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  • 251. Vergnaud, Anne-Claire
    et al.
    Romaguera, Dora
    Peeters, Petra H.
    van Gils, Carla H.
    Chan, Doris S. M.
    Romieu, Isabelle
    Freisling, Heinz
    Ferrari, Pietro
    Clavel-Chapelon, Francoise
    Fagherazzi, Guy
    Dartois, Laureen
    Li, Kuanrong
    Tikk, Kaja
    Bergmann, Manuela M.
    Boeing, Heiner
    Tjonneland, Anne
    Olsen, Anja
    Overvad, Kim
    Dahm, Christina C.
    Luisa Redondo, Maria
    Agudo, Antonio
    Sanchez, Maria-Jose
    Amiano, Pilar
    Chirlaque, Maria-Dolores
    Ardanaz, Eva
    Khaw, Kay-Tee
    Wareham, Nick J.
    Crowe, Francesca
    Trichopoulou, Antonia
    Orfanos, Philippos
    Trichopoulos, Dimitrios
    Masala, Giovanna
    Sieri, Sabina
    Tumino, Rosario
    Vineis, Paolo
    Panico, Salvatore
    Bueno-de-Mesquita, H. Bas
    Ros, Martine M.
    May, Anne
    Wirfalt, Elisabet
    Sonestedt, Emily
    Johansson, Ingegerd
    Umeå University, Faculty of Medicine, Department of Odontology, School of Dentistry.
    Hallmans, Goran
    Umeå University, Faculty of Medicine, Department of Biobank Research. Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Nutritional Research.
    Lund, Eiliv
    Weiderpass, Elisabete
    Parr, Christine L.
    Riboli, Elio
    Norat, Teresa
    Adherence to the World Cancer Research Fund/American Institute for Cancer Research guidelines and risk of death in Europe: results from the European Prospective Investigation into Nutrition and Cancer cohort study2013In: American Journal of Clinical Nutrition, ISSN 0002-9165, E-ISSN 1938-3207, Vol. 97, no 5, p. 1107-1120Article in journal (Refereed)
    Abstract [en]

    Background: In 2007, the World Cancer Research Fund (WCRF) and the American Institute for Cancer Research (AICR) issued recommendations on diet, physical activity, and weight management for cancer prevention on the basis of the most comprehensive collection of available evidence. Objective: We investigated whether concordance with WCRF/AICR recommendations is related to risk of death. Design: The current study included 378,864 participants from 9 European countries enrolled in the European Prospective Investigation into Cancer and Nutrition study. At recruitment (1992-1998), dietary, anthropometric, and lifestyle information was collected. A WCRF/AICR score, which incorporated 6 of the WCRF/AICR recommendations for men [regarding body fatness, physical activity, foods and drinks that promote weight gain, plant foods, animal foods, and alcoholic drinks (score range: 0-6)] and 7 WCRF/AICR recommendations for women [plus breastfeeding (score range: 0-7)], was constructed. Higher scores indicated greater concordance with WCRF/AICR recommendations. Associations between the WCRF/AICR score and risks of total and cause-specific death were estimated by using Cox regression analysis. Results: After a median follow-up time of 12.8 y, 23,828 deaths were identified. Participants within the highest category of the WCRF/AICR score (5-6 points in men; 6-7 points in women) had a 34% lower hazard of death (95% CI: 0.59, 0.75) compared with participants within the lowest category of the WCRF/AICR score (0-2 points in men; 0-3 points in women). Significant inverse associations were observed in all countries. The WCRF/AICR score was also significantly associated with a lower hazard of dying from cancer, circulatory disease, and respiratory disease. Conclusion: Results of this study suggest that following WCRF/AICR recommendations could significantly increase longevity.

  • 252. Vermeulen, Roel
    et al.
    Saberi Hosnijeh, Fatemeh
    Bodinier, Barbara
    Portengen, Lützen
    Liquet, Benoît
    Garrido-Manriquez, Javiera
    Lokhorst, Henk
    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.
    Kyrtopoulos, Soterios A
    Johansson, Ann-Sofie
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Georgiadis, Panagiotis
    Melin, Beatrice
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Palli, Domenico
    Krogh, Vittorio
    Panico, Salvatore
    Sacerdote, Carlotta
    Tumino, Rosario
    Vineis, Paolo
    Castagné, Raphaële
    Chadeau-Hyam, Marc
    Botsivali, Maria
    Chatziioannou, Aristotelis
    Valavanis, Ioannis
    Kleinjans, Jos C S
    de Kok, Theo M C M
    Keun, Hector C
    Athersuch, Toby J
    Kelly, Rachel
    Lenner, Per
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    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.
    Stephanou, Euripides G
    Myridakis, Antonis
    Kogevinas, Manolis
    Fazzo, Lucia
    De Santis, Marco
    Comba, Pietro
    Bendinelli, Benedetta
    Kiviranta, Hannu
    Rantakokko, Panu
    Airaksinen, Riikka
    Ruokojarvi, Paivi
    Gilthorpe, Mark
    Fleming, Sarah
    Fleming, Thomas
    Tu, Yu-Kang
    Lundh, Thomas
    Chien, Kuo-Liong
    Chen, Wei J
    Lee, Wen-Chung
    Kate Hsiao, Chuhsing
    Kuo, Po-Hsiu
    Hung, Hung
    Liao, Shu-Fen
    Pre-diagnostic blood immune markers, incidence and progression of B-cell lymphoma and multiple myeloma: univariate and functionally informed multivariate analyses2018In: International Journal of Cancer, ISSN 0020-7136, E-ISSN 1097-0215, Vol. 143, no 6, p. 1335-1347Article in journal (Refereed)
    Abstract [en]

    Recent prospective studies have shown that dysregulation of the immune system may precede the development of B‐cell lymphomas (BCL) in immunocompetent individuals. However, to date, the studies were restricted to a few immune markers, which were considered separately. Using a nested case–control study within two European prospective cohorts, we measured plasma levels of 28 immune markers in samples collected a median of 6 years before diagnosis (range 2.01–15.97) in 268 incident cases of BCL (including multiple myeloma [MM]) and matched controls. Linear mixed models and partial least square analyses were used to analyze the association between levels of immune marker and the incidence of BCL and its main histological subtypes and to investigate potential biomarkers predictive of the time to diagnosis. Linear mixed model analyses identified associations linking lower levels of fibroblast growth factor‐2 (FGF‐2 p = 7.2 × 10−4) and transforming growth factor alpha (TGF‐α, p = 6.5 × 10−5) and BCL incidence. Analyses stratified by histological subtypes identified inverse associations for MM subtype including FGF‐2 (p = 7.8 × 10−7), TGF‐α (p = 4.08 × 10−5), fractalkine (p = 1.12 × 10−3), monocyte chemotactic protein‐3 (p = 1.36 × 10−4), macrophage inflammatory protein 1‐alpha (p = 4.6 × 10−4) and vascular endothelial growth factor (p = 4.23 × 10−5). Our results also provided marginal support for already reported associations between chemokines and diffuse large BCL (DLBCL) and cytokines and chronic lymphocytic leukemia (CLL). Case‐only analyses showed that Granulocyte‐macrophage colony stimulating factor levels were consistently higher closer to diagnosis, which provides further evidence of its role in tumor progression. In conclusion, our study suggests a role of growth‐factors in the incidence of MM and of chemokine and cytokine regulation in DLBCL and CLL.

  • 253. Vlaanderen, Jelle
    et al.
    Leenders, Max
    Chadeau-Hyam, Marc
    Portengen, Lutzen
    Kyrtopoulos, Soterios A.
    Bergdahl, Ingvar A.
    Umeå University, Faculty of Medicine, Department of Biobank Research.
    Johansson, Ann-Sofie
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Hebels, Dennie D. G. A. J.
    de Kok, Theo M. C. M.
    Vineis, Paolo
    Vermeulen, Roel C. H.
    Exploring the nature of prediagnostic blood transcriptome markers of chronic lymphocytic leukemia by assessing their overlap with the transcriptome at the clinical stage2017In: BMC Genomics, ISSN 1471-2164, E-ISSN 1471-2164, Vol. 18, article id 239Article in journal (Refereed)
    Abstract [en]

    Background: We recently identified 700 genes whose expression levels were predictive of chronic lymphocytic leukemia (CLL) in a genome-wide gene expression analysis of prediagnostic blood from future cases and matched controls. We hypothesized that a large fraction of these markers were likely related to early disease manifestations. Here we aim to gain a better understanding of the natural history of the identified markers by comparing results from our prediagnostic analysis, the only prediagnostic analysis to date, to results obtained from a meta-analysis of a series of publically available transcriptomics profiles obtained in incident CLL cases and controls.

    Results: We observed considerable overlap between the results from our prediagnostic study and the clinical CLL signals (p-value for overlap Bonferroni significant markers 0.01; p-value for overlap nominal significant markers < 2.20e-16). We observed similar patterns with time to diagnosis and similar functional annotations for the markers that were identified in both settings compared to the markers that were only identified in the prediagnostic study. These results suggest that both gene sets operate in similar pathways.

    Conclusion: An overlap exists between expression levels of genes predictive of CLL identified in prediagnostic blood and expression levels of genes associated to CLL at the clinical stage. Our analysis provides insight in a set of genes for which expression levels can be used to follow the time-course of the disease; providing an opportunity to study CLL progression in more detail in future studies.

  • 254. Vrieling, Alina
    et al.
    Bueno-De-Mesquita, H. Bas
    Ros, Martine M.
    Kampman, Ellen
    Aben, Katja K.
    Buchner, Frederike L.
    Jansen, Eugene H.
    Roswall, Nina
    Tjonneland, Anne
    Boutron-Ruault, Marie-Christine
    Cadeau, Claire
    Chang-Claude, Jenny
    Kaaks, Rudolf
    Weikert, Steffen
    Boeing, Heiner
    Trichopoulou, Antonia
    Lagiou, Pagona
    Trichopoulos, Dimitrios
    Sieri, Sabina
    Palli, Domenico
    Panico, Salvatore
    Peeters, Petra H.
    Weiderpass, Elisabete
    Skeie, Guri
    Jakszyn, Paula
    Chirlaque, Maria-Dolores
    Ardanaz, Eva
    Sanchez, Maria-Jose
    Ehrnstrom, Roy
    Malm, Johan
    Ljungberg, Börje
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Urology and Andrology.
    Khaw, Kay-Tee
    Wareham, Nick J.
    Brennan, Paul
    Johansson, Mattias
    Umeå University, Faculty of Medicine, Department of Biobank Research. Genetic Epidemiology Group, International Agency for Research on Cancer (IARC), Lyon, France.
    Riboli, Elio
    Kiemeney, Lambertus A.
    One-carbon metabolism biomarkers and risk of urothelial cell carcinoma in the European prospective investigation into cancer and nutrition2019In: International Journal of Cancer, ISSN 0020-7136, E-ISSN 1097-0215, Vol. 145, no 9, p. 2349-2359Article in journal (Refereed)
    Abstract [en]

    Published associations between dietary folate and bladder cancer risk are inconsistent. Biomarkers may provide more accurate measures of nutrient status. This nested case-control analysis within the European Prospective Investigation into Cancer and Nutrition (EPIC) investigated associations between pre-diagnostic serum folate, homocysteine, vitamins B6 and B12 and the risk of urothelial cell carcinomas of the bladder (UCC). A total of 824 patients with newly diagnosed UCC were matched with 824 cohort members. Serum folate, homocysteine, and vitamins B6 and B12 were measured. Odds ratios (OR) and 95% confidence intervals (CI) for total, aggressive, and non-aggressive UCC were estimated using conditional logistic regression with adjustment for smoking status, smoking duration and intensity, and other potential confounders. Additionally, statistical interaction with smoking status was assessed. A halving in serum folate concentrations was moderately associated with risk of UCC (OR: 1.18; 95% CI: 0.98-1.43), in particular aggressive UCC (OR: 1.34; 95% CI: 1.02-1.75; p-heterogeneity = 0.19). Compared to never smokers in the highest quartile of folate concentrations, this association seemed only apparent among current smokers in the lowest quartile of folate concentrations (OR: 6.26; 95% CI: 3.62-10.81, p-interaction = 0.07). Dietary folate was not associated with aggressive UCC (OR: 1.26; 95% CI: 0.81-1.95; p-heterogeneity = 0.14). No association was observed between serum homocysteine, vitamins B6 and B12 and risk of UCC. This study suggests that lower serum folate concentrations are associated with increased UCC risk, in particular aggressive UCC. Residual confounding by smoking cannot be ruled out and these findings require confirmation in future studies with multiple measurements.

  • 255.
    Wadsten, Charlotta
    et al.
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences.
    Wennstig, A. K.
    Garmo, H.
    Nilsson, G.
    Blomqvist, C.
    Holmberg, L.
    Fredriksson, I.
    Wärnberg, Fredrik
    Sund, Malin
    Umeå University, Faculty of Medicine, Department of Biobank Research. Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences.
    Biomarkers in DCIS associated with breast cancer related deathManuscript (preprint) (Other (popular science, discussion, etc.))
  • 256. Wang, Zhaoming
    et al.
    Rajaraman, Preetha
    Melin, Beatrice S.
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Chung, Charles C.
    Zhang, Weijia
    McKean-Cowdin, Roberta
    Michaud, Dominique
    Yeager, Meredith
    Ahlbom, Anders
    Albanes, Demetrius
    Andersson, Ulrika
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Freeman, Laura E. Beane
    Buring, Julie E.
    Butler, Mary Ann
    Carreon, Tania
    Feychting, Maria
    Gapstur, Susan M.
    Gaziano, J. Michael
    Giles, Graham G.
    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.
    Henriksson, Roger
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Hoffman-Bolton, Judith
    Inskip, Peter D.
    Kitahara, Cari M.
    Marchand, Loic Le
    Linet, Martha S.
    Li, Shengchao
    Peters, Ulrike
    Purdue, Mark P.
    Rothman, Nathaniel
    Ruder, Avima M.
    Sesso, Howard D.
    Severi, Gianluca
    Stampfer, Meir
    Stevens, Victoria L.
    Visvanathan, Kala
    Wang, Sophia S.
    White, Emily
    Zeleniuch-Jacquotte, Anne
    Hoover, Robert
    Fraumeni, Joseph F.
    Chatterjee, Nilanjan
    Hartge, Patricia
    Chanock, Stephen J.
    Further Confirmation of Germline Glioma Risk Variant rs78378222 in TP53 and Its Implication in Tumor Tissues via Integrative Analysis of TCGA Data2015In: Human Mutation, ISSN 1059-7794, E-ISSN 1098-1004, Vol. 36, no 7, p. 684-688Article in journal (Refereed)
    Abstract [en]

    We confirmed strong association of rs78378222:A>C (per allele odds ratio [OR] = 3.14; P = 6.48 x 10(-11)), a germline rare single-nucleotide polymorphism (SNP) in TP53, via imputation of a genome-wide association study of glioma (1,856 cases and 4,955 controls). We subsequently performed integrative analyses on the Cancer Genome Atlas (TCGA) data for GBM (glioblastoma multiforme) and LUAD (lung adenocarcinoma). Based on SNP data, we imputed genotypes for rs78378222 and selected individuals carrying rare risk allele (C). Using RNA sequencing data, we observed aberrant transcripts with approximate to 3 kb longer than normal for those individuals. Using exome sequencing data, we further showed that loss of haplotype carrying common protective allele (A) occurred somatically in GBM but not in LUAD. Our bioinformatic analysis suggests rare risk allele (C) disrupts mRNA termination, and an allelic loss of a genomic region harboring common protective allele (A) occurs during tumor initiation or progression for glioma.

  • 257. Wang, Zhaoming
    et al.
    Zhu, Bin
    Zhang, Mingfeng
    Parikh, Hemang
    Jia, Jinping
    Chung, Charles C
    Sampson, Joshua N
    Hoskins, Jason W
    Hutchinson, Amy
    Burdette, Laurie
    Ibrahim, Abdisamad
    Hautman, Christopher
    Raj, Preethi S
    Abnet, Christian C
    Adjei, Andrew A
    Ahlbom, Anders
    Albanes, Demetrius
    Allen, Naomi E
    Ambrosone, Christine B
    Aldrich, Melinda
    Amiano, Pilar
    Amos, Christopher
    Andersson, Ulrika
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Andriole, Gerald
    Andrulis, Irene L
    Arici, Cecilia
    Arslan, Alan A
    Austin, Melissa A
    Baris, Dalsu
    Barkauskas, Donald A
    Bassig, Bryan A
    Beane Freeman, Laura E
    Berg, Christine D
    Berndt, Sonja I
    Bertazzi, Pier Alberto
    Biritwum, Richard B
    Black, Amanda
    Blot, William
    Boeing, Heiner
    Boffetta, Paolo
    Bolton, Kelly
    Boutron-Ruault, Marie-Christine
    Bracci, Paige M
    Brennan, Paul
    Brinton, Louise A
    Brotzman, Michelle
    Bueno-de-Mesquita, H Bas
    Buring, Julie E
    Butler, Mary Ann
    Cai, Qiuyin
    Cancel-Tassin, Geraldine
    Canzian, Federico
    Cao, Guangwen
    Caporaso, Neil E
    Carrato, Alfredo
    Carreon, Tania
    Carta, Angela
    Chang, Gee-Chen
    Chang, I-Shou
    Chang-Claude, Jenny
    Che, Xu
    Chen, Chien-Jen
    Chen, Chih-Yi
    Chen, Chung-Hsing
    Chen, Constance
    Chen, Kuan-Yu
    Chen, Yuh-Min
    Chokkalingam, Anand P
    Chu, Lisa W
    Clavel-Chapelon, Francoise
    Colditz, Graham A
    Colt, Joanne S
    Conti, David
    Cook, Michael B
    Cortessis, Victoria K
    Crawford, E David
    Cussenot, Olivier
    Davis, Faith G
    De Vivo, Immaculata
    Deng, Xiang
    Ding, Ti
    Dinney, Colin P
    Di Stefano, Anna Luisa
    Diver, W Ryan
    Duell, Eric J
    Elena, Joanne W
    Fan, Jin-Hu
    Feigelson, Heather Spencer
    Feychting, Maria
    Figueroa, Jonine D
    Flanagan, Adrienne M
    Fraumeni, Joseph F
    Freedman, Neal D
    Fridley, Brooke L
    Fuchs, Charles S
    Gago-Dominguez, Manuela
    Gallinger, Steven
    Gao, Yu-Tang
    Gapstur, Susan M
    Garcia-Closas, Montserrat
    Garcia-Closas, Reina
    Gastier-Foster, Julie M
    Gaziano, J Michael
    Gerhard, Daniela S
    Giffen, Carol A
    Giles, Graham G
    Gillanders, Elizabeth M
    Giovannucci, Edward L
    Goggins, Michael
    Gokgoz, Nalan
    Goldstein, Alisa M
    Gonzalez, Carlos
    Gorlick, Richard
    Greene, Mark H
    Gross, Myron
    Grossman, H Barton
    Grubb, Robert
    Gu, Jian
    Guan, Peng
    Haiman, Christopher A
    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.
    Hankinson, Susan E
    Harris, Curtis C
    Hartge, Patricia
    Hattinger, Claudia
    Hayes, Richard B
    He, Qincheng
    Helman, Lee
    Henderson, Brian E
    Henriksson, Roger
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Hoffman-Bolton, Judith
    Hohensee, Chancellor
    Holly, Elizabeth A
    Hong, Yun-Chul
    Hoover, Robert N
    Hosgood, H Dean
    Hsiao, Chin-Fu
    Hsing, Ann W
    Hsiung, Chao Agnes
    Hu, Nan
    Hu, Wei
    Hu, Zhibin
    Huang, Ming-Shyan
    Hunter, David J
    Inskip, Peter D
    Ito, Hidemi
    Jacobs, Eric J
    Jacobs, Kevin B
    Jenab, Mazda
    Ji, Bu-Tian
    Johansen, Christoffer
    Johansson, Mattias
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine. International Agency for Research on Cancer (IARC-WHO), Lyon, France.
    Johnson, Alison
    Kaaks, Rudolf
    Kamat, Ashish M
    Kamineni, Aruna
    Karagas, Margaret
    Khanna, Chand
    Khaw, Kay-Tee
    Kim, Christopher
    Kim, In-Sam
    Kim, Jin Hee
    Kim, Yeul Hong
    Kim, Young-Chul
    Kim, Young Tae
    Kang, Chang Hyun
    Jung, Yoo Jin
    Kitahara, Cari M
    Klein, Alison P
    Klein, Robert
    Kogevinas, Manolis
    Koh, Woon-Puay
    Kohno, Takashi
    Kolonel, Laurence N
    Kooperberg, Charles
    Kratz, Christian P
    Krogh, Vittorio
    Kunitoh, Hideo
    Kurtz, Robert C
    Kurucu, Nilgun
    Lan, Qing
    Lathrop, Mark
    Lau, Ching C
    Lecanda, Fernando
    Lee, Kyoung-Mu
    Lee, Maxwell P
    Le Marchand, Loic
    Lerner, Seth P
    Li, Donghui
    Liao, Linda M
    Lim, Wei-Yen
    Lin, Dongxin
    Lin, Jie
    Lindstrom, Sara
    Linet, Martha S
    Lissowska, Jolanta
    Liu, Jianjun
    Ljungberg, Börje
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Urology and Andrology.
    Lloreta, Josep
    Lu, Daru
    Ma, Jing
    Malats, Nuria
    Mannisto, Satu
    Marina, Neyssa
    Mastrangelo, Giuseppe
    Matsuo, Keitaro
    McGlynn, Katherine A
    McKean-Cowdin, Roberta
    McNeill, Lorna H
    McWilliams, Robert R
    Melin, Beatrice S
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Meltzer, Paul S
    Mensah, James E
    Miao, Xiaoping
    Michaud, Dominique S
    Mondul, Alison M
    Moore, Lee E
    Muir, Kenneth
    Niwa, Shelley
    Olson, Sara H
    Orr, Nick
    Panico, Salvatore
    Park, Jae Yong
    Patel, Alpa V
    Patino-Garcia, Ana
    Pavanello, Sofia
    Peeters, Petra H M
    Peplonska, Beata
    Peters, Ulrike
    Petersen, Gloria M
    Picci, Piero
    Pike, Malcolm C
    Porru, Stefano
    Prescott, Jennifer
    Pu, Xia
    Purdue, Mark P
    Qiao, You-Lin
    Rajaraman, Preetha
    Riboli, Elio
    Risch, Harvey A
    Rodabough, Rebecca J
    Rothman, Nathaniel
    Ruder, Avima M
    Ryu, Jeong-Seon
    Sanson, Marc
    Schned, Alan
    Schumacher, Fredrick R
    Schwartz, Ann G
    Schwartz, Kendra L
    Schwenn, Molly
    Scotlandi, Katia
    Seow, Adeline
    Serra, Consol
    Serra, Massimo
    Sesso, Howard D
    Severi, Gianluca
    Shen, Hongbing
    Shen, Min
    Shete, Sanjay
    Shiraishi, Kouya
    Shu, Xiao-Ou
    Siddiq, Afshan
    Sierrasesumaga, Luis
    Sierri, Sabina
    Loon Sihoe, Alan Dart
    Silverman, Debra T
    Simon, Matthias
    Southey, Melissa C
    Spector, Logan
    Spitz, Margaret
    Stampfer, Meir
    Stattin, Pär
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Urology and Andrology.
    Stern, Mariana C
    Stevens, Victoria L
    Stolzenberg-Solomon, Rachael Z
    Stram, Daniel O
    Strom, Sara S
    Su, Wu-Chou
    Sund, Malin
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Surgery.
    Sung, Sook Whan
    Swerdlow, Anthony
    Tan, Wen
    Tanaka, Hideo
    Tang, Wei
    Tang, Ze-Zhang
    Tardon, Adonina
    Tay, Evelyn
    Taylor, Philip R
    Tettey, Yao
    Thomas, David M
    Tirabosco, Roberto
    Tjonneland, Anne
    Tobias, Geoffrey S
    Toro, Jorge R
    Travis, Ruth C
    Trichopoulos, Dimitrios
    Troisi, Rebecca
    Truelove, Ann
    Tsai, Ying-Huang
    Tucker, Margaret A
    Tumino, Rosario
    Van Den Berg, David
    Van Den Eeden, Stephen K
    Vermeulen, Roel
    Vineis, Paolo
    Visvanathan, Kala
    Vogel, Ulla
    Wang, Chaoyu
    Wang, Chengfeng
    Wang, Junwen
    Wang, Sophia S
    Weiderpass, Elisabete
    Weinstein, Stephanie J
    Wentzensen, Nicolas
    Wheeler, William
    White, Emily
    Wiencke, John K
    Wolk, Alicja
    Wolpin, Brian M
    Wong, Maria Pik
    Wrensch, Margaret
    Wu, Chen
    Wu, Tangchun
    Wu, Xifeng
    Wu, Yi-Long
    Wunder, Jay S
    Xiang, Yong-Bing
    Xu, Jun
    Yang, Hannah P
    Yang, Pan-Chyr
    Yatabe, Yasushi
    Ye, Yuanqing
    Yeboah, Edward D
    Yin, Zhihua
    Ying, Chen
    Yu, Chong-Jen
    Yu, Kai
    Yuan, Jian-Min
    Zanetti, Krista A
    Zeleniuch-Jacquotte, Anne
    Zheng, Wei
    Zhou, Baosen
    Mirabello, Lisa
    Savage, Sharon A
    Kraft, Peter
    Chanock, Stephen J
    Yeager, Meredith
    Landi, Maria Terese
    Shi, Jianxin
    Chatterjee, Nilanjan
    Amundadottir, Laufey T
    Imputation and subset-based association analysis across different cancer types identifies multiple independent risk loci in the TERT-CLPTM1L region on chromosome 5p15.332014In: Human Molecular Genetics, ISSN 0964-6906, E-ISSN 1460-2083, Vol. 23, no 24, p. 6616-6633Article in journal (Refereed)
    Abstract [en]

    Genome-wide association studies (GWAS) have mapped risk alleles for at least 10 distinct cancers to a small region of 63 000 bp on chromosome 5p15.33. This region harbors the TERT and CLPTM1L genes; the former encodes the catalytic subunit of telomerase reverse transcriptase and the latter may play a role in apoptosis. To investigate further the genetic architecture of common susceptibility alleles in this region, we conducted an agnostic subset-based meta-analysis (association analysis based on subsets) across six distinct cancers in 34 248 cases and 45 036 controls. Based on sequential conditional analysis, we identified as many as six independent risk loci marked by common single-nucleotide polymorphisms: five in the TERT gene (Region 1: rs7726159, P = 2.10 × 10(-39); Region 3: rs2853677, P = 3.30 × 10(-36) and PConditional = 2.36 × 10(-8); Region 4: rs2736098, P = 3.87 × 10(-12) and PConditional = 5.19 × 10(-6), Region 5: rs13172201, P = 0.041 and PConditional = 2.04 × 10(-6); and Region 6: rs10069690, P = 7.49 × 10(-15) and PConditional = 5.35 × 10(-7)) and one in the neighboring CLPTM1L gene (Region 2: rs451360; P = 1.90 × 10(-18) and PConditional = 7.06 × 10(-16)). Between three and five cancers mapped to each independent locus with both risk-enhancing and protective effects. Allele-specific effects on DNA methylation were seen for a subset of risk loci, indicating that methylation and subsequent effects on gene expression may contribute to the biology of risk variants on 5p15.33. Our results provide strong support for extensive pleiotropy across this region of 5p15.33, to an extent not previously observed in other cancer susceptibility loci.

  • 258. Ward, Heather A.
    et al.
    Wark, Petra A.
    Muller, David C.
    Steffen, Annika
    Johansson, Mattias
    Umeå University, Faculty of Medicine, Department of Biobank Research. Int Agcy Res Canc IARC WHO, Lyon, France.
    Norat, Teresa
    Gunter, Marc J.
    Overvad, Kim
    Dahm, Christina C.
    Halkjaer, Jytte
    Tojonneland, Anne
    Boutron-Ruault, Marie-Christine
    Fagherazzi, Guy
    Mesrine, Sylvie
    Brennan, Paul
    Freisling, Heinz
    Li, Kuanrong
    Kaaks, Rudolf
    Trichopoulou, Antonia
    Lagiou, Pagona
    Panico, Salavatore
    Grioni, Sara
    Tumino, Rosario
    Vineis, Paolo
    Palli, Domenico
    Peeters, Petra H. M.
    Bueno-de-Mesquita, H. Bas.
    Weiderpass, Elisabete
    Agudo, Antonio
    Ramon Quiros, Jose
    Larranaga, Nerea
    Ardanaz, Eva
    Maria Huerta, Jose
    Sanchez, Maria-Jose
    Laurell, Goran
    Johansson, Ingegerd
    Umeå University, Faculty of Medicine, Department of Odontology.
    Westin, Ulla
    Wallstrom, Peter
    Bradbury, Kathryn E.
    Wareham, Nicholas J.
    Khaw, Kay-Tee
    Pearson, Clare
    Boeing, Heiner
    Riboli, Elio
    Measured Adiposity in Relation to Head and Neck Cancer Risk in the European Prospective Investigation into Cancer and Nutrition2017In: Cancer Epidemiology, Biomarkers and Prevention, ISSN 1055-9965, E-ISSN 1538-7755, Vol. 26, no 6, p. 895-904Article in journal (Refereed)
    Abstract [en]

    Background: Emerging evidence from cohort studies indicates that adiposity is associated with greater incidence of head and neck cancer. However, most studies have used self-reported anthropometry which is prone to error. Methods: Among 363,094 participants in the European Prospective Investigation into Cancer and Nutrition study (EPIC) with measured anthropometry, there were 837 incident cases of head and neck cancer. Head and neck cancer risk was examined in relation to body mass index (BMI) [lean: <22.5 kg/m(2), normal weight (reference): 22.5-24.9 kg/m(2), overweight 25-29.9 kg/m(2), obese: >= 30 kg/m(2)], waist circumference (WC), hip circumference (HC), and waist-to-hip ratio (WHR) using Cox proportional hazards models. Results: Among men, a BMI <22.5 kg/m(2) was associated with higher head and neck cancer risk [HR 1.62; 95% confidence interval (CI), 1.23-2.12)]; BMI was not associated with head and neck cancer among women. WC and WHR were associated with greater risk of head and neck cancer among women (WC per 5 cm: HR, 1.08; 95% CI, 1.02-1.15; WHR per 0.1 unit: HR, 1.64; 95% CI, 1.38-1.93). After stratification by smoking status, the association for WHR was present only among smokers (P-interaction = 0.004). Among men, WC and WHR were associated with head and neck cancer only upon additional adjustment for BMI (WC per 5 cm: HR 1.16; 95% CI, 1.07-1.26; WHR per 0.1 unit: HR, 1.42; 95% CI, 1.21-1.65). Conclusions: Central adiposity, particularly among women, may have a stronger association with head and neck cancer risk than previously estimated.

  • 259. Watts, Eleanor L.
    et al.
    Perez-Cornago, Aurora
    Appleby, Paul N.
    Albanes, Demetrius
    Ardanaz, Eva
    Black, Amanda
    Bueno-de-Mesquita, H. Bas
    Chan, June M.
    Chen, Chu
    Chubb, S. A. Paul
    Cook, Michael B.
    Deschasaux, Mélanie
    Donovan, Jenny L.
    English, Dallas R.
    Flicker, Leon
    Freedman, Neal D.
    Galan, Pilar
    Giles, Graham G.
    Giovannucci, Edward L.
    Gunter, Marc J.
    Habel, Laurel A.
    Häggström, Christel
    Umeå University, Faculty of Medicine, Department of Biobank Research.
    Haiman, Christopher
    Hamdy, Freddie C.
    Hercberg, Serge
    Holly, Jeff M.
    Huang, Jiaqi
    Huang, Wen-Yi
    Johansson, Mattias
    Kaaks, Rudolf
    Kubo, Tatsuhiko
    Lane, J. Athene
    Layne, Tracy M.
    Le Marchand, Loic
    Martin, Richard M.
    Metter, E. Jeffrey
    Mikami, Kazuya
    Milne, Roger L.
    Morris, Howard A
    Mucci, Lorelei A.
    Neal, David E.
    Neuhouser, Marian L.
    Oliver, Steven E
    Overvad, Kim
    Ozasa, Kotaro
    Pala, Valeria
    Pernar, Claire H.
    Pollak, Michael
    Rowlands, Mari-Anne
    Schaefer, Catherine A.
    Schenk, Jeannette M.
    Stattin, Pär
    Tamakoshi, Akiko
    Thysell, Elin
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Touvier, Mathilde
    Trichopoulou, Antonia
    Tsilidis, Konstantinos K.
    Van Den Eeden, Stephen K.
    Weinstein, Stephanie J.
    Wilkens, Lynne
    Yeap, Bu B.
    Key, Timothy J.
    Allen, Naomi E.
    Travis, Ruth C.
    The associations of anthropometric, behavioural and sociodemographic factors with circulating concentrations of IGF‐I, IGF‐II, IGFBP‐1, IGFBP‐2 and IGFBP‐3 in a pooled analysis of 16,024 men from 22 studies2019In: International Journal of Cancer, ISSN 0020-7136, E-ISSN 1097-0215, Vol. 145, no 12, p. 3244-3256Article in journal (Refereed)
    Abstract [en]

    Insulin‐like growth factors (IGFs) and insulin‐like growth factor binding proteins (IGFBPs) have been implicated in the aetiology of several cancers. To better understand whether anthropometric, behavioural and sociodemographic factors may play a role in cancer risk via IGF signalling, we examined the cross‐sectional associations of these exposures with circulating concentrations of IGFs (IGF‐I and IGF‐II) and IGFBPs (IGFBP‐1, IGFBP‐2 and IGFBP‐3). The Endogenous Hormones, Nutritional Biomarkers and Prostate Cancer Collaborative Group dataset includes individual participant data from 16,024 male controls (i.e. without prostate cancer) aged 22–89 years from 22 prospective studies. Geometric means of protein concentrations were estimated using analysis of variance, adjusted for relevant covariates. Older age was associated with higher concentrations of IGFBP‐1 and IGFBP‐2 and lower concentrations of IGF‐I, IGF‐II and IGFBP‐3. Higher body mass index was associated with lower concentrations of IGFBP‐1 and IGFBP‐2. Taller height was associated with higher concentrations of IGF‐I and IGFBP‐3 and lower concentrations of IGFBP‐1. Smokers had higher concentrations of IGFBP‐1 and IGFBP‐2 and lower concentrations of IGFBP‐3 than nonsmokers. Higher alcohol consumption was associated with higher concentrations of IGF‐II and lower concentrations of IGF‐I and IGFBP‐2. African Americans had lower concentrations of IGF‐II, IGFBP‐1, IGFBP‐2 and IGFBP‐3 and Hispanics had lower IGF‐I, IGF‐II and IGFBP‐3 than non‐Hispanic whites. These findings indicate that a range of anthropometric, behavioural and sociodemographic factors are associated with circulating concentrations of IGFs and IGFBPs in men, which will lead to a greater understanding of the mechanisms through which these factors influence cancer risk.

  • 260. Weihe, Pál
    et al.
    Bjerregaard, Peter
    Bonefeld-Jørgensen, Eva
    Dudarev, Alexey
    Halling, Jónrit
    Hansen, Solrunn
    Muckle, Gina
    Nøst, Therese
    Odland, Jon Øyvind
    Petersen, Maria Skaalum
    Rautio, Arja
    Veyhe, Anna Sofia
    Wennberg, Maria
    Umeå University, Faculty of Medicine, Department of Biobank Research.
    Bergdahl, Ingvar
    Umeå University, Faculty of Medicine, Department of Biobank Research.
    Overview of ongoing cohort and dietary studies in the Arctic2016In: International Journal of Circumpolar Health, ISSN 1239-9736, E-ISSN 2242-3982, Vol. 75, article id 33803Article in journal (Refereed)
    Abstract [en]

    This article gives an overview of the ongoing cohort and dietary studies underlying the assessment of population health in the Arctic. The emphasis here is on a description of the material, methods and results or preliminary results for each study. Detailed exposure information is available in an article in this journal, whereas another paper describes the effects associated with contaminant exposure in the Arctic. The cohort descriptions have been arranged geographically, beginning in Norway and moving east to Finland, Sweden, Russia and the other Arctic countries and ultimately to the Faroe Islands. No cohort studies have been reported for Alaska or Iceland.

  • 261.
    Wennberg, Maria
    et al.
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Nutritional Research.
    Jansson, Jan-Håkan
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine.
    Norberg, Margareta
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Epidemiology and Global Health.
    Skerfving, Staffan
    Strömberg, Ulf
    Wiklund, Per-Gunnar
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine.
    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.
    Fish consumption and risk of stroke: a second prospective case-control study from northern Sweden2016In: Nutrition Journal, ISSN 1475-2891, E-ISSN 1475-2891, Vol. 15, no 1, article id 98Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: Fish consumption has been concluded to be associated with decreased risk of stroke in several reviews. However, among men, but not women, an increased risk of stroke was previously found at high fish consumption (>3 meals/week) in northern Sweden. This study investigates if previous results on elevated stroke risk with high fish consumption in men in northern Sweden can be confirmed in a larger study with new cases in the same population.

    METHODS: A prospective nested case-control study was performed within the population-based Northern Sweden Health and Disease Study cohort. Information on fish consumption, other lifestyle and medical data was collected at baseline. Incident stroke cases (1987-2007, n = 735) were identified and 2698 controls matched for gender, age, year of baseline and geographical region.

    RESULTS: There were no associations between total fish or fatty fish consumption and stroke risk; thus the previous finding of increased risk of stroke with high fish consumption in men could not be repeated. High intake of lean fish (>twice/week compared to < once/month) was associated with increased stroke risk in men [OR 1.80 (95% CI 1.00, 3.21), but not in women [OR 0.50 (95% CI 0.24, 1.10)]. The association was driven by men living alone.

    CONCLUSIONS: The previous association between high total fish consumption and risk of stroke in men could not be repeated. The increased risk found in men with high intake of lean fish may be due to chance or confounding specific for this group.

  • 262.
    Wennberg, Maria
    et al.
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Nutritional Research.
    Lindh, Christian
    Occupational and Environmental Medicine, Lund University, Lund, Sweden.
    Bergdahl, Ingvar
    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.
    Organiska miljöföroreningar i urin hos unga i norra och södra Sverige2018Report (Other academic)
    Abstract [sv]

    Det är viktigt att följa halter av miljöföroreningar hos människor, för riskvärdering och för att få kunskap om hur exponeringen kan minskas.

    Organiska miljöföroreningar (ftalat-metaboliter, bisfenol A, bisfenol F, triklosan, pesticiderna 3-PBA och TCP samt PAH-metaboliten 1-HP) analyserades i urin hos 204 unga i Skåne (gymnasieelever, år 2013) och hos 143 unga i MONICA-studien i norra Sverige (25-35 år, år 2014). Koncentrationer jämfördes statistiskt mellan studierna och kopplingar till levnadsvanor som efterfrågades i båda studierna undersöktes (rökning, fiskintag, intag av mat från konserver och typ av golv i sovrum). En kompletterande enkätstudie gjordes på deltagarna i MONICA-studien som uppgav att de hade plastgolv i sovrummet (n=65), för att utröna om golvvärme under plastgolv i sovrummet kan öka exponering av "plast-ftalaten" MBzP.

    De statistiskt säkerställda skillnader som uppdagades var att de unga i norr hade högre koncentration av de flesta ftalat-metaboliter och av pesticiden 3-PBA medan de unga i söder hade högre koncentration av triklosan.

    Ftalat-metaboliten MBzP kunde kopplas till att ha plastgolv i sovrummet i båda studiepopulationerna. Då endast fyra personer i MONICA-studien uppgav golvvärme under plastgolv och den gruppen inte hade anmärkningsvärt hög MBzP-koncentration i urin kan inte högre användning av golvvärme i norr vara förklaringen till högre koncentration av MBzP i norra Sverige.

    Skillnader i levnadsförhållanden av betydelse för exponering av miljöföroreningarna som beror på den åldersskillnad som fanns mellan studiepopulationerna i norr och söder, och inte undersöktes i den här studien, kan inte uteslutas. Framtida geografiska jämförelser av miljöföroreningar hos människor bör om möjligt göras på människor i samma åldersintervall.

  • 263.
    Wennberg, Maria
    et al.
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Nutritional Research.
    Lundh, Thomas
    Nilsson Sommar, Johan
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Occupational and Environmental Medicine.
    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.
    Time trends and exposure determinants of lead and cadmium in the adult population of northern Sweden 1990-20142017In: Environmental Research, ISSN 0013-9351, E-ISSN 1096-0953, Vol. 159, p. 111-117Article in journal (Refereed)
    Abstract [en]

    INTRODUCTION: This study follows cadmium and lead concentrations in blood in the adult population in northern Sweden over 24 years.

    MATERIAL AND METHODS: Concentrations of lead and cadmium were measured in single whole blood samples (B-Pb and B-Cd) from 619 men and 926 women participating in the Northern Sweden WHO MONICA Study on one occasion 1990-2014. Associations with smoking and dietary factors were investigated. Consumption of moose meat was asked for in 2014.

    RESULTS: In the adult population in northern Sweden, the median B-Pb in 2014 was 11.0µg/L in young (25-35 years) men and 9.69µg/L in young women. In an older age-group (50-60 years), the median B-Pb was 15.1µg/L in men and 13.1µg/L in women. B-Pb decreased from 1990 to 2009, after which time no further decrease was observed. B-Pb was higher in smokers than in non-smokers. In never-smokers, positive associations were found between B-Pb and consumption of wine and brewed coffee (women only) in 2004-2014. Higher B-Pb with consumption of moose meat was demonstrated in men, but not in women. B-Cd was essentially stable over the whole period, but an increase in B-Cd, of 3% per year, was detected in never-smoking women between 2009 and 2014. In 2014, median B-Cd in never-smokers in the four groups was; 0.11µg/L in younger men, 0.15µg/L in younger women, 0.14µg/L in older men, and 0.21µg/L in older women. B-Cd was higher in smokers than in non-smokers. The only positive association between B-Cd and food items in 2004-2014 was with consumption of brewed coffee (men only).

    CONCLUSIONS: The lack of a decrease in B-Cd from 1990 to 2014 and the absence of a further decrease in B-Pb after 2009 are unsatisfactory considering the health risks these metals pose in the general population at current concentrations.

  • 264.
    Wennberg, Maria
    et al.
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Nutritional Research.
    Ruuth, Anders
    Department of Obstetrics and Gynaecology, Sunderby Hospital, Luleå, Sweden.
    Andersson, Liselott
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Obstetrics and Gynecology. Department of Obstetrics and Gynaecology, Sunderby Hospital, Luleå, Sweden.
    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.
    Mercury concentrations in pregnant women in circumpolar Sweden (Kiruna)2018Report (Other academic)
    Abstract [en]

    High exposure to mercury have been found in populations living in circumpolar areas, due to high consumption of sea food and accumulation of mercury closer to the north pole. The developing fetus is especially sensitive to effects of mercury. Exposure to mercury has previously been examined in pregnant women in Sweden, but not in pregnant women residing in Sweden north of the polar circle.

    In the years 2015-2016, mercury was measured in whole blood from 51 pregnant women living in the city of Kiruna in circumpolar Sweden, taking part in an international comparison between eight circumpolar countries. This report presents the Swedish results on mercury concentrations and associations with some exposure determinants. Also, compliance to dietary advice on fish consumption, appointed to fertile women, was examined.

    The median concentration of total-Hg in whole blood was 0.40 μg/L (min, max; <0.40, 1.88) among the 51 pregnant women in Kiruna. This is similar or lower compared to concentrations of mercury in pregnant women in other parts of Sweden. None of the women in the study had concentrations of mercury that are considered as dangerous.

    Mercury concentrations were associated with total fish consumption but not to consumption of predatory fish, known to be higher in mercury. All of the women in the study had knowledge about dietary advice on fish consumption. One woman exceeded the recommended consumption of predatory fish, limited due to risk of high mercury content, but this woman did not have high concentrations of mercury. While the vast majority of women thus followed the recommendations of not eating too much polluted fish, only 15 % of the women reported sufficient fish consumption to comply with the dietary advice (2-3 times/week).

    In conclusion, pregnant women in circumpolar Sweden have low exposure to mercury, and do not deviant from pregnant women in other parts of Sweden. Knowledge about dietary advice on fish consumption appointed to fertile women is very good. The public health concern though, is that pregnant women in circumpolar Sweden do not eat enough fish.

  • 265. Wessel, Jennifer
    et al.
    Chu, Audrey Y.
    Willems, Sara M.
    Wang, Shuai
    Yaghootkar, Hanieh
    Brody, Jennifer A.
    Dauriz, Marco
    Hivert, Marie-France
    Raghavan, Sridharan
    Lipovich, Leonard
    Hidalgo, Bertha
    Fox, Keolu
    Huffman, Jennifer E.
    An, Ping
    Lu, Yingchang
    Rasmussen-Torvik, Laura J.
    Grarup, Niels
    Ehm, Margaret G.
    Li, Li
    Baldridge, Abigail S.
    Stancakova, Alena
    Abrol, Ravinder
    Besse, Celine
    Boland, Anne
    Bork-Jensen, Jette
    Fornage, Myriam
    Freitag, Daniel F.
    Garcia, Melissa E.
    Guo, Xiuqing
    Hara, Kazuo
    Isaacs, Aaron
    Jakobsdottir, Johanna
    Lange, Leslie A.
    Layton, Jill C.
    Li, Man
    Zhao, Jing Hua
    Meidtner, Karina
    Morrison, Alanna C.
    Nalls, Mike A.
    Peters, Marjolein J.
    Sabater-Lleal, Maria
    Schurmann, Claudia
    Silveira, Angela
    Smith, Albert V.
    Southam, Lorraine
    Stoiber, Marcus H.
    Strawbridge, Rona J.
    Taylor, Kent D.
    Varga, Tibor V.
    Allin, Kristine H.
    Amin, Najaf
    Aponte, Jennifer L.
    Aung, Tin
    Barbieri, Caterina
    Bihlmeyer, Nathan A.
    Boehnke, Michael
    Bombieri, Cristina
    Bowden, Donald W.
    Burns, Sean M.
    Chen, Yuning
    Chen, Yii-Deri
    Cheng, Ching-Yu
    Correa, Adolfo
    Czajkowski, Jacek
    Dehghan, Abbas
    Ehret, Georg B.
    Eiriksdottir, Gudny
    Andersson Escher, Stefan
    Farmaki, Aliki-Eleni
    Franberg, Mattias
    Gambaro, Giovanni
    Giulianini, Franco
    Goddard, William A., III
    Goel, Anuj
    Gottesman, Omri
    Grove, Megan L.
    Gustafsson, Stefan
    Hai, Yang
    Hallmans, Goeran
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Nutritional Research. Umeå University, Faculty of Medicine, Department of Biobank Research.
    Heo, Jiyoung
    Hoffmann, Per
    Ikram, Mohammad K.
    Jensen, Richard A.
    Jorgensen, Marit E.
    Jorgensen, Torben
    Karaleftheri, Maria
    Khor, Chiea C.
    Kirkpatrick, Andrea
    Kraja, Aldi T.
    Kuusisto, Johanna
    Lange, Ethan M.
    Lee, I. T.
    Lee, Wen-Jane
    Leong, Aaron
    Liao, Jiemin
    Liu, Chunyu
    Liu, Yongmei
    Lindgren, Cecilia M.
    Linneberg, Allan
    Malerba, Giovanni
    Mamakou, Vasiliki
    Marouli, Eirini
    Maruthur, Nisa M.
    Matchan, Angela
    McKean-Cowdin, Roberta
    McLeod, Olga
    Metcalf, Ginger A.
    Mohlke, Karen L.
    Muzny, Donna M.
    Ntalla, Ioanna
    Palmer, Nicholette D.
    Pasko, Dorota
    Peter, Andreas
    Rayner, Nigel W.
    Renstroem, Frida
    Umeå University, Faculty of Medicine, Department of Biobank Research.
    Rice, Ken
    Sala, Cinzia F.
    Sennblad, Bengt
    Serafetinidis, Ioannis
    Smith, Jennifer A.
    Soranzo, Nicole
    Speliotes, Elizabeth K.
    Stahl, Eli A.
    Stirrups, Kathleen
    Tentolouris, Nikos
    Thanopoulou, Anastasia
    Torres, Mina
    Traglia, Michela
    Tsafantakis, Emmanouil
    Javad, Sundas
    Yanek, Lisa R.
    Zengini, Eleni
    Becker, Diane M.
    Bis, Joshua C.
    Brown, James B.
    Cupples, L. Adrienne
    Hansen, Torben
    Ingelsson, Erik
    Karter, Andrew J.
    Lorenzo, Carlos
    Mathias, Rasika A.
    Norris, Jill M.
    Peloso, Gina M.
    Sheu, Wayne H. -H.
    Toniolo, Daniela
    Vaidya, Dhananjay
    Varma, Rohit
    Wagenknecht, Lynne E.
    Boeing, Heiner
    Bottinger, Erwin P.
    Dedoussis, George
    Deloukas, Panos
    Ferrannini, Ele
    Franco, Oscar H.
    Franks, Paul W.
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine.
    Gibbs, Richard A.
    Gudnason, Vilmundur
    Hamsten, Anders
    Harris, Tamara B.
    Hattersley, Andrew T.
    Hayward, Caroline
    Hofman, Albert
    Jansson, Jan-Håkan
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine.
    Langenberg, Claudia
    Launer, Lenore J.
    Levy, Daniel
    Oostra, Ben A.
    O'Donnell, Christopher J.
    O'Rahilly, Stephen
    Padmanabhan, Sandosh
    Pankow, James S.
    Polasek, Ozren
    Province, Michael A.
    Rich, Stephen S.
    Ridker, Paul M.
    Rudan, Igor
    Schulze, Matthias B.
    Smith, Blair H.
    Uitterlinden, Andre G.
    Walker, Mark
    Watkins, Hugh
    Wong, Tien Y.
    Zeggini, Eleftheria
    Laakso, Markku
    Borecki, Ingrid B.
    Chasman, Daniel I.
    Pedersen, Oluf
    Psaty, Bruce M.
    Tai, E. Shyong
    van Duijn, Cornelia M.
    Wareham, Nicholas J.
    Waterworth, Dawn M.
    Boerwinkle, Eric
    Kao, W. H. Linda
    Florez, Jose C.
    Loos, Ruth J. F.
    Wilson, James G.
    Frayling, Timothy M.
    Siscovick, David S.
    Dupuis, Josee
    Rotter, Jerome I.
    Meigs, James B.
    Scott, Robert A.
    Goodarzi, Mark O.
    Sharp, Stephen J.
    Forouhi, Nita G.
    Kerrison, Nicola D.
    Lucarelli, Debora M. E.
    Sims, Matt
    Barroso, Ines
    McCarthy, Mark I.
    Arriola, Larraitz
    Balkau, Beverley
    Barricarte, Aurelio
    Gonzalez, Carlos
    Grioni, Sara
    Kaaks, Rudolf
    Key, Timothy J.
    Navarro, Carmen
    Nilsson, Peter M.
    Overvad, Kim
    Palli, Domenico
    Panico, Salvatore
    Quiros, J. Ramon
    Rolandsson, Olov
    Umeå University, Faculty of Medicine, Department of Biobank Research.
    Sacerdote, Carlotta
    Sanchez, Maria-Jose
    Slimani, Nadia
    Tjonneland, Anne
    Tumino, Rosario
    van der A, Daphne L.
    van der Schouw, Yvonne T.
    Riboli, Elio
    Low-frequency and rare exome chip variants associate with fasting glucose and type 2 diabetes susceptibility2015In: Nature Communications, ISSN 2041-1723, E-ISSN 2041-1723, Vol. 6, article id 5897Article in journal (Refereed)
    Abstract [en]

    Fasting glucose and insulin are intermediate traits for type 2 diabetes. Here we explore the role of coding variation on these traits by analysis of variants on the HumanExome BeadChip in 60,564 non-diabetic individuals and in 16,491 T2D cases and 81,877 controls. We identify a novel association of a low-frequency nonsynonymous SNV in GLP1R (A316T; rs10305492; MAF = 1.4%) with lower FG (beta = -0.09 +/- 0.01 mmol l(-1), P = 3.4 x 10(-12)), T2D risk (OR[95% CI] = 0.86[0.76-0.96], P = 0.010), early insulin secretion (beta = -0.07 +/- 0.035 pmol(insulin) mmol(glucose)(-1), P = 0.048), but higher 2-h glucose (beta = 0.16 +/- 0.05 mmol l(-1), P = 4.3 x 10(-4)). We identify a gene-based association with FG at G6PC2 (p(SKAT) = 6.8 x 10(-6)) driven by four rare protein-coding SNVs (H177Y, Y207S, R283X and S324P). We identify rs651007 (MAF = 20%) in the first intron of ABO at the putative promoter of an antisense lncRNA, associating with higher FG (beta = 0.02 +/- 0.004 mmol l(-1), P = 1.3 x 10(-8)). Our approach identifies novel coding variant associations and extends the allelic spectrum of variation underlying diabetes-related quantitative traits and T2D susceptibility.

  • 266. Willems, Sara M.
    et al.
    Wright, Daniel J.
    Day, Felix R.
    Trajanoska, Katerina
    Joshi, Peter K.
    Morris, John A.
    Matteini, Amy M.
    Garton, Fleur C.
    Grarup, Niels
    Oskolkov, Nikolay
    Thalamuthu, Anbupalam
    Mangino, Massimo
    Liu, Jun
    Demirkan, Ayse
    Lek, Monkol
    Xu, Liwen
    Wang, Guan
    Oldmeadow, Christopher
    Gaulton, Kyle J.
    Lotta, Luca A.
    Miyamoto-Mikami, Eri
    Rivas, Manuel A.
    White, Tom
    Loh, Po-Ru
    Aadahl, Mette
    Amin, Najaf
    Attia, John R.
    Austin, Krista
    Benyamin, Beben
    Brage, Soren
    Cheng, Yu-Ching
    Cieszczyk, Pawel
    Derave, Wim
    Eriksson, Karl-Fredrik
    Eynon, Nir
    Linneberg, Allan
    Lucia, Alejandro
    Massidda, Myosotis
    Mitchell, Braxton D.
    Miyachi, Motohiko
    Murakami, Haruka
    Padmanabhan, Sandosh
    Pandey, Ashutosh
    Papadimitriou, Loannis
    Rajpal, Deepak K.
    Sale, Craig
    Schnurr, Theresia M.
    Sessa, Francesco
    Shrine, Nick
    Tobin, Martin D.
    Varley, Ian
    Wain, Louise V.
    Wray, Naomi R.
    Lindgren, Cecilia M.
    MacArthur, Daniel G.
    Waterworth, Dawn M.
    McCarthy, Mark I.
    Pedersen, Oluf
    Khaw, Kay-Tee
    Kie, Douglas P.
    Pitsiladis, Yannis
    Fuku, Noriyuki
    Franks, Paul W.
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine. Umeå University, Faculty of Medicine, Department of Biobank Research. Genetic and Molecular Epidemiology Unit, Department of Clinical Sciences, Lund University, Skånes University Hospital, 222 41 Lund, Sweden.
    North, Kathryn N.
    van Duijn, Cornelia M.
    Mather, Karen A.
    Hansen, Torben
    Hansson, Ola
    Spector, Tim
    Murabito, Joanne M.
    Richards, J. Brent
    Rivadeneira, Fernando
    Langenberg, Claudia
    Perry, John R. B.
    Wareham, Nick J.
    Scott, Robert A.
    Large-scale GWAS identifies multiple loci for hand grip strength providing biological insights into muscular fitness2017In: Nature Communications, ISSN 2041-1723, E-ISSN 2041-1723, Vol. 8, article id 16015Article in journal (Refereed)
    Abstract [en]

    Hand grip strength is a widely used proxy of muscular fitness, a marker of frailty, and predictor of a range of morbidities and all-cause mortality. To investigate the genetic determinants of variation in grip strength, we perform a large-scale genetic discovery analysis in a combined sample of 195,180 individuals and identify 16 loci associated with grip strength (P<5 x 10(-8)) in combined analyses. A number of these loci contain genes implicated in structure and function of skeletal muscle fibres (ACTG1), neuronal maintenance and signal transduction (PEX14, TGFA, SYT1), or monogenic syndromes with involvement of psychomotor impairment (PEX14, LRPPRC and KANSL1). Mendelian randomization analyses are consistent with a causal effect of higher genetically predicted grip strength on lower fracture risk. In conclusion, our findings provide new biological insight into the mechanistic underpinnings of grip strength and the causal role of muscular strength in age-related morbidities and mortality.

  • 267.
    Winkvist, Anna
    et al.
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Nutritional Research. Department of Internal Medicine and Clinical Nutrition, Sahlgenska Academy, University of Gothenburg, Box 459SE-405 30 Gothenburg, Sweden.
    Klingberg, Sofia
    Nilsson, Lena Maria
    Umeå University, Arctic Research Centre at Umeå University.
    Wennberg, Maria
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Nutritional Research.
    Renström, Frida
    Umeå University, Faculty of Medicine, Department of Biobank Research. Department of Clinical Sciences, Genetic & Molecular Epidemiology Unit, Lund University, Malmö, Sweden.
    Hallmans, Göran
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Nutritional Research.
    Boman, Kurt
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine.
    Johansson, Ingegerd
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Nutritional Research.
    Longitudinal 10-year changes in dietary intake and associations with cardio-metabolic risk factors in the Northern Sweden Health and Disease Study2017In: Nutrition Journal, ISSN 1475-2891, E-ISSN 1475-2891, Vol. 16, article id 20Article in journal (Refereed)
    Abstract [en]

    Background: Dietary risks today constitute the largest proportion of disability-adjusted life years (DALYs) globally and in Sweden. An increasing number of people today consume highly processed foods high in saturated fat, refined sugar and salt and low in dietary fiber, vitamins and minerals. It is important that dietary trends over time are monitored to predict changes in disease risk.

    Methods: In total, 15,995 individuals with two visits 10 (±1) years apart in the population-based Västerbotten Intervention Programme 1996–2014 were included. Dietary intake was captured with a 64-item food frequency questionnaire. Percent changes in intake of dietary components, Healthy Diet Score and Dietary Inflammatory Index were calculated and related to body mass index (BMI), serum cholesterol and triglyceride levels and blood pressure at the second visit in multivariable regression analyses.

    Results: For both sexes, on group level, proportion of energy intake (E%) from carbohydrates and sucrose decreased (largest carbohydrate decrease among 40 year-olds) and E% protein and total fat as well as saturated and poly-unsaturated fatty acids (PUFA) increased (highest protein increase among 30 year-olds and highest fat increase among 60 year-olds) over the 10-year period. Also, E% trans-fatty acids decreased. On individual basis, for both sexes decreases in intake of cholesterol and trans-fatty acids were associated with lower BMI and serum cholesterol at second visit (all P < 0.05). For men, increases in intake of whole grain and Healthy Diet Score were associated with lower BMI and serum cholesterol at second visit (all P < 0.05). Also for men, decreases in intake of trans-fatty acids and increases in Healthy Diet Score were associated with lower systolic blood pressure at second visit (P = 0.002 and P < 0.000). For women, increases in intake of PUFA and Healthy Diet Score were associated with lower BMI at second visit (P = 0.01 and P < 0.05). Surprisingly, increases in intake of sucrose among women were associated with lower BMI at second visit (P = 0.02).

    Conclusions: In this large population-based sample, dietary changes over 10 years towards less carbohydrates and more protein and fat were noted. Individual changes towards the Nordic dietary recommendations were associated with healthier cardio-metabolic risk factor profile at second visit.

  • 268.
    Wirén, Sara
    et al.
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Urology and Andrology.
    Häggström, Christel
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Urology and Andrology.
    Ulmer, Hanno
    Manjer, Jonas
    Bjørge, Tone
    Nagel, Gabriele
    Johansen, Dorthe
    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.
    Engeland, Anders
    Concin, Hans
    Jonsson, Håkan
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Selmer, Randi
    Tretli, Steinar
    Stocks, Tanja
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Urology and Andrology.
    Stattin, Pär
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Urology and Andrology.
    Pooled cohort study on height and risk of cancer and cancer death2014In: Cancer Causes and Control, ISSN 0957-5243, E-ISSN 1573-7225, Vol. 25, no 2, p. 151-159Article in journal (Refereed)
    Abstract [en]

    PURPOSE: To assess the association between height and risk of cancer and cancer death.

    METHODS: The metabolic syndrome and cancer project is a prospective pooled cohort study of 585,928 participants from seven cohorts in Austria, Norway, and Sweden. Hazard ratios (HRs) and 95 % confidence intervals (CIs) for cancer incidence and death were estimated in height categories and per 5-cm increment for each cancer site using Cox proportional hazards model.

    RESULTS: During a mean follow-up of 12.7 years (SD = 7.2), 38,862 participants were diagnosed with cancer and 13,547 participants died of cancer. Increased height (per 5-cm increment) was associated with an increased overall cancer risk in women, HR 1.07 (95 % CI 1.06-1.09), and in men, HR 1.04 (95 % CI 1.03-1.06). The highest HR was seen for malignant melanoma in women, HR 1.17 (95 % CI 1.11-1.24), and in men HR 1.12 (95 % CI 1.08-1.19). Height was also associated with increased risk of cancer death in women, HR 1.03 (95 % CI 1.01-1.16), and in men, HR 1.03 (95 % CI 1.01-1.05). The highest HR was observed for breast cancer death in postmenopausal women (>60 years), HR 1.10 (95 % CI 1.00-1.21), and death from renal cell carcinoma in men, HR 1.18 (95 % CI 1.07-1.30). All these associations were independent of body mass index.

    CONCLUSION: Height was associated with risk of cancer and cancer death indicating that factors related to height such as hormonal and genetic factors stimulate both cancer development and progression.

  • 269. Wood, Andrew R
    et al.
    Esko, Tonu
    Yang, Jian
    Vedantam, Sailaja
    Pers, Tune H
    Gustafsson, Stefan
    Chu, Audrey Y
    Estrada, Karol
    Luan, Jian'an
    Kutalik, Zoltán
    Amin, Najaf
    Buchkovich, Martin L
    Croteau-Chonka, Damien C
    Day, Felix R
    Duan, Yanan
    Fall, Tove
    Fehrmann, Rudolf
    Ferreira, Teresa
    Jackson, Anne U
    Karjalainen, Juha
    Lo, Ken Sin
    Locke, Adam E
    Mägi, Reedik
    Mihailov, Evelin
    Porcu, Eleonora
    Randall, Joshua C
    Scherag, André
    Vinkhuyzen, Anna A E
    Westra, Harm-Jan
    Winkler, Thomas W
    Workalemahu, Tsegaselassie
    Zhao, Jing Hua
    Absher, Devin
    Albrecht, Eva
    Anderson, Denise
    Baron, Jeffrey
    Beekman, Marian
    Demirkan, Ayse
    Ehret, Georg B
    Feenstra, Bjarke
    Feitosa, Mary F
    Fischer, Krista
    Fraser, Ross M
    Goel, Anuj
    Gong, Jian
    Justice, Anne E
    Kanoni, Stavroula
    Kleber, Marcus E
    Kristiansson, Kati
    Lim, Unhee
    Lotay, Vaneet
    Lui, Julian C
    Mangino, Massimo
    Mateo Leach, Irene
    Medina-Gomez, Carolina
    Nalls, Michael A
    Nyholt, Dale R
    Palmer, Cameron D
    Pasko, Dorota
    Pechlivanis, Sonali
    Prokopenko, Inga
    Ried, Janina S
    Ripke, Stephan
    Shungin, Dmitry
    Umeå University, Faculty of Medicine, Department of Odontology. Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine. Department of Clinical Sciences, Genetic and Molecular Epidemiology Unit, Lund University Diabetes Center, Skåne University Hospital, Malmö, Sweden.
    Stancáková, Alena
    Strawbridge, Rona J
    Sung, Yun Ju
    Tanaka, Toshiko
    Teumer, Alexander
    Trompet, Stella
    van der Laan, Sander W
    van Setten, Jessica
    Van Vliet-Ostaptchouk, Jana V
    Wang, Zhaoming
    Yengo, Loïc
    Zhang, Weihua
    Afzal, Uzma
    Arnlöv, Johan
    Arscott, Gillian M
    Bandinelli, Stefania
    Barrett, Amy
    Bellis, Claire
    Bennett, Amanda J
    Berne, Christian
    Blüher, Matthias
    Bolton, Jennifer L
    Böttcher, Yvonne
    Boyd, Heather A
    Bruinenberg, Marcel
    Buckley, Brendan M
    Buyske, Steven
    Caspersen, Ida H
    Chines, Peter S
    Clarke, Robert
    Claudi-Boehm, Simone
    Cooper, Matthew
    Daw, E Warwick
    De Jong, Pim A
    Deelen, Joris
    Delgado, Graciela
    Denny, Josh C
    Dhonukshe-Rutten, Rosalie
    Dimitriou, Maria
    Doney, Alex S F
    Dörr, Marcus
    Eklund, Niina
    Eury, Elodie
    Folkersen, Lasse
    Garcia, Melissa E
    Geller, Frank
    Giedraitis, Vilmantas
    Go, Alan S
    Grallert, Harald
    Grammer, Tanja B
    Gräßler, Jürgen
    Grönberg, Henrik
    de Groot, Lisette C P G M
    Groves, Christopher J
    Haessler, Jeffrey
    Hall, Per
    Haller, Toomas
    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.
    Hannemann, Anke
    Hartman, Catharina A
    Hassinen, Maija
    Hayward, Caroline
    Heard-Costa, Nancy L
    Helmer, Quinta
    Hemani, Gibran
    Henders, Anjali K
    Hillege, Hans L
    Hlatky, Mark A
    Hoffmann, Wolfgang
    Hoffmann, Per
    Holmen, Oddgeir
    Houwing-Duistermaat, Jeanine J
    Illig, Thomas
    Isaacs, Aaron
    James, Alan L
    Jeff, Janina
    Johansen, Berit
    Johansson, Asa
    Jolley, Jennifer
    Juliusdottir, Thorhildur
    Junttila, Juhani
    Kho, Abel N
    Kinnunen, Leena
    Klopp, Norman
    Kocher, Thomas
    Kratzer, Wolfgang
    Lichtner, Peter
    Lind, Lars
    Lindström, Jaana
    Lobbens, Stéphane
    Lorentzon, Mattias
    Lu, Yingchang
    Lyssenko, Valeriya
    Magnusson, Patrik K E
    Mahajan, Anubha
    Maillard, Marc
    McArdle, Wendy L
    McKenzie, Colin A
    McLachlan, Stela
    McLaren, Paul J
    Menni, Cristina
    Merger, Sigrun
    Milani, Lili
    Moayyeri, Alireza
    Monda, Keri L
    Morken, Mario A
    Müller, Gabriele
    Müller-Nurasyid, Martina
    Musk, Arthur W
    Narisu, Narisu
    Nauck, Matthias
    Nolte, Ilja M
    Nöthen, Markus M
    Oozageer, Laticia
    Pilz, Stefan
    Rayner, Nigel W
    Renström, Frida
    Umeå University, Faculty of Medicine, Department of Biobank Research. Department of Clinical Sciences, Genetic and Molecular Epidemiology Unit, Lund University Diabetes Center, Skåne University Hospital, Malmö, Sweden.
    Robertson, Neil R
    Rose, Lynda M
    Roussel, Ronan
    Sanna, Serena
    Scharnagl, Hubert
    Scholtens, Salome
    Schumacher, Fredrick R
    Schunkert, Heribert
    Scott, Robert A
    Sehmi, Joban
    Seufferlein, Thomas
    Shi, Jianxin
    Silventoinen, Karri
    Smit, Johannes H
    Smith, Albert Vernon
    Smolonska, Joanna
    Stanton, Alice V
    Stirrups, Kathleen
    Stott, David J
    Stringham, Heather M
    Sundström, Johan
    Swertz, Morris A
    Syvänen, Ann-Christine
    Tayo, Bamidele O
    Thorleifsson, Gudmar
    Tyrer, Jonathan P
    van Dijk, Suzanne
    van Schoor, Natasja M
    van der Velde, Nathalie
    van Heemst, Diana
    van Oort, Floor V A
    Vermeulen, Sita H
    Verweij, Niek
    Vonk, Judith M
    Waite, Lindsay L
    Waldenberger, Melanie
    Wennauer, Roman
    Wilkens, Lynne R
    Willenborg, Christina
    Wilsgaard, Tom
    Wojczynski, Mary K
    Wong, Andrew
    Wright, Alan F
    Zhang, Qunyuan
    Arveiler, Dominique
    Bakker, Stephan J L
    Beilby, John
    Bergman, Richard N
    Bergmann, Sven
    Biffar, Reiner
    Blangero, John
    Boomsma, Dorret I
    Bornstein, Stefan R
    Bovet, Pascal
    Brambilla, Paolo
    Brown, Morris J
    Campbell, Harry
    Caulfield, Mark J
    Chakravarti, Aravinda
    Collins, Rory
    Collins, Francis S
    Crawford, Dana C
    Cupples, L Adrienne
    Danesh, John
    de Faire, Ulf
    den Ruijter, Hester M
    Erbel, Raimund
    Erdmann, Jeanette
    Eriksson, Johan G
    Farrall, Martin
    Ferrannini, Ele
    Ferrières, Jean
    Ford, Ian
    Forouhi, Nita G
    Forrester, Terrence
    Gansevoort, Ron T
    Gejman, Pablo V
    Gieger, Christian
    Golay, Alain
    Gottesman, Omri
    Gudnason, Vilmundur
    Gyllensten, Ulf
    Haas, David W
    Hall, Alistair S
    Harris, Tamara B
    Hattersley, Andrew T
    Heath, Andrew C
    Hengstenberg, Christian
    Hicks, Andrew A
    Hindorff, Lucia A
    Hingorani, Aroon D
    Hofman, Albert
    Hovingh, G Kees
    Humphries, Steve E
    Hunt, Steven C
    Hypponen, Elina
    Jacobs, Kevin B
    Jarvelin, Marjo-Riitta
    Jousilahti, Pekka
    Jula, Antti M
    Kaprio, Jaakko
    Kastelein, John J P
    Kayser, Manfred
    Kee, Frank
    Keinanen-Kiukaanniemi, Sirkka M
    Kiemeney, Lambertus A
    Kooner, Jaspal S
    Kooperberg, Charles
    Koskinen, Seppo
    Kovacs, Peter
    Kraja, Aldi T
    Kumari, Meena
    Kuusisto, Johanna
    Lakka, Timo A
    Langenberg, Claudia
    Le Marchand, Loic
    Lehtimäki, Terho
    Lupoli, Sara
    Madden, Pamela A F
    Männistö, Satu
    Manunta, Paolo
    Marette, André
    Matise, Tara C
    McKnight, Barbara
    Meitinger, Thomas
    Moll, Frans L
    Montgomery, Grant W
    Morris, Andrew D
    Morris, Andrew P
    Murray, Jeffrey C
    Nelis, Mari
    Ohlsson, Claes
    Oldehinkel, Albertine J
    Ong, Ken K
    Ouwehand, Willem H
    Pasterkamp, Gerard
    Peters, Annette
    Pramstaller, Peter P
    Price, Jackie F
    Qi, Lu
    Raitakari, Olli T
    Rankinen, Tuomo
    Rao, D C
    Rice, Treva K
    Ritchie, Marylyn
    Rudan, Igor
    Salomaa, Veikko
    Samani, Nilesh J
    Saramies, Jouko
    Sarzynski, Mark A
    Schwarz, Peter E H
    Sebert, Sylvain
    Sever, Peter
    Shuldiner, Alan R
    Sinisalo, Juha
    Steinthorsdottir, Valgerdur
    Stolk, Ronald P
    Tardif, Jean-Claude
    Tönjes, Anke
    Tremblay, Angelo
    Tremoli, Elena
    Virtamo, Jarmo
    Vohl, Marie-Claude
    Amouyel, Philippe
    Asselbergs, Folkert W
    Assimes, Themistocles L
    Bochud, Murielle
    Boehm, Bernhard O
    Boerwinkle, Eric
    Bottinger, Erwin P
    Bouchard, Claude
    Cauchi, Stéphane
    Chambers, John C
    Chanock, Stephen J
    Cooper, Richard S
    de Bakker, Paul I W
    Dedoussis, George
    Ferrucci, Luigi
    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 Diabetes Center, Skåne University Hospital, Malmö, Sweden.
    Froguel, Philippe
    Groop, Leif C
    Haiman, Christopher A
    Hamsten, Anders
    Hayes, M Geoffrey
    Hui, Jennie
    Hunter, David J
    Hveem, Kristian
    Jukema, J Wouter
    Kaplan, Robert C
    Kivimaki, Mika
    Kuh, Diana
    Laakso, Markku
    Liu, Yongmei
    Martin, Nicholas G
    März, Winfried
    Melbye, Mads
    Moebus, Susanne
    Munroe, Patricia B
    Njølstad, Inger
    Oostra, Ben A
    Palmer, Colin N A
    Pedersen, Nancy L
    Perola, Markus
    Pérusse, Louis
    Peters, Ulrike
    Powell, Joseph E
    Power, Chris
    Quertermous, Thomas
    Rauramaa, Rainer
    Reinmaa, Eva
    Ridker, Paul M
    Rivadeneira, Fernando
    Rotter, Jerome I
    Saaristo, Timo E
    Saleheen, Danish
    Schlessinger, David
    Slagboom, P Eline
    Snieder, Harold
    Spector, Tim D
    Strauch, Konstantin
    Stumvoll, Michael
    Tuomilehto, Jaakko
    Uusitupa, Matti
    van der Harst, Pim
    Völzke, Henry
    Walker, Mark
    Wareham, Nicholas J
    Watkins, Hugh
    Wichmann, H-Erich
    Wilson, James F
    Zanen, Pieter
    Deloukas, Panos
    Heid, Iris M
    Lindgren, Cecilia M
    Mohlke, Karen L
    Speliotes, Elizabeth K
    Thorsteinsdottir, Unnur
    Barroso, Inês
    Fox, Caroline S
    North, Kari E
    Strachan, David P
    Beckmann, Jacques S
    Berndt, Sonja I
    Boehnke, Michael
    Borecki, Ingrid B
    McCarthy, Mark I
    Metspalu, Andres
    Stefansson, Kari
    Uitterlinden, André G
    van Duijn, Cornelia M
    Franke, Lude
    Willer, Cristen J
    Price, Alkes L
    Lettre, Guillaume
    Loos, Ruth J F
    Weedon, Michael N
    Ingelsson, Erik
    O'Connell, Jeffrey R
    Abecasis, Goncalo R
    Chasman, Daniel I
    Goddard, Michael E
    Visscher, Peter M
    Hirschhorn, Joel N
    Frayling, Timothy M
    Defining the role of common variation in the genomic and biological architecture of adult human height2014In: Nature Genetics, ISSN 1061-4036, E-ISSN 1546-1718, Vol. 46, no 11, p. 1173-1186Article in journal (Refereed)
    Abstract [en]

    Using genome-wide data from 253,288 individuals, we identified 697 variants at genome-wide significance that together explained one-fifth of the heritability for adult height. By testing different numbers of variants in independent studies, we show that the most strongly associated ∼2,000, ∼3,700 and ∼9,500 SNPs explained ∼21%, ∼24% and ∼29% of phenotypic variance. Furthermore, all common variants together captured 60% of heritability. The 697 variants clustered in 423 loci were enriched for genes, pathways and tissue types known to be involved in growth and together implicated genes and pathways not highlighted in earlier efforts, such as signaling by fibroblast growth factors, WNT/β-catenin and chondroitin sulfate-related genes. We identified several genes and pathways not previously connected with human skeletal growth, including mTOR, osteoglycin and binding of hyaluronic acid. Our results indicate a genetic architecture for human height that is characterized by a very large but finite number (thousands) of causal variants.

  • 270. Wu, Chen
    et al.
    Kraft, Peter
    Stolzenberg-Solomon, Rachael
    Steplowski, Emily
    Brotzman, Michelle
    Xu, Mousheng
    Mudgal, Poorva
    Amundadottir, Laufey
    Arslan, Alan A
    Bueno-de-Mesquita, H Bas
    Gross, Myron
    Helzlsouer, Kathy
    Jacobs, Eric J
    Kooperberg, Charles
    Petersen, Gloria M
    Zheng, Wei
    Albanes, Demetrius
    Boutron-Ruault, Marie-Christine
    Buring, Julie E
    Canzian, Federico
    Cao, Guangwen
    Duell, Eric J
    Elena, Joanne W
    Gaziano, J Michael
    Giovannucci, Edward L
    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.
    Hutchinson, Amy
    Hunter, David J
    Jenab, Mazda
    Jiang, Guoliang
    Khaw, Kay-Tee
    Lacroix, Andrea
    Li, Zhaoshen
    Mendelsohn, Julie B
    Panico, Salvatore
    Patel, Alpa V
    Qian, Zhi Rong
    Riboli, Elio
    Sesso, Howard
    Shen, Hongbing
    Shu, Xiao-Ou
    Tjonneland, Anne
    Tobias, Geoffrey S
    Trichopoulos, Dimitrios
    Virtamo, Jarmo
    Visvanathan, Kala
    Wactawski-Wende, Jean
    Wang, Chengfeng
    Yu, Kai
    Zeleniuch-Jacquotte, Anne
    Chanock, Stephen
    Hoover, Robert
    Hartge, Patricia
    Fuchs, Charles S
    Lin, Dongxin
    Wolpin, Brian M
    Genome-wide association study of survival in patients with pancreatic adenocarcinoma2014In: Gut, ISSN 0017-5749, E-ISSN 1468-3288, Vol. 63, no 1, p. 152-160Article in journal (Refereed)
    Abstract [en]

    BACKGROUND AND OBJECTIVE: Survival of patients with pancreatic adenocarcinoma is limited and few prognostic factors are known. We conducted a two-stage genome-wide association study (GWAS) to identify germline variants associated with survival in patients with pancreatic adenocarcinoma. METHODS: We analysed overall survival in relation to single nucleotide polymorphisms (SNPs) among 1005 patients from two large GWAS datasets, PanScan I and ChinaPC. Cox proportional hazards regression was used in an additive genetic model with adjustment for age, sex, clinical stage and the top four principal components of population stratification. The first stage included 642 cases of European ancestry (PanScan), from which the top SNPs (p≤10(-5)) were advanced to a joint analysis with 363 additional patients from China (ChinaPC). RESULTS: In the first stage of cases of European descent, the top-ranked loci were at chromosomes 11p15.4, 18p11.21 and 1p36.13, tagged by rs12362504 (p=1.63×10(-7)), rs981621 (p=1.65×10(-7)) and rs16861827 (p=3.75×10(-7)), respectively. 131 SNPs with p≤10(-5) were advanced to a joint analysis with cases from the ChinaPC study. In the joint analysis, the top-ranked SNP was rs10500715 (minor allele frequency, 0.37; p=1.72×10(-7)) on chromosome 11p15.4, which is intronic to the SET binding factor 2 (SBF2) gene. The HR (95% CI) for death was 0.74 (0.66 to 0.84) in PanScan I, 0.79 (0.65 to 0.97) in ChinaPC and 0.76 (0.68 to 0.84) in the joint analysis. CONCLUSIONS: Germline genetic variation in the SBF2 locus was associated with overall survival in patients with pancreatic adenocarcinoma of European and Asian ancestry. This association should be investigated in additional large patient cohorts.

  • 271. Zheng, Hou-Feng
    et al.
    Forgetta, Vincenzo
    Hsu, Yi-Hsiang
    Estrada, Karol
    Rosello-Diez, Alberto
    Leo, Paul J.
    Dahia, Chitra L.
    Park-Min, Kyung Hyun
    Tobias, Jonathan H.
    Kooperberg, Charles
    Kleinman, Aaron
    Styrkarsdottir, Unnur
    Liu, Ching-Ti
    Uggla, Charlotta
    Evans, Daniel S.
    Nielson, Carrie M.
    Walter, Klaudia
    Pettersson-Kymmer, Ulrika
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Nutritional Research. Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Pharmacology.
    McCarthy, Shane
    Eriksson, Joel
    Kwan, Tony
    Jhamai, Mila
    Trajanoska, Katerina
    Memari, Yasin
    Min, Josine
    Huang, Jie
    Danecek, Petr
    Wilmot, Beth
    Li, Rui
    Chou, Wen-Chi
    Mokry, Lauren E.
    Moayyeri, Alireza
    Claussnitzer, Melina
    Cheng, Chia-Ho
    Cheung, Warren
    Medina-Gomez, Carolina
    Ge, Bing
    Chen, Shu-Huang
    Choi, Kwangbom
    Oei, Ling
    Fraser, James
    Kraaij, Robert
    Hibbs, Matthew A.
    Gregson, Celia L.
    Paquette, Denis
    Hofman, Albert
    Wibom, Carl
    Umeå University, Faculty of Medicine, Department of Radiation Sciences.
    Tranah, Gregory J.
    Marshall, Mhairi
    Gardiner, Brooke B.
    Cremin, Katie
    Auer, Paul
    Hsu, Li
    Ring, Sue
    Tung, Joyce Y.
    Thorleifsson, Gudmar
    Enneman, Anke W.
    van Schoor, Natasja M.
    de Groot, Lisette C. P. G. M.
    van der Velde, Nathalie
    Melin, Beatrice
    Umeå University, Faculty of Medicine, Department of Radiation Sciences.
    Kemp, John P.
    Christiansen, Claus
    Sayers, Adrian
    Zhou, Yanhua
    Calderari, Sophie
    van Rooij, Jeroen
    Carlson, Chris
    Peters, Ulrike
    Berlivet, Soizik
    Dostie, Josee
    Uitterlinden, Andre G.
    Williams, Stephen R.
    Farber, Charles
    Grinberg, Daniel
    LaCroix, Andrea Z.
    Haessler, Jeff
    Chasman, Daniel I.
    Giulianini, Franco
    Rose, Lynda M.
    Ridker, Paul M.
    Eisman, John A.
    Nguyen, Tuan V.
    Center, Jacqueline R.
    Nogues, Xavier
    Garcia-Giralt, Natalia
    Launer, Lenore L.
    Gudnason, Vilmunder
    Mellstrom, Dan
    Vandenput, Liesbeth
    Amin, Najaf
    van Duijn, Cornelia M.
    Karlsson, Magnus K.
    Ljunggren, Osten
    Svensson, Olle
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences.
    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.
    Rousseau, Francois
    Giroux, Sylvie
    Bussiere, Johanne
    Arp, Pascal P.
    Koromani, Fjorda
    Prince, Richard L.
    Lewis, Joshua R.
    Langdahl, Bente L.
    Hermann, A. Pernille
    Jensen, Jens-Erik B.
    Kaptoge, Stephen
    Khaw, Kay-Tee
    Reeve, Jonathan
    Formosa, Melissa M.
    Xuereb-Anastasi, Angela
    Akesson, Kristina
    McGuigan, Fiona E.
    Garg, Gaurav
    Olmos, Jose M.
    Zarrabeitia, Maria T.
    Riancho, Jose A.
    Ralston, Stuart H.
    Alonso, Nerea
    Jiang, Xi
    Goltzman, David
    Pastinen, Tomi
    Grundberg, Elin
    Gauguier, Dominique
    Orwoll, Eric S.
    Karasik, David
    Davey-Smith, George
    Smith, Albert V.
    Siggeirsdottir, Kristin
    Harris, Tamara B.
    Zillikens, M. Carola
    van Meurs, Joyce B. J.
    Thorsteinsdottir, Unnur
    Maurano, Matthew T.
    Timpson, Nicholas J.
    Soranzo, Nicole
    Durbin, Richard
    Wilson, ScottG.
    Ntzani, Evangelia E.
    Brown, Matthew A.
    Stefansson, Kari
    Hinds, David A.
    Spector, Tim
    Cupples, L. Adrienne
    Ohlsson, Claes
    Greenwood, Celia M. T.
    Jackson, Rebecca D.
    Rowe, David W.
    Loomis, Cynthia A.
    Evans, David M.
    Ackert-Bicknell, Cheryl L.
    Joyner, Alexandra L.
    Duncan, Emma L.
    Kiel, Douglas P.
    Rivadeneira, Fernando
    Richards, J. Brent
    Whole-genome sequencing identifies EN1 as a determinant of bone density and fracture2015In: Nature, ISSN 0028-0836, E-ISSN 1476-4687, Vol. 526, no 7571, p. 112-+Article in journal (Refereed)
    Abstract [en]

    The extent to which low-frequency (minor allele frequency (MAF) between 1-5%) and rare (MAF <= 1%) variants contribute to complex traits and disease in the general population is mainly unknown. Bone mineral density (BMD) is highly heritable, a major predictor of osteoporotic fractures, and has been previously associated with common genetic variants(1-8), as well as rare, population specific, coding variants(9). Here we identify novel non-coding genetic variants with large effects on BMD (n(total) = 53,236) and fracture (n(total) = 508,253) in individuals of European ancestry from the general population. Associations for BMD were derived from whole-genome sequencing (n = 2,882 from UK10K (ref. 10); a population-based genome sequencing consortium), whole-exome sequencing (n = 3,549), deep imputation of genotyped samples using a combined UK10K/1000 Genomes reference panel (n = 26,534), and de novo replication genotyping (n = 20,271). We identified a low-frequency non-coding variant near a novel locus, EN1, with an effect size fourfold larger than the mean of previously reported common variants for lumbar spine BMD8 (rs11692564(T), MAF51.6%, replication effect size510.20 s.d., P-meta = 2 x 10(-14)), which was also associated with a decreased risk of fracture (odds ratio = 0.85; P = 2 x 10(-11); ncases = 98,742 and ncontrols = 409,511). Using an En1cre/flox mouse model, we observed that conditional loss of En1 results in low bone mass, probably as a consequence of high bone turnover. We also identified a novel low frequency non-coding variant with large effects on BMD near WNT16 (rs148771817(T), MAF = 1.2%, replication effect size +10.41 s.d., P-meta = 1 x 10(-11)). In general, there was an excess of association signals arising from deleterious coding and conserved non-coding variants. These findings provide evidence that low-frequency non-coding variants have large effects on BMD and fracture, thereby providing rationale for whole-genome sequencing and improved imputation reference panels to study the genetic architecture of complex traits and disease in the general population.

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