van Rooij, Frank J A
    Deloukas, Panos
    Sjögren, Per
    Kähönen, Mika
    Djousse, Luc
    Perola, Markus
    Barroso, Inês
    Hofman, Albert
    Stirrups, Kathleen
    Viikari, Jorma
    Uitterlinden, André G
    Kalafati, Ioanna P
    Franco, Oscar H.
    Mozaffarian, Dariush
    Salomaa, Veikko
    Borecki, Ingrid B
    Knekt, Paul
    Kritchevsky, Stephen B
    Eriksson, Johan G
    Dedoussis, George V
    Qi, Lu
    Ferrucci, Luigi
    Orho-Melander, Marju
    Zillikens, M Carola
    Ingelsson, Erik
    Lehtimäki, Terho
    Renström, Frida
    Umeå University, Faculty of Medicine, Department of Biobank Research. Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Nutritional Research. Department of Clinical Sciences, Genetic and Molecular Epidemiology Unit, Lund University, Sweden.
    Cupples, L Adrienne
    Loos, Ruth J F
    Franks, Paul W
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine. Department of Clinical Sciences, Genetic and Molecular Epidemiology Unit, Lund University, Sweden; Department of Nutrition, Harvard Chan School of Public Health, Boston, MA, USA.
    Gene x dietary pattern interactions in obesity: analysis of up to 68 317 adults of European ancestry2015In: Human Molecular Genetics, ISSN 0964-6906, E-ISSN 1460-2083, Vol. 24, no 16, p. 4728-4738Article in journal (Refereed)
    Abstract [en]

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

  • 172.
    Nilsson, Lena Maria
    et al.
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Nutritional Research.
    Winkvist, A
    Clinical Nutrition, University of Gothenburg.
    Hallmans, Göran
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Nutritional Research. Umeå University, Faculty of Medicine, Department of Biobank Research.
    Johansson, Ingegerd
    Umeå University, Faculty of Medicine, Department of Odontology.
    Lindahl, Bernt
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Occupational and Environmental Medicine.
    Lenner, Per
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Van Guelpen, Bethany
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Low-carbohydrate, high-protein score and cancer incidence and mortality in a northern swedish population2011In: Abstract Book: 2011 European Multidisciplinary Cancer Congress, Oxford: Elsevier, 2011, Vol. 47, p. S249-S249Conference paper (Refereed)
  • 173.
    Nilsson, Lena Maria
    et al.
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Nutritional Research. Umeå University, Faculty of Medicine, Department of Biobank Research.
    Winkvist, Anna
    Göteborgs universitet.
    Eliasson, Mats
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine.
    Jansson, Jan-Håkan
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine.
    Hallmans, Göran
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Nutritional Research. Umeå University, Faculty of Medicine, Department of Biobank Research.
    Johansson, Ingegerd
    Umeå University, Faculty of Medicine, Department of Odontology, Cariology.
    Lindahl, Bernt
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Occupational and Environmental Medicine.
    Lenner, Per
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Van Guelpen, Bethany
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Low-carbohydrate, high-protein score and mortality in a northern Swedish population2012In: European Journal of Clinical Nutrition, ISSN 0954-3007, E-ISSN 1476-5640, Vol. 66, no 6, p. 694-700Article in journal (Refereed)
    Abstract [en]

    BACKGROUND/OBJECTIVE: Long-term effects of carbohydrate-restricted diets are unclear. We examined a low-carbohydrate, high-protein (LCHP) score in relation to mortality.

    SUBJECTS/METHODS: This is a population-based cohort study on adults in the northern Swedish county of Vasterbotten. In 37 639 men (1460 deaths) and 39 680 women (923 deaths) from the population-based Vasterbotten Intervention Program, deciles of energy-adjusted carbohydrate (descending) and protein (ascending) intake were added to create an LCHP score (2-20 points). Sex-specific hazard ratios (HR) were calculated by Cox regression.

    RESULTS: Median intakes of carbohydrates, protein and fat in subjects with LCHP scores 2-20 ranged from 61.0% to 38.6%, 11.3% to 19.2% and 26.6% to 41.5% of total energy intake, respectively. High LCHP score (14-20 points) did not predict all-cause mortality compared with low LCHP score (2-8 points), after accounting for saturated fat intake and established risk factors (men: HR for high vs low 1.03 (95% confidence interval (CI) 0.88-1.20), P for continuous 0.721; women: HR for high vs low 1.10 (95% CI 0.91-1.32), P for continuous 0.229). For cancer and cardiovascular disease, no clear associations were found. Carbohydrate intake was inversely associated with all-cause mortality, though only statistically significant in women (multivariate HR per decile increase 0.95 (95% CI 0.91-0.99), P = 0.010).

    CONCLUSION: Our results do not support a clear, general association between LCHP score and mortality. Studies encompassing a wider range of macronutrient consumption may be necessary to detect such an association.

  • 174.
    Nilsson, Lena Maria
    et al.
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Nutritional Research. Umeå University, Arctic Research Centre at Umeå University.
    Winkvist, Anna
    Univ Gothenburg, Sahlgrenska Acad, Dept Internal Med & Clin Nutr, SE-40530 Gothenburg, Sweden.
    Johansson, Ingegerd
    Umeå University, Faculty of Medicine, Department of Odontology, Cariology.
    Lindahl, Bernt
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Occupational and Environmental Medicine. Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Nutritional Research.
    Hallmans, Göran
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Nutritional Research. Umeå University, Faculty of Medicine, Department of Biobank Research.
    Lenner, Per
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Van Guelpen, Bethany
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Low-carbohydrate, high-protein diet score and risk of incident cancer: a prospective cohort study2013In: Nutrition Journal, ISSN 1475-2891, E-ISSN 1475-2891, Vol. 12, p. 58-Article in journal (Refereed)
    Abstract [en]

    Background: Although carbohydrate reduction of varying degrees is a popular and controversial dietary trend, potential long-term effects for health, and cancer in specific, are largely unknown. Methods: We studied a previously established low-carbohydrate, high-protein (LCHP) score in relation to the incidence of cancer and specific cancer types in a population-based cohort in northern Sweden. Participants were 62,582 men and women with up to 17.8 years of follow-up (median 9.7), including 3,059 prospective cancer cases. Cox regression analyses were performed for a LCHP score based on the sum of energy-adjusted deciles of carbohydrate (descending) and protein (ascending) intake labeled 1 to 10, with higher scores representing a diet lower in carbohydrates and higher in protein. Important potential confounders were accounted for, and the role of metabolic risk profile, macronutrient quality including saturated fat intake, and adequacy of energy intake reporting was explored. Results: For the lowest to highest LCHP scores, 2 to 20, carbohydrate intakes ranged from median 60.9 to 38.9% of total energy intake. Both protein (primarily animal sources) and particularly fat (both saturated and unsaturated) intakes increased with increasing LCHP scores. LCHP score was not related to cancer risk, except for a non-dose-dependent, positive association for respiratory tract cancer that was statistically significant in men. The multivariate hazard ratio for medium (9-13) versus low (2-8) LCHP scores was 1.84 (95% confidence interval: 1.05-3.23; p-trend = 0.38). Other analyses were largely consistent with the main results, although LCHP score was associated with colorectal cancer risk inversely in women with high saturated fat intakes, and positively in men with higher LCHP scores based on vegetable protein. Conclusion: These largely null results provide important information concerning the long-term safety of moderate carbohydrate reduction and consequent increases in protein and, in this cohort, especially fat intakes. In order to determine the effects of stricter carbohydrate restriction, further studies encompassing a wider range of macronutrient intakes are warranted.

  • 175.
    Nilsson Sommar, Johan
    et al.
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Occupational and Environmental Medicine.
    Pettersson-Kymmer, Ulrika
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine. Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Pharmacology.
    Lundh, Thomas
    Svensson, Olle
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Orthopaedics.
    Hallmans, Göran
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Nutritional Research. Umeå University, Faculty of Medicine, Department of Biobank Research.
    Bergdahl, Ingvar A.
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Occupational and Environmental Medicine. Umeå University, Faculty of Medicine, Department of Biobank Research.
    Hip Fracture Risk and Cadmium in Erythrocytes: A Nested Case-Control Study with Prospectively Collected Samples2014In: Calcified Tissue International, ISSN 0171-967X, E-ISSN 1432-0827, Vol. 94, no 2, p. 183-190Article in journal (Refereed)
    Abstract [en]

    Several studies have investigated the relation between bone mass density and cadmium exposure, but only few studies have been performed on fractures and biomarkers of cadmium. This study analyzed the association between hip fracture risk and cadmium in erythrocytes (Ery-Cd). Prospective samples from the Northern Sweden Health and Disease Study's biobank were used for 109 individuals who later in life had sustained a low-trauma hip fracture, matched with two controls of the same age and gender. The mean concentration of Ery-Cd (±SD) in case samples was 1.3 ± 1.4 versus 0.9 ± 1.0 μg/L in controls. The odds ratio (OR) was 1.63 [95 % confidence interval (CI) 1.10-2.42] for suffering a hip fracture for each microgram per liter increase in Ery-Cd. However, when taking smoking into consideration (never, former, or current), neither Ery-Cd nor smoking showed a statistically significant increase in fracture risk. Using multiple conditional logistic regression with BMI, height, and smoking, the estimated OR for a 1-μg/L increase in Ery-Cd was 1.52 (95 % CI 0.77-2.97). Subgroup analysis showed an increased fracture risk among women (OR = 1.94, 95 % CI 1.18-3.20, for a 1 μg/L increase), which also remained in the multiple analysis (OR = 3.33, 95 % CI 1.29-8.56). This study shows that fracture risk is associated with Ery-Cd. It is, however, not possible to draw firm conclusions on whether cadmium is the causal factor or whether other smoking-related factors cause this association. Subgroup analysis shows that cadmium is a risk factor for hip fracture among women.

  • 176.
    Nilsson Sommar, Johan
    et al.
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Occupational and Environmental Medicine.
    Svensson, Maria K
    Department of Molecular and Clinical Medicine-Nephrology, Institute of Medicine, Sahlgrenska Academy at University of Gothenburg, Gothenburg, Sweden.
    Björ, Bodil
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Occupational and Environmental Medicine.
    Elmståhl, Sölve
    Department of Health Sciences, Division of Geriatric Medicine, Lund University, Lund, Sweden.
    Hallmans, Göran
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Nutritional Research. Umeå University, Faculty of Medicine, Department of Biobank Research.
    Lundh, Thomas
    Division of Occupational and Environmental Medicine, University Hospital, Lund, Sweden.
    Schön, Staffan Mi
    Diaverum Renal Services Group, Lund, Sweden & Swedish Renal Registry, Jönköping, Sweden.
    Skerfving, Staffan
    Division of Occupational and Environmental Medicine, University Hospital, Lund, Sweden.
    Bergdahl, Ingvar
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Occupational and Environmental Medicine.
    End-stage renal disease and low level exposure to lead, cadmium and mercury: a population-based, prospective nested case-referent study in Sweden2013In: Environmental health, ISSN 1476-069X, E-ISSN 1476-069X, Vol. 12, no 9Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: Cadmium (Cd), lead (Pb), and mercury (Hg) cause toxicological renal effects, but the clinical relevance at low-level exposures in general populations is unclear. The objective of this study is to assess the risk of developing end-stage renal disease in relation to Cd, Pb, and Hg exposure.

    METHODS: A total of 118 cases who later in life developed end-stage renal disease, and 378 matched (sex, age, area, and time of blood sampling) referents were identified among participants in two population-based prospective cohorts (130,000 individuals). Cd, Pb, and Hg concentrations were determined in prospectively collected samples.

    RESULTS: Erythrocyte lead was associated with an increased risk of developing end-stage renal disease (mean in cases 76 μg/L; odds ratio (OR) 1.54 for an interquartile range increase, 95% confidence interval (CI) 1.18-2.00), while erythrocyte mercury was negatively associated (2.4 μg/L; OR 0.75 for an interquartile range increase, CI 0.56-0.99). For erythrocyte cadmium, the OR of developing end-stage renal disease was 1.15 for an interquartile range increase (CI 0.99-1.34; mean Ery-Cd among cases: 1.3 μg/L). The associations for erythrocyte lead and erythrocyte mercury, but not for erythrocyte cadmium, remained after adjusting for the other two metals, smoking, BMI, diabetes, and hypertension. Gender-specific analyses showed that men carried almost all of the erythrocyte lead and erythrocyte cadmium associated risks.

    CONCLUSIONS: Erythrocyte lead is associated with end-stage renal disease but further studies are needed to evaluate causality. Gender-specific analyses suggest potential differences in susceptibility or in exposure biomarker reliability.

  • 177. Nitter, M.
    et al.
    Norgard, B.
    de Vogel, S.
    Eussen, S. J. P. M.
    Meyer, K.
    Ulvik, A.
    Ueland, P. M.
    Nygard, O.
    Vollset, S. E.
    Bjorge, T.
    Tjonneland, A.
    Hansen, L.
    Boutron-Ruault, M.
    Racine, A.
    Cottet, V.
    Kaaks, R.
    Kuehn, T.
    Trichopoulou, A.
    Bamia, C.
    Naska, A.
    Grioni, S.
    Palli, D.
    Panico, S.
    Tumino, R.
    Vineis, P.
    Bueno-de-Mesquita, H. B.
    van Kranen, H.
    Peeters, P. H.
    Weiderpass, E.
    Dorronsoro, M.
    Jakszyn, P.
    Sanchez, M.
    Argueelles, M.
    Huerta, J. M.
    Barricarte, A.
    Johansson, Mattias
    Umeå University, Faculty of Medicine, Department of Biobank Research.
    Ljuslinder, Inger
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Khaw, K.
    Wareham, N.
    Freisling, H.
    Duarte-Salles, T.
    Stepien, M.
    Gunter, M. J.
    Riboli, E.
    Plasma methionine, choline, betaine, and dimethylglycine in relation to colorectal cancer risk in the European Prospective Investigation into Cancer and Nutrition (EPIC)2014In: Annals of Oncology, ISSN 0923-7534, E-ISSN 1569-8041, Vol. 25, no 8, p. 1609-1615Article in journal (Refereed)
    Abstract [en]

    Background: Disturbances in one carbon metabolism may contribute to carcinogenesis by affecting methylation and synthesis of DNA. Choline and its oxidation product betaine are involved in this metabolism and can serve as alternative methyl group donors when folate status is low. Patients and methods: We conducted a case-control study nested within the European Prospective Investigation into Cancer and Nutrition (EPIC), to investigate plasma concentrations of the methyl donors methionine, choline, betaine (trimethylglycine), and dimethylglycine (DMG) in relation to colorectal cancer (CRC) risk. Our study included 1367 incident CRC cases (965 colon and 402 rectum) and 2323 controls matched by gender, age group, and study center. Multivariate-adjusted odds ratios (ORs) and 95% confidence intervals (95% CIs) for CRC risk were estimated by conditional logistic regression, comparing the fifth to the first quintile of plasma concentrations. Results: Overall, methionine (OR: 0.79, 95% CI: 0.63-0.99, P-trend = 0.05), choline (OR: 0.77, 95% CI: 0.60-0.99, P-trend = 0.07), and betaine (OR: 0.85, 95% CI: 0.66-1.09, P-trend = 0.06) concentrations were inversely associated with CRC risk of borderline significance. In participants with folate concentration below the median of 11.3 nmol/l, high betaine concentration was associated with reduced CRC risk (OR: 0.71, 95% CI: 0.50-1.00, P-trend = 0.02), which was not observed for those having a higher folate status. Among women, but not men, high choline concentration was associated with decreased CRC risk (OR: 0.62, 95% CI: 0.43-0.88, P-trend = 0.01). Plasma DMG was not associated with CRC risk. Conclusions: Individuals with high plasma concentrations of methionine, choline, and betaine may be at reduced risk of CRC.

  • 178. Nyholm, Maria
    et al.
    Lissner, Lauren
    Hörnell, Agneta
    Umeå University, Faculty of Social Sciences, Department of Food and Nutrition.
    Johansson, Ingegerd
    Umeå University, Faculty of Medicine, Department of Odontology, School of Dentistry.
    Hallmans, Göran
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Nutritional Research. Umeå University, Faculty of Medicine, Department of Biobank Research.
    Weinehall, Lars
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Epidemiology and Global Health.
    Winkvist, Anna
    Exploring dietary patterns, obesity and sources of bias: the Västerbotten Intervention Programme (VIP)2013In: Public Health Nutrition, ISSN 1368-9800, E-ISSN 1475-2727, Vol. 16, no 4, p. 631-638Article in journal (Refereed)
    Abstract [en]

    Objective: Dietary patterns capture the overall diet and thereby provide information on how nutrients are consumed in combinations, and have been suggested to be a better method than studying single nutrients. The present study explored the relationship between dietary patterns at baseline and incidence of obesity at 10-year follow-up in women.

    Design: A longitudinal study using baseline measurements from 1992-1996, including food intake, medication, heredity, socio-economic status, lifestyle and measured body composition, and follow-up data collected in 2002-2006 including measured body composition.

    Setting: Data from the Västerbotten Intervention Programme (VIP) in Sweden.

    Subjects: A total of 6545 initially non-obese women aged 30-50 years.

    Results: Among women reporting plausible energy intakes, the 'Fruit and vegetables cluster' predicted the highest incidence of obesity (OR = 1·76, 95 % CI 1·11, 2·76; P = 0·015) compared with women in the other food pattern groups combined. When adjusting for metabolic factors and BMI at baseline, the risk for obesity in the 'Fruit and vegetables cluster' was attenuated to non-significance. In contrast, high intake of fruit per se was associated with a decreased risk of developing obesity (OR = 0·69, 95 % CI 0·51, 0·91; P = 0·010).

    Conclusions: Dietary pattern groups identified by cluster analysis are likely to reflect characteristics in addition to diet, including lifestyle, previous and current health status and risk factors for future disease, whereas intake of fruit per se was a stable indicator and less affected by baseline characteristics. These results underscore the need for complementary methods in understanding diet-disease relationships.

  • 179. Obón-Santacana, M.
    et al.
    Slimani, N.
    Lujan-Barroso, L.
    Travier, N.
    Hallmans, Göran
    Umeå University, Faculty of Medicine, Department of Biobank Research. Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Nutritional Research.
    Freisling, H.
    Ferrari, P.
    Boutron-Ruault, M. C.
    Racine, A.
    Clavel, F.
    Saieva, C.
    Pala, V.
    Tumino, R.
    Mattiello, A.
    Vineis, P.
    Argüelles, M.
    Ardanaz, E.
    Amiano, P.
    Navarro, C.
    Sánchez, M. J.
    Molina Montes, E.
    Key, T.
    Khaw, K.-T.
    Wareham, N.
    Peeters, P. H.
    Trichopoulou, A.
    Bamia, C.
    Trichopoulos, D.
    Boeing, H..
    Kaaks, R
    Katzke, V.
    Ye, W.
    Umeå University, Faculty of Medicine, Department of Biobank Research.
    Sund, Malin
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Surgery.
    Ericson, U.
    Wirfält, E..
    Overvad, K.
    Tjønneland, A.
    Olsen, A.
    Skeie, G.
    Asli, L. A.
    Weiderpass, E.
    Riboli, E.
    Bueno-de-Mesquita, H. B.
    Duell, EJ
    Dietary intake of acrylamide and pancreatic cancer risk in the European Prospective Investigation into Cancer and Nutrition (EPIC) cohort2013In: Annals of Oncology, ISSN 0923-7534, E-ISSN 1569-8041, Vol. 24, no 10, p. 2645-2651Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: In 1994, acrylamide (AA) was classified as a probable human carcinogen by the International Agency for Research on Cancer. In 2002, AA was discovered at relatively high concentrations in some starchy, plant-based foods cooked at high temperatures.

    PATIENTS AND METHODS: A prospective analysis was conducted to evaluate the association between the dietary intake of AA and ductal adenocarcinoma of the exocrine pancreatic cancer (PC) risk in the European Prospective Investigation into Cancer and Nutrition (EPIC) cohort using Cox regression modeling. EPIC includes >500 000 men and women aged 35-75 at enrollment from 10 European countries. AA intake was estimated for each participant by combining questionnaire-based food consumption data with a harmonized AA database derived from the EU monitoring database of AA levels in foods, and evaluated in quintiles and continuously.

    RESULTS: After a mean follow-up of 11 years, 865 first incident adenocarcinomas of the exocrine pancreas were observed and included in the present analysis. At baseline, the mean dietary AA intake in EPIC was 26.22 µg/day. No overall association was found between continuous or quintiles of dietary AA intake and PC risk in EPIC (HR:0.95, 95%CI:0.89-1.01 per 10 µg/day). There was no effect measure modification by smoking status, sex, diabetes, alcohol intake or geographic region. However, there was an inverse association (HR: 0.73, 95% CI: 0.61-0.88 per 10 µg/day) between AA intake and PC risk in obese persons as defined using the body mass index (BMI, ≥30 kg/m(2)), but not when body fatness was defined using waist and hip circumference or their ratio.

    CONCLUSIONS: Dietary intake of AA was not associated with an increased risk of PC in the EPIC cohort.

  • 180. Obón-Santacana, Mireia
    et al.
    Lujan-Barroso, Leila
    Freisling, Heinz
    Cadeau, Claire
    Fagherazzi, Guy
    Boutron-Ruault, Marie-Christine
    Kaaks, Rudolf
    Fortner, Renée T
    Boeing, Heiner
    Ramón Quirós, J
    Molina-Montes, Esther
    Chamosa, Saioa
    Castaño, José María Huerta
    Ardanaz, Eva
    Khaw, Kay-Tee
    Wareham, Nick
    Key, Tim
    Trichopoulou, Antonia
    Lagiou, Pagona
    Naska, Androniki
    Palli, Domenico
    Grioni, Sara
    Tumino, Rosario
    Vineis, Paolo
    De Magistris, Maria Santucci
    Bueno-de-Mesquita, H B
    Peeters, Petra H
    Wennberg, Maria
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Nutritional Research.
    Bergdahl, Ingvar A
    Umeå University, Faculty of Medicine, Department of Biobank Research.
    Vesper, Hubert
    Riboli, Elio
    Duell, Eric J
    Dietary and lifestyle determinants of acrylamide and glycidamide hemoglobin adducts in non-smoking postmenopausal women from the EPIC cohort2017In: European Journal of Nutrition, ISSN 1436-6207, E-ISSN 1436-6215, Vol. 56, no 3, p. 1157-1168Article in journal (Refereed)
    Abstract [en]

    PURPOSE: Acrylamide was classified as 'probably carcinogenic' to humans in 1994 by the International Agency for Research on Cancer. In 2002, public health concern increased when acrylamide was identified in starchy, plant-based foods, processed at high temperatures. The purpose of this study was to identify which food groups and lifestyle variables were determinants of hemoglobin adduct concentrations of acrylamide (HbAA) and glycidamide (HbGA) in 801 non-smoking postmenopausal women from eight countries in the European Prospective Investigation into Cancer and Nutrition (EPIC) cohort.

    METHODS: Biomarkers of internal exposure were measured in red blood cells (collected at baseline) by high-performance liquid chromatography/tandem mass spectrometry (HPLC/MS/MS) . In this cross-sectional analysis, four dependent variables were evaluated: HbAA, HbGA, sum of total adducts (HbAA + HbGA), and their ratio (HbGA/HbAA). Simple and multiple regression analyses were used to identify determinants of the four outcome variables. All dependent variables (except HbGA/HbAA) and all independent variables were log-transformed (log2) to improve normality. Median (25th-75th percentile) HbAA and HbGA adduct levels were 41.3 (32.8-53.1) pmol/g Hb and 34.2 (25.4-46.9) pmol/g Hb, respectively.

    RESULTS: The main food group determinants of HbAA, HbGA, and HbAA + HbGA were biscuits, crackers, and dry cakes. Alcohol intake and body mass index were identified as the principal determinants of HbGA/HbAA. The total percent variation in HbAA, HbGA, HbAA + HbGA, and HbGA/HbAA explained in this study was 30, 26, 29, and 13 %, respectively.

    CONCLUSIONS: Dietary and lifestyle factors explain a moderate proportion of acrylamide adduct variation in non-smoking postmenopausal women from the EPIC cohort.

  • 181. Oei, Ling
    et al.
    Hsu, Yi-Hsiang
    Styrkarsdottir, Unnur
    Eussen, Bert H
    de Klein, Annelies
    Peters, Marjolein J
    Halldorsson, Bjarni
    Liu, Ching-Ti
    Alonso, Nerea
    Kaptoge, Stephen K
    Thorleifsson, Gudmar
    Hallmans, Göran
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Nutritional Research. Umeå University, Faculty of Medicine, Department of Biobank Research.
    Hocking, Lynne J
    Husted, Lise Bjerre
    Jameson, Karen A
    Kruk, Marcin
    Lewis, Joshua R
    Patel, Millan S
    Scollen, Serena
    Svensson, Olle
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Orthopaedics.
    Trompet, Stella
    van Schoor, Natasja M
    Zhu, Kun
    Buckley, Brendan M
    Cooper, Cyrus
    Ford, Ian
    Goltzman, David
    González-Macías, Jesús
    Langdahl, Bente Lomholt
    Leslie, William D
    Lips, Paul
    Lorenc, Roman S
    Olmos, José M
    Pettersson-Kymmer, Ulrika
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Clinical Pharmacology. Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine.
    Reid, David M
    Riancho, José A
    Slagboom, P Eline
    Garcia-Ibarbia, Carmen
    Ingvarsson, Thorvaldur
    Johannsdottir, Hrefna
    Luben, Robert
    Medina-Gómez, Carolina
    Arp, Pascal
    Nandakumar, Kannabiran
    Palsson, Stefan Th
    Sigurdsson, Gunnar
    van Meurs, Joyce B J
    Zhou, Yanhua
    Hofman, Albert
    Jukema, J Wouter
    Pols, Huibert A P
    Prince, Richard L
    Cupples, L Adrienne
    Marshall, Christian R
    Pinto, Dalila
    Sato, Daisuke
    Scherer, Stephen W
    Reeve, Jonathan
    Thorsteinsdottir, Unnur
    Karasik, David
    Richards, J Brent
    Stefansson, Kari
    Uitterlinden, André G
    Ralston, Stuart H
    Ioannidis, John P A
    Kiel, Douglas P
    Rivadeneira, Fernando
    Estrada, Karol
    A genome-wide copy number association study of osteoporotic fractures points to the 6p25.1 locus2014In: Journal of Medical Genetics, ISSN 0022-2593, E-ISSN 1468-6244, Vol. 51, no 2, p. 122-131Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: Osteoporosis is a systemic skeletal disease characterised by reduced bone mineral density and increased susceptibility to fracture; these traits are highly heritable. Both common and rare copy number variants (CNVs) potentially affect the function of genes and may influence disease risk.

    AIM: To identify CNVs associated with osteoporotic bone fracture risk.

    METHOD: We performed a genome-wide CNV association study in 5178 individuals from a prospective cohort in the Netherlands, including 809 osteoporotic fracture cases, and performed in silico lookups and de novo genotyping to replicate in several independent studies.

    RESULTS: A rare (population prevalence 0.14%, 95% CI 0.03% to 0.24%) 210 kb deletion located on chromosome 6p25.1 was associated with the risk of fracture (OR 32.58, 95% CI 3.95 to 1488.89; p=8.69×10(-5)). We performed an in silico meta-analysis in four studies with CNV microarray data and the association with fracture risk was replicated (OR 3.11, 95% CI 1.01 to 8.22; p=0.02). The prevalence of this deletion showed geographic diversity, being absent in additional samples from Australia, Canada, Poland, Iceland, Denmark, and Sweden, but present in the Netherlands (0.34%), Spain (0.33%), USA (0.23%), England (0.15%), Scotland (0.10%), and Ireland (0.06%), with insufficient evidence for association with fracture risk.

    CONCLUSIONS: These results suggest that deletions in the 6p25.1 locus may predispose to higher risk of fracture in a subset of populations of European origin; larger and geographically restricted studies will be needed to confirm this regional association. This is a first step towards the evaluation of the role of rare CNVs in osteoporosis.

  • 182. Ose, Jennifer
    et al.
    Fortner, Renée T.
    Rinaldi, Sabina
    Schock, Helena
    Overvad, Kim
    Tjonneland, Anne
    Hansen, Louise
    Dossus, Laure
    Fournier, Agnes
    Baglietto, Laura
    Romieu, Isabelle
    Kuhn, Elisabetta
    Boeing, Heiner
    Trichopoulou, Antonia
    Lagiou, Pagona
    Trichopoulos, Dimitrios
    Palli, Domenico
    Masala, Giovanna
    Sieri, Sabina
    Tumino, Rosario
    Sacerdote, Carlotta
    Mattiello, Amalia
    Ramon Quiros, Jose
    Obón-Santacana, Mireia
    Larrañaga, Nerea
    Chirlaque, María-Dolores
    Sánchez, María-José
    Barricarte, Aurelio
    Peeters, Petra H.
    Bueno-de-Mesquita, H. B(as)
    Onland-Moret, N. Charlotte
    Brändstedt, Jenny
    Lundin, Eva
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology. Umeå University, Faculty of Medicine, Department of Biobank Research.
    Idahl, Annika
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Obstetrics and Gynaecology. Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Nutritional Research. Umeå University, Faculty of Medicine, Department of Biobank Research.
    Weiderpass, Elisabete
    Gram, Inger T.
    Lund, Eiliv
    Kaw, Kay-Tee
    Travis, Ruth C.
    Merritt, Melissa A.
    Gunther, Marc J.
    Riboli, Elio
    Kaaks, Rudolf
    Endogenous androgens and risk of epithelial invasive ovarian cancer by tumor characteristics in the European Prospective Investigation into Cancer and Nutrition2015In: International Journal of Cancer, ISSN 0020-7136, E-ISSN 1097-0215, Vol. 136, no 2, p. 399-410Article in journal (Refereed)
    Abstract [en]

    The role of endogenous androgens and sex hormone-binding globulin (SHBG) in ovarian carcinogenesis is poorly understood. Epithelial invasive ovarian cancer (EOC) is a heterogeneous disease and there are no prospective data on endogenous androgens and EOC risk by tumor characteristics (histology, grade, stage) or the dualistic model of ovarian carcinogenesis (i.e. type I vs. type II, leading to less or more aggressive tumors). We conducted a nested case-control study in the European Prospective Investigation into Cancer and Nutrition (EPIC) cohort evaluating androgens and SHBG and invasive EOC risk by tumor characteristics. Female participants who provided a blood sample and were not using exogenous hormones at blood donation were eligible (n = 183,257). A total of 565 eligible women developed EOC; two controls (n = 1,097) were matched per case. We used multivariable conditional logistic regression models. We observed no association between androgens, SHBG and EOC overall. A doubling of androstenedione reduced risk of serous carcinomas by 21% (odds ratio (OR)log2=0.79, 95% confidence interval [CI]=[0.64-0.97]). Moreover, associations differed for low-grade and high-grade carcinomas, with positive associations for low-grade and inverse associations for high-grade carcinomas (e.g. androstenedione: low grade: ORlog2=1.99 [0.98-4.06]; high grade: ORlog2=0.75 [0.61-0.93], p(het)0.01), similar associations were observed for type I/II tumors. This is the first prospective study to evaluate androgens, SHBG and EOC risk by tumor characteristics and type I/II status. Our findings support a possible role of androgens in ovarian carcinogenesis. Additional studies exploring this association are needed. What's new? There appear to be several types of epithelial invasive ovarian cancer (EOC), and hormone-related risk factors are poorly understood. In this study, the authors found that the impact of endogenous androgens on the risk of developing EOC differed depending upon tumor characteristics. Androgen concentrations were positively associated with the risk of low-grade and type-I carcinomas, but the study found an inverse association for high-grade tumors. These findings support a possible role for androgens in ovarian carcinogenesis, and emphasize the need for additional research.

  • 183. Papadimitriou, Nikos
    et al.
    Muller, David
    van den Brandt, Piet A.
    Geybels, Milan
    Patel, Chirag J.
    Gunter, Marc J.
    Lopez, David S.
    Key, Timothy J.
    Perez-Cornago, Aurora
    Ferrari, Pietro
    Vineis, Paolo
    Weiderpass, Elisabete
    Boeing, Heiner
    Agudo, Antonio
    Sanchez, Maria-Jose
    Overvad, Kim
    Kuehn, Tilman
    Fortner, Renee T.
    Palli, Domenico
    Drake, Isabel
    Bjartell, Anders
    Santiuste, Carmen
    Bueno-de-Mesquita, Bas H.
    Krogh, Vittorio
    Tjonneland, Anne
    Lauritzen, Dorthe Furstrand
    Gurrea, Aurelio Barricarte
    Quiros, Jose Ramon
    Stattin, Par
    Trichopoulou, Antonia
    Martimianaki, Georgia
    Karakatsani, Anna
    Thysell, Elin
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology. Umeå University, Faculty of Medicine, Department of Biobank Research.
    Johansson, Ingegerd
    Umeå University, Faculty of Medicine, Department of Odontology. Umeå University, Faculty of Medicine, Department of Biobank Research. Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Cardiology.
    Ricceri, Fulvio
    Tumino, Rosario
    Larranaga, Nerea
    Khaw, Kay Tee
    Riboli, Elio
    Tzoulaki, Ioanna
    Tsilidis, Konstantinos K.
    A nutrient-wide association study for risk of prostate cancer in the European Prospective Investigation into Cancer and Nutrition and the Netherlands Cohort Study2019In: European Journal of Nutrition, ISSN 1436-6207, E-ISSN 1436-6215Article in journal (Refereed)
    Abstract [en]

    Purpose: The evidence from the literature regarding the association of dietary factors and risk of prostate cancer is inconclusive.

    Methods: A nutrient-wide association study was conducted to systematically and comprehensively evaluate the associations between 92 foods or nutrients and risk of prostate cancer in the European Prospective Investigation into Cancer and Nutrition (EPIC). Cox proportional hazard regression models adjusted for total energy intake, smoking status, body mass index, physical activity, diabetes and education were used to estimate hazard ratios and 95% confidence intervals for standardized dietary intakes. As in genome-wide association studies, correction for multiple comparisons was applied using the false discovery rate (FDR < 5%) method and suggested results were replicated in an independent cohort, the Netherlands Cohort Study (NLCS).

    Results: A total of 5916 and 3842 incident cases of prostate cancer were diagnosed during a mean follow-up of 14 and 20 years in EPIC and NLCS, respectively. None of the dietary factors was associated with the risk of total prostate cancer in EPIC (minimum FDR-corrected P, 0.37). Null associations were also observed by disease stage, grade and fatality, except for positive associations observed for intake of dry cakes/biscuits with low-grade and butter with aggressive prostate cancer, respectively, out of which the intake of dry cakes/biscuits was replicated in the NLCS.

    Conclusions: Our findings provide little support for an association for the majority of the 92 examined dietary factors and risk of prostate cancer. The association of dry cakes/biscuits with low-grade prostate cancer warrants further replication given the scarcity in the literature.

  • 184. Papadimitriou, Nikos
    et al.
    Tsilidis, Konstantinos K.
    Orfanos, Philippos
    Benetou, Vassiliki
    Ntzani, Evangelia E.
    Soerjomataram, Isabelle
    Kuenn-Nelen, Annemarie
    Pettersson-Kymmer, Ulrika
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Pharmacology.
    Eriksson, Sture
    Umeå University, Faculty of Medicine, Department of Biobank Research.
    Brenner, Hermann
    Schoettker, Ben
    Saum, Kai-Uwe
    Holleczek, Bernd
    Grodstein, Francine D.
    Feskanich, Diane
    Orsini, Nicola
    Wolk, Alicja
    Bellavia, Andrea
    Wilsgaard, Tom
    Jorgensen, Lone
    Boffetta, Paolo
    Trichopoulos, Dimitrios
    Trichopoulou, Antonia
    Burden of hip fracture using disability-adjusted life-years: a pooled analysis of prospective cohorts in the CHANCES consortium2017In: Lancet Public Health, ISSN 2468-2667, Vol. 2, no 5, p. E239-E246Article in journal (Refereed)
    Abstract [en]

    Background: No studies have estimated disability-adjusted life-years (DALYs) lost due to hip fractures using real-life follow-up cohort data. We aimed to quantify the burden of disease due to incident hip fracture using DALYs in prospective cohorts in the CHANCES consortium, and to calculate population attributable fractions based on DALYs for specific risk factors.

    Methods: We used data from six cohorts of participants aged 50 years or older at recruitment to calculate DALYs. We applied disability weights proposed by the National OsteoporosisFoundation and did a series of sensitivity analyses to examine the robustness of DALY estimates. We calculated population attributable fractions for smoking, body-mass index (BMI), physical activity, alcohol intake, type 2 diabetes and parity, use of hormone replacement therapy, and oral contraceptives in women. We calculated summary risk estimates across cohorts with pooled analysis and random-effects meta-analysis methods.

    Findings: 223 880 men and women were followed up for a mean of 13 years (SD 6). 7724 (3·5%) participants developed an incident hip fracture, of whom 413 (5·3%) died as a result. 5964 DALYs (27 per 1000 individuals) were lost due to hip fractures, 1230 (20·6%) of which were in the group aged 75–79 years. 4150 (69·6%) DALYs were attributed to disability. Current smoking was the risk factor responsible for the greatest hip fracture burden (7·5%, 95% CI 5·2–9·7) followed by physical inactivity (5·5%, 2·1–8·5), history of diabetes (2·8%, 2·1–4·0), and low to average BMI (2·0%, 1·4–2·7), whereas low alcohol consumption (0·01–2·5 g per day) and high BMI had a protective effect.

    Interpretation: Hip fracture can lead to a substantial loss of healthy life-years in elderly people. National public health policies should be strengthened to reduce hip fracture incidence and mortality. Primary prevention measures should be strengthened to prevent falls, and reduce smoking and a sedentary lifestyle.

  • 185. Perez-Cornago, Aurora
    et al.
    Appleby, Paul N.
    Pischon, Tobias
    Tsilidis, Konstantinos K.
    Tjonneland, Anne
    Olsen, Anja
    Overvad, Kim
    Kaaks, Rudolf
    Kuehn, Tilman
    Boeing, Heiner
    Steffen, Annika
    Trichopoulou, Antonia
    Lagiou, Pagona
    Kritikou, Maria
    Krogh, Vittorio
    Palli, Domenico
    Sacerdote, Carlotta
    Tumino, Rosario
    Bueno-de-Mesquita, H. Bas
    Agudo, Antonio
    Larranaga, Nerea
    Molina-Portillo, Elena
    Barricarte, Aurelio
    Chirlaque, Maria-Dolores
    Ramon Quiros, J.
    Stattin, Pär
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Urology and Andrology. Department of Surgical Sciences, Uppsala University.
    Häggström, Christel
    Umeå University, Faculty of Medicine, Department of Biobank Research. Department of Surgical Sciences, Uppsala University.
    Wareham, Nick
    Khaw, Kay-Tee
    Schmidt, Julie A.
    Gunter, Marc
    Freisling, Heinz
    Aune, Dagfinn
    Ward, Heather
    Riboli, Elio
    Key, Timothy J.
    Travis, Ruth C.
    Tall height and obesity are associated with an increased risk of aggressive prostate cancer: results from the EPIC cohort study2017In: BMC Medicine, ISSN 1741-7015, E-ISSN 1741-7015, Vol. 15, article id 115Article in journal (Refereed)
    Abstract [en]

    Background: The relationship between body size and prostate cancer risk, and in particular risk by tumour characteristics, is not clear because most studies have not differentiated between high-grade or advanced stage tumours, but rather have assessed risk with a combined category of aggressive disease. We investigated the association of height and adiposity with incidence of and death from prostate cancer in 141,896 men in the European Prospective Investigation into Cancer and Nutrition (EPIC) cohort. Methods: Multivariable-adjusted Cox proportional hazards models were used to calculate hazard ratios (HRs) and 95% confidence intervals (CIs). After an average of 13.9 years of follow-up, there were 7024 incident prostate cancers and 934 prostate cancer deaths. Results: Height was not associated with total prostate cancer risk. Subgroup analyses showed heterogeneity in the association with height by tumour grade (P-heterogeneity = 0.002), with a positive association with risk for high-grade but not low-intermediate-grade disease (HR for high-grade disease tallest versus shortest fifth of height, 1.54; 95% CI, 1.18-2.03). Greater height was also associated with a higher risk for prostate cancer death (HR = 1.43, 1.14-1.80). Body mass index (BMI) was significantly inversely associated with total prostate cancer, but there was evidence of heterogeneity by tumour grade (P-heterogeneity = 0.01; HR = 0.89, 0.79-0.99 for low-intermediate grade and HR = 1.32, 1.01-1.72 for high-grade prostate cancer) and stage (P-heterogeneity = 0.01; HR = 0.86, 0.75-0.99 for localised stage and HR = 1.11, 0.92-1.33 for advanced stage). BMI was positively associated with prostate cancer death (HR = 1.35, 1.09-1.68). The results for waist circumference were generally similar to those for BMI, but the associations were slightly stronger for high-grade (HR = 1.43, 1.07-1.92) and fatal prostate cancer (HR = 1.55, 1.23-1.96). Conclusions: The findings from this large prospective study show that men who are taller and who have greater adiposity have an elevated risk of high-grade prostate cancer and prostate cancer death.

  • 186.
    Pettersson-Kymmer, Ulrika
    et al.
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine. Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Pharmacology.
    Lacroix, Andrea
    Eriksson, Joel
    Bergström, Ulrica
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences.
    Melin, Beatrice
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Wibom, Carl
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Vandenput, Liesbeth
    Rajaraman, Preetha
    Hartge, Patricia
    Chanock, Stephen
    Hallmans, Göran
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine. Umeå University, Faculty of Medicine, Department of Biobank Research.
    Duggan, David
    Kooperberg, Charles
    Handelman, Samuel
    Aragaki, Aaron
    Nethander, Maria
    Uitterlinden, Andre
    Rivadeneira, Fernando
    Jackson, Rebecca
    Ohlsson, Claes
    Genome-wide association study meta-analysis identifies the SOAT1/AXDND1 locus to be associated with hip and forearm fracture risk2013In: Bone Abstracts, 2013, Vol. 1Conference paper (Other academic)
    Abstract [en]

    Hip and forearm fractures are the two clinically most important non-vertebral fractures. Twin studies have demonstrated a high heritability of these fractures and the heritable component of fracture risk is largely independent of BMD. To identify common genetic variants associated with hip and forearm fractures, we performed a genome-wide association study (GWAS ~ 2.5 million SNPs) meta-analysis of two large fracture data sets within the well-characterized UFO cohort (UFO-hip; 1014 hip fractures and 862 controls, and UFO-forearm; 1060 forearm fractures and 1055 controls). All fractures were confirmed through radiographic reports. Replication was performed in the Women’s Health Initiative (WHI) cohort (1845 hip fractures verified by medical records and 2120 controls). We identified one SNP within the SOAT1/AXDND1 locus (1q25.2) that was associated with fracture risk at genome wide significance (OR per allele=1.33; P=3.1×10−8) in the UFO discovery meta-analysis. This SNP was associated with fracture risk both in the WHI replication cohort (OR 1.16, P=2.1×10−3) and in the combined analyses comprising 7956 subjects (3919 cases and 4037 controls; OR=1.24, P=5.6×10−10). However, it was not associated with BMD or biochemical bone markers, suggesting that its association with fractures is BMD-independent. A genetic score (GS), including information from 63 SNPs earlier shown to be reproducibly associated with BMD, was significantly associated with both hip (P=7.9×10−4) and forearm (P=8.6×10−5) fractures. Models including both the SNP in the SOAT1/AXDND1 locus and the GS demonstrated that the impact of the SNP in the SOAT1/AXDND1 locus on fracture risk was independent of the BMD-associated GS. In summary, both a BMD-associated GS and a non-BMD associated genetic variant in the SOAT1/AXDND1 locus are associated with hip and forearm fractures.

  • 187. Poveda, Alaitz
    et al.
    Chen, Yan
    Brändström, Anders
    Umeå University, Faculty of Social Sciences, Centre for Demographic and Ageing Research (CEDAR).
    Engberg, Elisabeth
    Umeå University, Faculty of Social Sciences, Centre for Demographic and Ageing Research (CEDAR).
    Hallmans, Göran
    Umeå University, Faculty of Medicine, Department of Biobank Research.
    Johansson, Ingegerd
    Umeå University, Faculty of Medicine, Department of Biobank Research.
    Renström, Frida
    Umeå University, Faculty of Medicine, Department of Biobank Research. Genetic and Molecular Epidemiology Unit, Department of Clinical Sciences, Clinical Research Centre, Lund University, Jan Waldenströms gata 35, Building 91, Skåne University Hospital, SE-20502 Malmö, Sweden.
    Kurbasic, Azra
    Franks, Paul W.
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine. Genetic and Molecular Epidemiology Unit, Department of Clinical Sciences, Clinical Research Centre, Lund University, Jan Waldenströms gata 35, Building 91, Skåne University Hospital, SE-20502 Malmö, Sweden; Department of Nutrition, Harvard T. H. Chan School of Public Health, Boston, MA, USA.
    The heritable basis of gene-environment interactions in cardiometabolic traits2017In: Diabetologia, ISSN 0012-186X, E-ISSN 1432-0428, Vol. 60, no 3, p. 442-452Article in journal (Refereed)
    Abstract [en]

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

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

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

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

  • 188. Poveda, Alaitz
    et al.
    Koivula, Robert W.
    Ahmad, Shafqat
    Barroso, Ines
    Hallmans, Göran
    Umeå University, Faculty of Medicine, Department of Biobank Research.
    Johansson, Ingegerd
    Umeå University, Faculty of Medicine, Department of Odontology.
    Renstrom, Frida
    Umeå University, Faculty of Medicine, Department of Biobank Research. Lund Univ, Dept Clin Sci, Genet & Mol Epidemiol Unit, Malmö, Sweden.
    Franks, Paul W.
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine.
    Innate biology versus lifestyle behaviour in the aetiology of obesity and type 2 diabetes: the GLACIER Study2016In: Diabetologia, ISSN 0012-186X, E-ISSN 1432-0428, Vol. 59, no 3, p. 462-471Article in journal (Refereed)
    Abstract [en]

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

  • 189. Price, Alison J
    et al.
    Travis, Ruth C
    Appleby, Paul N
    Albanes, Demetrius
    Barricarte Gurrea, Aurelio
    Bjørge, Tone
    Bueno-de-Mesquita, H Bas
    Chen, Chu
    Donovan, Jenny
    Gislefoss, Randi
    Goodman, Gary
    Gunter, Marc
    Hamdy, Freddie C
    Johansson, Mattias
    Umeå University, Faculty of Medicine, Department of Biobank Research. International Agency for Research on Cancer, Lyon, France.
    King, Irena B
    Kühn, Tilman
    Männistö, Satu
    Martin, Richard M
    Meyer, Klaus
    Neal, David E
    Neuhouser, Marian L
    Nygård, Ottar
    Stattin, Pär
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Urology and Andrology.
    Tell, Grethe S
    Trichopoulou, Antonia
    Tumino, Rosario
    Ueland, Per Magne
    Ulvik, Arve
    de Vogel, Stefan
    Vollset, Stein Emil
    Weinstein, Stephanie J
    Key, Timothy J
    Allen, Naomi E
    Circulating Folate and Vitamin B12 and Risk of Prostate Cancer: A Collaborative Analysis of Individual Participant Data from Six Cohorts Including 6875 Cases and 8104 Controls2016In: European Urology, ISSN 0302-2838, E-ISSN 1873-7560, Vol. 70, no 6, p. 941-951Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: Folate and vitamin B12 are essential for maintaining DNA integrity and may influence prostate cancer (PCa) risk, but the association with clinically relevant, advanced stage, and high-grade disease is unclear.

    OBJECTIVE: To investigate the associations between circulating folate and vitamin B12 concentrations and risk of PCa overall and by disease stage and grade.

    DESIGN, SETTING, AND PARTICIPANTS: A study was performed with a nested case-control design based on individual participant data from six cohort studies including 6875 cases and 8104 controls; blood collection from 1981 to 2008, and an average follow-up of 8.9 yr (standard deviation 7.3). Odds ratios (ORs) of incident PCa by study-specific fifths of circulating folate and vitamin B12 were calculated using multivariable adjusted conditional logistic regression.

    OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Incident PCa and subtype by stage and grade.

    RESULTS AND LIMITATIONS: Higher folate and vitamin B12 concentrations were associated with a small increase in risk of PCa (ORs for the top vs bottom fifths were 1.13 [95% confidence interval (CI), 1.02-1.26], ptrend=0.018, for folate and 1.12 [95% CI, 1.01-1.25], ptrend=0.017, for vitamin B12), with no evidence of heterogeneity between studies. The association with folate varied by tumour grade (pheterogeneity<0.001); higher folate concentration was associated with an elevated risk of high-grade disease (OR for the top vs bottom fifth: 2.30 [95% CI, 1.28-4.12]; ptrend=0.001), with no association for low-grade disease. There was no evidence of heterogeneity in the association of folate with risk by stage or of vitamin B12 with risk by stage or grade of disease (pheterogeneity>0.05). Use of single blood-sample measurements of folate and B12 concentrations is a limitation.

    CONCLUSIONS: The association between higher folate concentration and risk of high-grade disease, not evident for low-grade disease, suggests a possible role for folate in the progression of clinically relevant PCa and warrants further investigation.

    PATIENT SUMMARY: Folate, a vitamin obtained from foods and supplements, is important for maintaining cell health. In this study, however, men with higher blood folate levels were at greater risk of high-grade (more aggressive) prostate cancer compared with men with lower folate levels. Further research is needed to investigate the possible role of folate in the progression of this disease.

  • 190. Racine, A.
    et al.
    Carbonnel, F.
    Chan, S.
    Hart, A.
    de Mesquita, B. Bueno
    Oldenburg, B.
    VanSchaik, F.
    Tjonneland, A.
    Olsen, A.
    Dahm, C.
    Key, T.
    Luben, R.
    Kaw, K. -T
    Riboli, E.
    Grip, O.
    Lindgren, S.
    Hallmans, Göran
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Nutritional Research. Umeå University, Faculty of Medicine, Department of Biobank Research.
    Karling, Pontus
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine.
    Clavel-Chapelon, F.
    Bergman, M.
    Boeing, H.
    Buijsse, B.
    Kaaks, R.
    Katzke, V.
    Palli, D.
    Masala, G.
    Jantchou, P.
    Ruault, M. C. Boutron
    Dietary patterns and risk of Inflammatory Bowel Disease in Europe: Results from the EPIC study2015In: Journal of Crohn's & Colitis, ISSN 1873-9946, E-ISSN 1876-4479, Vol. 9, p. S26-S26Article in journal (Other academic)
  • 191. Racine, Antoine
    et al.
    Carbonnel, Franck
    Chan, Simon S. M.
    Hart, Andrew R.
    Bueno-de-Mesquita, H. Bas
    Oldenburg, Bas
    van Schaik, Fiona D. M.
    Tjønneland, Anne
    Olsen, Anja
    Dahm, Christina C.
    Key, Timothy
    Luben, Robert
    Khaw, Kay-Tee
    Riboli, Elio
    Grip, Olof
    Lindgren, Stefan
    Hallmans, Göran
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Nutritional Research. Umeå University, Faculty of Medicine, Department of Biobank Research.
    Karling, Pontus
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine.
    Clavel-Chapelon, Francoise
    Bergman, Manuela M.
    Boeing, Heiner
    Kaaks, Rudolf
    Katzke, Verena A.
    Palli, Domenico
    Masala, G.
    Jantchou, Prevost
    Boutron-Ruault, Marie-Christine
    Dietary Patterns and Risk of Inflammatory Bowel Disease in Europe: Results from the EPIC Study2016In: Inflammatory Bowel Diseases, ISSN 1078-0998, E-ISSN 1536-4844, Vol. 22, no 2, p. 345-354Article in journal (Refereed)
    Abstract [en]

    Background: Specific nutrients or foods have been inconsistently associated with ulcerative colitis (UC) or Crohn’s disease (CD) risks. Thus, we investigated associations between diet as a whole, as dietary patterns, and UC and CD risks.

    Methods: Within the prospective EPIC (European Prospective Investigation into Cancer) study, we set up a nested matched case–control study among 366,351 participants with inflammatory bowel disease data, including 256 incident cases of UC and 117 of CD, and 4 matched controls per case. Dietary intake was recorded at baseline from validated food frequency questionnaires. Incidence rate ratios of developing UC and CD were calculated for quintiles of the Mediterranean diet score and a posteriori dietary patterns produced by factor analysis.

    Results: No dietary pattern was associated with either UC or CD risks. However, when excluding cases occurring within the first 2 years after dietary assessment, there was a positive association between a “high sugar and soft drinks” pattern and UC risk (incidence rate ratios for the fifth versus first quintile, 1.68 [1.00–2.82]; Ptrend ¼ 0.02). When considering the foods most associated with the pattern, high consumers of sugar and soft drinks were at higher UC risk only if they had low vegetables intakes.

  • 192. Rahmioglu, Nilufer
    et al.
    Macgregor, Stuart
    Drong, Alexander W
    Hedman, Asa K
    Harris, Holly R
    Randall, Joshua C
    Prokopenko, Inga
    Nyholt, Dale R
    Morris, Andrew P
    Montgomery, Grant W
    Missmer, Stacey A
    Lindgren, Cecilia M
    Zondervan, Krina T
    Hallmans, Göran
    Umeå University, Faculty of Medicine, Department of Biobank Research. Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Nutritional Research.
    Shungin, Dmitry
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Nutritional Research.
    Genome-wide enrichment analysis between endometriosis and obesity-related traits reveals novel susceptibility loci2015In: Human Molecular Genetics, ISSN 0964-6906, E-ISSN 1460-2083, Vol. 24, no 4, p. 1185-1199Article in journal (Refereed)
    Abstract [en]

    Endometriosis is a chronic inflammatory condition in women that results in pelvic pain and subfertility, and has been associated with decreased body mass index (BMI). Genetic variants contributing to the heritable component have started to emerge from genome-wide association studies (GWAS), although the majority remain unknown. Unexpectedly, we observed an intergenic locus on 7p15.2 that was genome-wide significantly associated with both endometriosis and fat distribution (waist-to-hip ratio adjusted for BMI; WHRadjBMI) in an independent meta-GWAS of European ancestry individuals. This led us to investigate the potential overlap in genetic variants underlying the aetiology of endometriosis, WHRadjBMI and BMI using GWAS data. Our analyses demonstrated significant enrichment of common variants between fat distribution and endometriosis (P = 3.7 × 10(-3)), which was stronger when we restricted the investigation to more severe (Stage B) cases (P = 4.5 × 10(-4)). However, no genetic enrichment was observed between endometriosis and BMI (P = 0.79). In addition to 7p15.2, we identify four more variants with statistically significant evidence of involvement in both endometriosis and WHRadjBMI (in/near KIFAP3, CAB39L, WNT4, GRB14); two of these, KIFAP3 and CAB39L, are novel associations for both traits. KIFAP3, WNT4 and 7p15.2 are associated with the WNT signalling pathway; formal pathway analysis confirmed a statistically significant (P = 6.41 × 10(-4)) overrepresentation of shared associations in developmental processes/WNT signalling between the two traits. Our results demonstrate an example of potential biological pleiotropy that was hitherto unknown, and represent an opportunity for functional follow-up of loci and further cross-phenotype comparisons to assess how fat distribution and endometriosis pathogenesis research fields can inform each other.

  • 193. Randall, Joshua C
    et al.
    Winkler, Thomas W
    Kutalik, Zoltán
    Berndt, Sonja I
    Jackson, Anne U
    Monda, Keri L
    Kilpeläinen, Tuomas O
    Esko, Tõnu
    Mägi, Reedik
    Li, Shengxu
    Workalemahu, Tsegaselassie
    Feitosa, Mary F
    Croteau-Chonka, Damien C
    Day, Felix R
    Fall, Tove
    Ferreira, Teresa
    Gustafsson, Stefan
    Locke, Adam E
    Mathieson, Iain
    Scherag, Andre
    Vedantam, Sailaja
    Wood, Andrew R
    Liang, Liming
    Steinthorsdottir, Valgerdur
    Thorleifsson, Gudmar
    Dermitzakis, Emmanouil T
    Dimas, Antigone S
    Karpe, Fredrik
    Min, Josine L
    Nicholson, George
    Clegg, Deborah J
    Person, Thomas
    Krohn, Jon P
    Bauer, Sabrina
    Buechler, Christa
    Eisinger, Kristina
    Bonnefond, Amélie
    Froguel, Philippe
    Hottenga, Jouke-Jan
    Prokopenko, Inga
    Waite, Lindsay L
    Harris, Tamara B
    Smith, Albert Vernon
    Shuldiner, Alan R
    McArdle, Wendy L
    Caulfield, Mark J
    Munroe, Patricia B
    Grönberg, Henrik
    Chen, Yii-Der Ida
    Li, Guo
    Beckmann, Jacques S
    Johnson, Toby
    Thorsteinsdottir, Unnur
    Teder-Laving, Maris
    Khaw, Kay-Tee
    Wareham, Nicholas J
    Zhao, Jing Hua
    Amin, Najaf
    Oostra, Ben A
    Kraja, Aldi T
    Province, Michael A
    Cupples, L Adrienne
    Heard-Costa, Nancy L
    Kaprio, Jaakko
    Ripatti, Samuli
    Surakka, Ida
    Collins, Francis S
    Saramies, Jouko
    Tuomilehto, Jaakko
    Jula, Antti
    Salomaa, Veikko
    Erdmann, Jeanette
    Hengstenberg, Christian
    Loley, Christina
    Schunkert, Heribert
    Lamina, Claudia
    Wichmann, H Erich
    Albrecht, Eva
    Gieger, Christian
    Hicks, Andrew A
    Johansson, Asa
    Pramstaller, Peter P
    Kathiresan, Sekar
    Speliotes, Elizabeth K
    Penninx, Brenda
    Hartikainen, Anna-Liisa
    Jarvelin, Marjo-Riitta
    Gyllensten, Ulf
    Boomsma, Dorret I
    Campbell, Harry
    Wilson, James F
    Chanock, Stephen J
    Farrall, Martin
    Goel, Anuj
    Medina-Gomez, Carolina
    Rivadeneira, Fernando
    Estrada, Karol
    Uitterlinden, André G
    Hofman, Albert
    Zillikens, M Carola
    den Heijer, Martin
    Kiemeney, Lambertus A
    Maschio, Andrea
    Hall, Per
    Tyrer, Jonathan
    Teumer, Alexander
    Völzke, Henry
    Kovacs, Peter
    Tönjes, Anke
    Mangino, Massimo
    Spector, Tim D
    Hayward, Caroline
    Rudan, Igor
    Hall, Alistair S
    Samani, Nilesh J
    Attwood, Antony Paul
    Sambrook, Jennifer G
    Hung, Joseph
    Palmer, Lyle J
    Lokki, Marja-Liisa
    Sinisalo, Juha
    Boucher, Gabrielle
    Huikuri, Heikki
    Lorentzon, Mattias
    Ohlsson, Claes
    Eklund, Niina
    Eriksson, Johan G
    Barlassina, Cristina
    Rivolta, Carlo
    Nolte, Ilja M
    Snieder, Harold
    Van der Klauw, Melanie M
    Van Vliet-Ostaptchouk, Jana V
    Gejman, Pablo V
    Shi, Jianxin
    Jacobs, Kevin B
    Wang, Zhaoming
    Bakker, Stephan J L
    Mateo Leach, Irene
    Navis, Gerjan
    van der Harst, Pim
    Martin, Nicholas G
    Medland, Sarah E
    Montgomery, Grant W
    Yang, Jian
    Chasman, Daniel I
    Ridker, Paul M
    Rose, Lynda M
    Lehtimäki, Terho
    Raitakari, Olli
    Absher, Devin
    Iribarren, Carlos
    Basart, Hanneke
    Hovingh, Kees G
    Hyppönen, Elina
    Power, Chris
    Anderson, Denise
    Beilby, John P
    Hui, Jennie
    Jolley, Jennifer
    Sager, Hendrik
    Bornstein, Stefan R
    Schwarz, Peter E H
    Kristiansson, Kati
    Perola, Markus
    Lindström, Jaana
    Swift, Amy J
    Uusitupa, Matti
    Atalay, Mustafa
    Lakka, Timo A
    Rauramaa, Rainer
    Bolton, Jennifer L
    Fowkes, Gerry
    Fraser, Ross M
    Price, Jackie F
    Fischer, Krista
    Krjutå Kov, Kaarel
    Metspalu, Andres
    Mihailov, Evelin
    Langenberg, Claudia
    Luan, Jian'an
    Ong, Ken K
    Chines, Peter S
    Keinanen-Kiukaanniemi, Sirkka M
    Saaristo, Timo E
    Edkins, Sarah
    Franks, Paul W
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine.
    Hallmans, Göran
    Umeå University, Faculty of Medicine, Department of Biobank Research. Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Nutritional Research.
    Shungin, Dmitry
    Umeå University, Faculty of Medicine, Department of Odontology. Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine.
    Morris, Andrew David
    Palmer, Colin N A
    Erbel, Raimund
    Moebus, Susanne
    Nöthen, Markus M
    Pechlivanis, Sonali
    Hveem, Kristian
    Narisu, Narisu
    Hamsten, Anders
    Humphries, Steve E
    Strawbridge, Rona J
    Tremoli, Elena
    Grallert, Harald
    Thorand, Barbara
    Illig, Thomas
    Koenig, Wolfgang
    Müller-Nurasyid, Martina
    Peters, Annette
    Boehm, Bernhard O
    Kleber, Marcus E
    März, Winfried
    Winkelmann, Bernhard R
    Kuusisto, Johanna
    Laakso, Markku
    Arveiler, Dominique
    Cesana, Giancarlo
    Kuulasmaa, Kari
    Virtamo, Jarmo
    Yarnell, John W G
    Kuh, Diana
    Wong, Andrew
    Lind, Lars
    de Faire, Ulf
    Gigante, Bruna
    Magnusson, Patrik K E
    Pedersen, Nancy L
    Dedoussis, George
    Dimitriou, Maria
    Kolovou, Genovefa
    Kanoni, Stavroula
    Stirrups, Kathleen
    Bonnycastle, Lori L
    Njølstad, Inger
    Wilsgaard, Tom
    Ganna, Andrea
    Rehnberg, Emil
    Hingorani, Aroon
    Kivimaki, Mika
    Kumari, Meena
    Assimes, Themistocles L
    Barroso, Inês
    Boehnke, Michael
    Borecki, Ingrid B
    Deloukas, Panos
    Fox, Caroline S
    Frayling, Timothy
    Groop, Leif C
    Haritunians, Talin
    Hunter, David
    Ingelsson, Erik
    Kaplan, Robert
    Mohlke, Karen L
    O'Connell, Jeffrey R
    Schlessinger, David
    Strachan, David P
    Stefansson, Kari
    van Duijn, Cornelia M
    Abecasis, Gonçalo R
    McCarthy, Mark I
    Hirschhorn, Joel N
    Qi, Lu
    Loos, Ruth J F
    Lindgren, Cecilia M
    North, Kari E
    Heid, Iris M
    Sex-stratified genome-wide association studies including 270,000 individuals show sexual dimorphism in genetic loci for anthropometric traits2013In: PLoS Genetics, ISSN 1553-7390, E-ISSN 1553-7404, Vol. 9, no 6, p. e1003500-Article in journal (Refereed)
    Abstract [en]

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

  • 194.
    Renström, Frida
    et al.
    Umeå University, Faculty of Medicine, Department of Biobank Research. Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Nutritional Research. Genetic and Molecular Epidemiology Unit, Department of Clinical Sciences, Lund University; Department of Nutrition, Harvard T.H. Chan School of Public Health, Boston, MA, USA.
    Koivula, Robert W.
    Varga, Tibor V.
    Hallmans, Göran
    Umeå University, Faculty of Medicine, Department of Biobank Research. Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Nutritional Research.
    Mulder, Hindrik
    Florez, Jose C.
    Hu, Frank B.
    Franks, Paul W.
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine. Genetic and Molecular Epidemiology Unit, Department of Clinical Sciences, Lund University; Department of Nutrition, Harvard T.H. Chan School of Public Health, Boston, MA, USA.
    Season-dependent associations of circadian rhythm-regulating loci (CRY1, CRY2 and MTNR1B) and glucose homeostasis: the GLACIER Study2015In: Diabetologia, ISSN 0012-186X, E-ISSN 1432-0428, Vol. 58, no 5, p. 997-1005Article in journal (Refereed)
    Abstract [en]

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

  • 195. Rentschler, Gerda
    et al.
    Rodushkin, Ilia
    Cerna, Milena
    Chen, Chunying
    Harari, Florencia
    Harari, Raúl
    Horvat, Milena
    Hruba, Frantiska
    Kasparova, Lucie
    Koppova, Kvetoslava
    Krskova, Andrea
    Krsnik, Mladen
    Laamech, Jawhar
    Li, Yu-Feng
    Löfmark, Lina
    Lundh, Thomas
    Lundström, Nils-Göran
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Occupational and Environmental Medicine.
    Lyoussi, Badiaa
    Mazej, Darja
    Osredkar, Josko
    Pawlas, Krystyna
    Pawlas, Natalia
    Prokopowicz, Adam
    Skerfving, Staffan
    Snoj Tratnik, Janja
    Spevackova, Vera
    Spiric, Zdravko
    Sundkvist, Anneli
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Occupational and Environmental Medicine.
    Strömberg, Ulf
    Vadla, Drazenka
    Wranova, Katerina
    Zizi, Soumia
    Bergdahl, Ingvar A
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Occupational and Environmental Medicine. Umeå University, Faculty of Medicine, Department of Biobank Research.
    Platinum, palladium, rhodium, molybdenum and strontium in blood of urban women in nine countries2018In: International journal of hygiene and environmental health (Print), ISSN 1438-4639, E-ISSN 1618-131X, Vol. 221, no 2, p. 223-230Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: There is little reliable information on human exposure to the metals platinum (Pt), palladium (Pd) and rhodium (Rh), despite their use in enormous quantities in catalytic converters for automobile exhaust systems.

    OBJECTIVES: To evaluate blood concentrations of Pt (B-Pt), Pd (B-Pd) and Rh (B-Rh) in women from six European and three non-European countries, and to identify potentially influential factors. In addition, molybdenum (Mo) and strontium (Sr) were analysed.

    METHODS: Blood from 248 women aged 47-61 was analysed by high resolution inductively coupled plasma mass spectrometry under strict quality control.

    RESULTS: The medians were: B-Pt 0.8 (range <0.6-5.2), B-Pd <5 (<5-9.3), B-Rh <0.4 (<0.4-3.6)ng/L and B-Mo 2.0 (0.2-16) and B-Sr 16.6 (3.5-49) μg/L. Two women with highly elevated B-Pt (242 and 60ng/L), previously cancer treated with cis-platinum, were not included in the data analysis. All elements varied geographically (2-3 times) (B-Pd P=0.05; all other elements P<0.001); variations within each area were generally 5-10 times. Traffic was not associated with increased concentrations.

    CONCLUSIONS: General population blood concentrations of Pt, Pd and Rh are within or below the single digit ng/L range, much lower than in most previous reports. This is probably due to improved analytical performance, allowing for more reliable information at ultra-trace levels. In general, Mo and Sr agreed with previously reported concentrations. All elements showed geographical and inter-individual variations, but no convincing relationships with self-reported traffic intensity were found. Pt from the antineoplastic drug cis-platinum is retained in the body for years.

  • 196. Riso, Lukas
    et al.
    Kaaks, Rudolf
    Kuehn, Tilman
    Sookthai, Disorn
    Forsgren, Lars
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Clinical Neuroscience. Umeå University, Faculty of Medicine, Department of Biobank Research.
    Trupp, Miles
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Clinical Neuroscience. Umeå University, Faculty of Medicine, Department of Biobank Research.
    Trichopoulou, Antonia
    La Vecchia, Carlo
    Karakatsani, Anna
    Gavrila, Diana
    Ferrari, Pietro
    Freisling, Heinz
    Petersson, Jesper
    Lewan, Susanne
    Vemeulen, Roel Ch.
    Panico, Salvatore
    Masala, Giovanna
    Ardanaz, Eva
    Krogh, Vittorio
    Perneczky, Robert
    Middleton, Lefkos T.
    Mokoroa, Olatz
    Sacerdote, Carlotta
    Sieri, Sabrina
    Hayat, Shabina A.
    Brayne, Carol
    Riboli, Elio
    Vineis, Paolo
    Gallo, Valentina
    Katzke, Verena A.
    General and abdominal adiposity and the risk of Parkinson's disease: A prospective cohort study2019In: Parkinsonism & Related Disorders, ISSN 1353-8020, E-ISSN 1873-5126, Vol. 62, p. 98-104Article in journal (Refereed)
    Abstract [en]

    Introduction: Due to demographic change, an increase in the frequency of Parkinson's disease (PD) patients is expected in the future and, thus, the identification of modifiable risk factors is urgently needed. We aimed to examine the associations of body mass index (BMI) and waist circumference (WC) with incident PD. Methods: In 13 of the 23 centers of the European Prospective Investigation into Cancer and Nutrition (EPIC) study, a total of 734 incident cases of PD were identified between 1992 and 2012 with a mean follow-up of 12 years. Cox proportional hazards regression was used to calculate hazard ratios (HR) with 95% confidence intervals (CI). We modelled anthropometric variables as continuous and categorical exposures and performed subgroup analyses by potential effect modifiers including sex and smoking. Results: We found no association between BMI, WC and incident PD, neither among men nor among women. Among never and former smokers, BMI and waist circumference were also not associated with PD risk. For male smokers, however, we observed a statistically significant inverse association between BMI and PD risk (HR 0.51, 95%CI: 0.30, 0.84) and the opposite for women, i.e. a significant direct association of BMI (HR 1.79, 95%CI: 1.04, 3.08) and waist circumference (HR 1.64, 95%CI: 1.03, 2.61) with risk of PD. Conclusion: Our data revealed no association between excess weight and PD risk but a possible interaction between anthropometry, sex and smoking.

  • 197. Rohrmann, Sabine
    et al.
    Linseisen, Jakob
    Overvad, Kim
    Lund Würtz, Anne Mette
    Roswall, Nina
    Tjønneland, Anne
    Boutron-Ruault, Marie-Christine
    Racine, Antoine
    Bastide, Nadia
    Palli, Domenico
    Agnoli, Claudia
    Panico, Salvatore
    Tumino, Rosario
    Sacerdote, Carlotta
    Weikert, Steffen
    Steffen, Annika
    Kühn, Tilman
    Li, Kuanrong
    Khaw, Kay-Tee
    Wareham, Nicholas J
    Bradbury, Kathryn E
    Peppa, Eleni
    Trichopoulou, Antonia
    Trichopoulos, Dimitrios
    Bueno-de-Mesquita, H Bas
    Peeters, Petra H M
    Hjartåker, Anette
    Skeie, Guri
    Weiderpass, Elisabete
    Jakszyn, Paula
    Dorronsoro, Miren
    Barricarte, Aurelio
    Santiuste de Pablos, Carmen
    Molina-Montes, Esther
    Alonso de la Torre, Ramón
    Ericson, Ulrika
    Sonestedt, Emily
    Johansson, Mattias
    Umeå University, Faculty of Medicine, Department of Biobank Research. International Agency for Research on Cancer (IARC), Lyon, France.
    Ljungberg, Börje
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Urology and Andrology.
    Freisling, Heinz
    Romieu, Isabelle
    Cross, Amanda J
    Vergnaud, Anne-Claire
    Riboli, Elio
    Boeing, Heiner
    Meat and fish consumption and the risk of renal cell carcinoma in the European prospective investigation into cancer and nutrition2015In: International Journal of Cancer, ISSN 0020-7136, E-ISSN 1097-0215, Vol. 136, no 5, p. E423-E431Article in journal (Refereed)
    Abstract [en]

    Renal cell cancer (RCC) incidence varies worldwide with a higher incidence in developed countries and lifestyle is likely to contribute to the development of this disease. We examined whether meat and fish consumption were related to the risk of RCC in the European Prospective Investigation into Cancer and Nutrition (EPIC). The analysis included 493,179 EPIC participants, recruited between 1992 and 2000. Until December 2008, 691 RCC cases have been identified. Meat and fish consumption was assessed at baseline using country-specific dietary assessment instruments; 24-hour recalls were applied in an 8% subsample for calibration purposes. Cox proportional hazards regression was used to calculate multivariable-adjusted hazard ratios (HR) and 95% confidence intervals (CI). Women with a high consumption of red meat (HR=1.36, 95% CI 1.14-1.62; calibrated, per 50 g/day) and processed meat (HR=1.78, 95% CI 1.05-3.03; calibrated, per 50 g/day) had a higher risk of RCC, while no association existed in men. For processed meat, the association with RCC incidence was prominent in premenopausal women and was lacking in postmenopausal women (p interaction=0.02). Neither poultry nor fish consumption were statistically significantly associated with the risk of RCC. The results show a distinct association of red and processed meat consumption with incident RCC in women but not in men. A biological explanation for these findings remains unclear. What's new? Kidney cancer strikes different populations with different frequency, with developed nations seeing more cases. In this paper, the authors investigate whether certain elements of diet might correlate with increased incidence of renal cell carcinoma. Using data from the European Prospective Investigation into Cancer and Nutrition (EPIC), they assessed the amount of meat and fish consumed in populations representing a wide range of dietary habits. They then correlated this data with renal cell carcinoma incidence. They found no effect from eating fish; consuming red and processed meats did increase risk in women, but not in men.

  • 198. Rohrmann, Sabine
    et al.
    Overvad, Kim
    Bueno-de-Mesquita, H Bas
    Jakobsen, Marianne U
    Egeberg, Rikke
    Tjonneland, Anne
    Nailler, Laura
    Boutron-Ruault, Marie-Christine
    Clavel-Chapelon, Francoise
    Krogh, Vittorio
    Palli, Domenico
    Panico, Salvatore
    Tumino, Rosario
    Ricceri, Fulvio
    Bergmann, Manuela M
    Boeing, Heiner
    Li, Kuanrong
    Kaaks, Rudolf
    Khaw, Kay-Tee
    Wareham, Nicholas J
    Crowe, Francesca L
    Key, Timothy J
    Naska, Androniki
    Trichopoulou, Antonia
    Trichopoulos, Dimitirios
    Leenders, Max
    Peeters, Petra HM
    Engeset, Dagrun
    Parr, Christine L
    Skeie, Guri
    Jakszyn, Paula
    Sanchez, Maria-Jose
    Huerta, Jose M
    Luisa Redondo, M
    Barricarte, Aurelio
    Amiano, Pilar
    Drake, Isabel
    Sonestedt, Emily
    Hallmans, Göran
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Nutritional Research. Umeå University, Faculty of Medicine, Department of Biobank Research.
    Johansson, Ingegerd
    Umeå University, Faculty of Medicine, Department of Odontology.
    Fedirko, Veronika
    Romieux, Isabelle
    Ferrari, Pietro
    Norat, Teresa
    Vergnaud, Anne C
    Riboli, Elio
    Linseisen, Jakob
    Meat consumption and mortality: results from the European Prospective Investigation into Cancer and Nutrition2013In: BMC Medicine, ISSN 1741-7015, E-ISSN 1741-7015, Vol. 11, p. 63-Article in journal (Refereed)
    Abstract [en]

    Background: Recently, some US cohorts have shown a moderate association between red and processed meat consumption and mortality supporting the results of previous studies among vegetarians. The aim of this study was to examine the association of red meat, processed meat, and poultry consumption with the risk of early death in the European Prospective Investigation into Cancer and Nutrition (EPIC).

    Methods: Included in the analysis were 448,568 men and women without prevalent cancer, stroke, or myocardial infarction, and with complete information on diet, smoking, physical activity and body mass index, who were between 35 and 69 years old at baseline. Cox proportional hazards regression was used to examine the association of meat consumption with all-cause and cause-specific mortality.

    Results: As of June 2009, 26,344 deaths were observed. After multivariate adjustment, a high consumption of red meat was related to higher all-cause mortality (hazard ratio (HR) = 1.14, 95% confidence interval (CI) 1.01 to 1.28, 160+ versus 10 to 19.9 g/day), and the association was stronger for processed meat (HR = 1.44, 95% CI 1.24 to 1.66, 160+ versus 10 to 19.9 g/day). After correction for measurement error, higher all-cause mortality remained significant only for processed meat (HR = 1.18, 95% CI 1.11 to 1.25, per 50 g/d). We estimated that 3.3% (95% CI 1.5% to 5.0%) of deaths could be prevented if all participants had a processed meat consumption of less than 20 g/day. Significant associations with processed meat intake were observed for cardiovascular diseases, cancer, and 'other causes of death'. The consumption of poultry was not related to all-cause mortality.

    Conclusions: The results of our analysis support a moderate positive association between processed meat consumption and mortality, in particular due to cardiovascular diseases, but also to cancer.

  • 199. Romieu, Isabelle
    et al.
    Scoccianti, Chiara
    Chajes, Veronique
    de Batlle, Jordi
    Biessy, Carine
    Dossus, Laure
    Baglietto, Laura
    Clavel-Chapelon, Françoise
    Overvad, Kim
    Olsen, Anja
    Tjønneland, Anne
    Kaaks, Rudolf
    Lukanova, Annekatrin
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Boeing, Heiner
    Trichopoulou, Antonia
    Lagiou, Pagona
    Trichopoulos, Dimitrios
    Palli, Domenico
    Sieri, Sabina
    Tumino, Rosario
    Vineis, Paolo
    Panico, Salvatore
    Bueno-de-Mesquita, H B As
    Gils, Carla H
    Peeters, Petra
    Lund, Eiliv
    Skeie, Guri
    Weiderpass, Elisabete
    Quirós, J Ramón
    Chirlaque, María-Dolores
    Ardanaz, Eva
    Sánchez, María-José
    Duell, Eric J
    Amiano, Pilar
    Borgquist, Signe
    Wirfält, Elisabet
    Hallmans, Göran
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Nutritional Research. Umeå University, Faculty of Medicine, Department of Biobank Research.
    Johansson, Ingegerd
    Umeå University, Faculty of Medicine, Department of Odontology. Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Nutritional Research.
    Nilsson, Lena Maria
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Nutritional Research.
    Khaw, Kay-Tee
    Wareham, Nick
    Key, Timothy J
    Travis, Ruth C
    Murphy, Neil
    Wark, Petra A
    Ferrari, Pietro
    Riboli, Elio
    Alcohol intake and breast cancer in the European Prospective investigation into Cancer and Nutrition: Short title2015In: International Journal of Cancer, ISSN 0020-7136, E-ISSN 1097-0215, Vol. 137, no 8, p. 1921-1930Article in journal (Refereed)
    Abstract [en]

    Alcohol intake has been associated to breast cancer in pre and postmenopausal women; however results are inconclusive regarding tumor hormonal receptor status, and potential modifying factors like age at start drinking. Therefore, we investigated the relation between alcohol intake and the risk of breast cancer using prospective observational data from the European Prospective Investigation into Cancer and Nutrition (EPIC). Up to 334,850 women, aged 35-70 years at baseline, were recruited in ten European countries and followed up an average of 11 years. Alcohol intake at baseline and average lifetime alcohol intake were calculated from country-specific dietary and lifestyle questionnaires. The study outcomes were the Hazard ratios (HR) of developing breast cancer according to hormonal receptor status. During 3,670,439 person-years, 11,576 incident breast cancer cases were diagnosed. Alcohol intake was significantly related to breast cancer risk, for each 10 g/day increase in alcohol intake the HR increased by 4.2% (95% CI: 2.7-5.8%). Taking 0 to 5 g/day as reference, alcohol intake of >5 to 15 g/day was related to a 5.9% increase in breast cancer risk (95% CI: 1-11%). Significant increasing trends were observed between alcohol intake and ER+/PR+, ER-/PR-, HER2- and ER-/PR-HER2- tumors. Breast cancer risk was stronger among women who started drinking prior to first full-time pregnancy. Overall, our results confirm the association between alcohol intake and both hormone receptor positive and hormone receptor negative breast tumors, suggesting that timing of exposure to alcohol drinking may affect the risk. Therefore, women should be advised to control their alcohol consumption. What's new? Although it is now established that alcohol consumption increases breast cancer risk, many questions remain. Using a prospective study design with 11,576 incident breast cancer cases across 10 European countries, the authors confirmed the increased risk of alcohol on breast cancer development. They further show that women who started drinking before their first full-term pregnancy have a higher risk than women who started afterwards. These effects were observed in hormone-receptor positive and -negative tumors pointing to non-hormonal pathways that need to be further investigated.

  • 200. Roulland, Sandrine
    et al.
    Kelly, Rachel S.
    Morgado, Ester
    Sungalee, Stephanie
    Solal-Celigny, Philippe
    Colombat, Philippe
    Jouve, Nathalie
    Palli, Domenico
    Pala, Valeria
    Tumino, Rosario
    Panico, Salvatore
    Sacerdote, Carlotta
    Quiros, Jose R.
    Gonzales, Carlos A.
    Sanchez, Maria-Jose
    Dorronsoro, Miren
    Navarro, Carmen
    Barricarte, Aurelio
    Tjønneland, Anne
    Olsen, Anja
    Overvad, Kim
    Canzian, Federico
    Kaaks, Rudolf
    Boeing, Heiner
    Drogan, Dagmar
    Nieters, Alexandra
    Clavel-Chapelon, Francoise
    Trichopoulou, Antonia
    Trichopoulos, Dimitrios
    Lagiou, Pagona
    Bueno-de-Mesquita, H. Bas
    Peeters, Petra H. M.
    Vermeulen, Roel
    Hallmans, Göran
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Nutritional Research. Umeå University, Faculty of Medicine, Department of Biobank Research.
    Melin, Beatrice
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Borgquist, Signe
    Carlson, Joyce
    Lund, Eiliv
    Weiderpass, Elisabete
    Khaw, Kay-Tee
    Wareham, Nick
    Key, Timothy J.
    Travis, Ruth C.
    Ferrari, Pietro
    Romieu, Isabelle
    Riboli, Elio
    Salles, Gilles
    Vineis, Paolo
    Nadel, Bertrand
    t(14;18) Translocation: a predictive blood biomarker for follicular lymphoma2014In: Journal of Clinical Oncology, ISSN 0732-183X, E-ISSN 1527-7755, Vol. 32, no 13, p. 1347-+Article in journal (Refereed)
    Abstract [en]

    Purpose The (14;18) translocation constitutes both a genetic hallmark and critical early event in the natural history of follicular lymphoma (FL). However, t(14;18) is also detectable in the blood of otherwise healthy persons, and its relationship with progression to disease remains unclear. Here we sought to determine whether t(14;18)-positive cells in healthy individuals represent tumor precursors and whether their detection could be used as an early predictor for FL. Participants and Methods Among 520,000 healthy participants enrolled onto the EPIC (European Prospective Investigation Into Cancer and Nutrition) cohort, we identified 100 who developed FL 2 to 161 months after enrollment. Prediagnostic blood from these and 218 controls were screened for t(14;18) using sensitive polymerase chain reaction-based assays. Results were subsequently validated in an independent cohort (65 case participants; 128 controls). Clonal relationships between t(14;18) cells and FL were also assessed by molecular backtracking of paired prediagnostic blood and tumor samples. Results Clonal analysis of t(14;18) junctions in paired prediagnostic blood versus tumor samples demonstrated that progression to FL occurred from t(14;18)-positive committed precursors. Furthermore, healthy participants at enrollment who developed FL up to 15 years later showed a markedly higher t(14;18) prevalence and frequency than controls (P < .001). Altogether, we estimated a 23-fold higher risk of subsequent FL in blood samples associated with a frequency > 10(-4) (odds ratio, 23.17; 95% CI, 9.98 to 67.31; P < .001). Remarkably, risk estimates remained high and significant up to 15 years before diagnosis. Conclusion High t(14;18) frequency in blood from healthy individuals defines the first predictive biomarker for FL, effective years before diagnosis.

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