Trans-ancestry genome-wide association study identifies 12 genetic loci influencing blood pressure and implicates a role for DNA methylation

Norihiro Kato, Marie Loh, Fumihiko Takeuchi, Niek Verweij, Xu Wang, Weihua Zhang, Tanika NKelly, Danish Saleheen, Benjamin Lehne, Irene Mateo Leach, Alexander W. Drong, James Abbott, Simone Wahl, Sian Tsung Tan, William R. Scott, Gianluca Campanella, Marc Chadeau-Hyam, Uzma Afzal, Tarunveer S. Ahluwalia, Marc Jan BonderPeng Chen, Abbas Dehghan, Todd L. Edwards, Tõnu Esko, Min Jin Go, Sarah E. Harris, Jaana Hartiala, Silva Kasela, Anuradhani Kasturiratne, Chiea Chuen Khor, Marcus E. Kleber, Huaixing Li, Zuan Yu Mok, Masahiro Nakatochi, Nur Sabrina Sapari, Richa Saxena, Alexandre F R Stewart, Lisette Stolk, Yasuharu Tabara, Ai Ling Teh, Ying Wu, Jer Yuarn Wu, Yi Zhang, Imke Aits, Alexessander Da Silva Couto Alves, Shikta Das, Rajkumar Dorajoo, Jemma CHopewell, Yun Kyoung Kim, Robert WKoivula, Jian'An Luan, Leo Pekka Lyytikäinen, Quang NNguyen, Mark A. Pereira, Iris Postmus, Olli TRaitakari, Molly Scannell Bryan, Robert A. Scott, Rossella Sorice, Vinicius Tragante, Michela Traglia, Jon White, Ken Yamamoto, Yonghong Zhang, Linda S. Adair, Alauddin Ahmed, Koichi Akiyama, Rasheed Asif, Tin Aung, Inês Barroso, Andrew Bjonnes, Timothy R. Braun, Hui Cai, Li Ching Chang, Chien Hsiun Chen, Ching Yu Cheng, Yap Seng Chong, Rory Collins, Regina Courtney, Gail Davies, Graciela Delgado, Loi D. Do, Pieter A. Doevendans, Ron T. Gansevoort, Yu Tang Gao, Tanja B. Grammer, Niels Grarup, Jagvir Grewal, Dongfeng Gu, Gurpreet SWander, Anna Liisa Hartikainen, Stanley L. Hazen, Jing He, Chew Kiat Heng, E. James Ames Hixso, Albert Hofman, Chris Hsu, Wei Huang, Lise L N Husemoen, Joo Yeon Hwang, Sahoko Ichihara, Michiya Igase, Masato Isono, Johanne M. Justesen, Tomohiro Katsuya, Muhammad GKibriya, Young Jin Kim, Miyako Kishimoto, Woon Puay Koh, Katsuhiko Kohara, Meena Kumari, Kenneth Kwek, Nanette R. Lee, Jeannette Lee, Jiemin Liao, Wolfgang Lieb, David C M Liewald, Tatsuaki Matsubara, Yumi Matsushita, Thomas Meitinger, Evelin Mihailov, Lili Milani, Rebecca Mills, Nina Mononen, Martina Müller-Nurasyid, Toru Nabika, Eitaro Nakashima, Hong Kiat Ng, Kjell Nikus, Teresa Nutile, Takayoshi Ohkubo, Keizo Ohnaka, Sarah Parish, Lavinia Paternoster, Hao Peng, Annette Peters, Son TPham, Mohitha J. Pinidiyapathirage, Mahfuzar Rahman, Hiromi Rakugi, Olov Rolandsson, Michelle Ann Rozario, Daniela Ruggiero, Cinzia F. Sala, Ralhan Sarju, Kazuro Shimokawa, Harold Snieder, Thomas SparsØ, Wilko Spiering, John M. Starr, David J. Stott, Daniel OStram, Takao Sugiyama, Silke Szymczak, W. H Wilson Tang, Lin Tong, Stella Trompet, Väinö Turjanmaa, Hirotsugu Ueshima, André G. Uitterlinden, Satoshi Umemura, Marja Vaarasmaki, Rob Mvan Dam, Wiek H. Van Gilst, Dirk J. Van Veldhuisen, Jorma S. Viikari, Melanie Waldenberger, Yiqin Wang, Aili Wang, Rory Wilson, Tien Yin Wong, Yong Bing Xiang, Shuhei Yamaguchi, Xingwang Ye, Robin D. Young, Terri L. Young, Jian Min Yuan, Xueya Zhou, Folkert W. Asselbergs, Marina Ciullo, Robert Clarke, Panos Deloukas, Andre Franke, W. Frank Paul, Steve Franks, Yechiel Friedlander, Myron D. Gross, Zhirong Guo, Torben Hansen, Marjo Riitta Jarvelin, Torben JØrgensen, J. Wouter Jukema, Mika Kähönen, Hiroshi Kajio, Mika Kivimaki, Jong Young Lee, Terho Lehtimäki, Allan Linneberg, Tetsuro Miki, Oluf Pedersen, Nilesh J. Samani, Thorkild I A SØrensen, Ryoichi Takayanagi, Daniela Toniolo, Habibul Ahsan, Hooman Allayee, Yuan Tsong Chen, John Danesh, Ian J. Deary, Oscar H. Franco, Lude Franke, Bastiaan THeijman, Joanna D. Holbrook, Aaron Isaacs, Bong Jo Kim, Xu Lin, Jianjun Liu, Winfried März, Andres Metspalu, Karen L. Mohlke, K. Sangher, Dharambir Harambir, Xiao Ou Shu, Joyce B J Van Meurs, Eranga Vithana, Ananda R. Wickremasinghe, Cisca Wijmenga, Bruce H W Wolffenbuttel, Mitsuhiro Yokota, Wei Zheng, Dingliang Zhu, Paolo Vineis, Soterios A. Kyrtopoulos, Jos C S Kleinjans, Mark I. McCarthy, Richie Soong, Christian Gieger, James Scott, Yik Ying Teo, Jiang He, Paul Elliott, E. Shyong Tai, Pim Van Der Harst, Jaspal S. Kooner, John C. Chambers

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Abstract

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

Original languageEnglish (US)
Pages (from-to)1282-1293
Number of pages12
JournalNature Genetics
Volume47
Issue number11
DOIs
StatePublished - Nov 1 2015

Bibliographical note

Funding Information:
We acknowledge the use of data from the International Consortium for Blood Pressure Genome-Wide Association Studies8,9. AASC.This work was supported by Grants for Scientific Research (24390084, 21390099 and 20390185) from the Ministry of Education, Culture, Sports, Science and Technology of Japan; a Science and Technology Incubation Program in Advanced Regions, Japanese Science and Technology Agency; the Japanese Atherosclerosis Prevention Fund; the Takeda Medical Research Foundation; and National Cardiovascular Research Grants. AIDHS/SDS. This study was supported by US National Institutes of Health (NIH) grants R01DK082766 (D.K.S.) funded by the National Institute of Diabetes and Digestive and Kidney Diseases and NOT-HG-11-009 (D.K.S.) funded by the National Human Genome Research Institute (D.K.S.) and by a VPR bridge grant (D.K.S.) from the University of Oklahoma Health Sciences Center. BIOS-consortium. The BIOS-consortium is funded by BBMRI-NL, a research infrastructure financed by the Netherlands Organization for Scientific Research (NWO project 184.021.007). CAGE-Amagasaki. We acknowledge the outstanding contributions of the employees of the National Center for Global Health and Medicine who provided technical and infrastructural support for this work. Above all, we thank the participants who made this work possible and who gave it value. We also thank T. Ogihara, Y. Yamori, A. Fujioka, C. Makibayashi, S. Katsuya, K. Sugimoto, K. Kamide, R. Morishita and the many physicians of the participating hospitals and medical institutions in the Amagasaki Medical Association for their assistance in collecting the DNA samples and accompanying clinical information. This work was supported by Grants for Scientific Research (22390186, 24591060, 25253059 and 25461127) from the Ministry of Education, Culture, Sports, Science and Technology of Japan. CAGE-Fukuoka. This work was supported by Grants-in-Aid for the 21st Century Center of Excellence Program (Kyushu University) from the Ministry of Education, Culture, Sports, Science and Technology of Japan and Grants-in-Aid for Scientific Research (category A) from the Japanese Society for the Promotion of Science. We are grateful to all participants of this study. We also especially thank S. Kono for his management of the DNA samples and clinical information.

Funding Information:
CAGE_GWAS1. The CAGE Network studies were supported by grants for Core Research for Evolutional Science and Technology (CREST) from the Japanese Science and Technology Agency; the Program for the Promotion of Fundamental Studies in Health Sciences, National Institute of Biomedical Innovation Organization (NIBIO); KAKENHI (Grant-in-Aid for Scientific Research) on Priority Area ‘Applied Genomics’ from the Ministry of Education, Culture, Sports, Science and Technology of Japan; and a grant from the National Center for Global Health and Medicine. N.K. is a recipient of the Okinaga Scholarship and thanks S. Okinaga, H. Okinaga and other staff at Teikyo University, Japan, for their considerable support of doctoral work. CAGE-KING. This study was supported in part by Grants-in-Aid for Scientific Research, including ones from categories A and B and the NEXT program of the Japanese Society for the Promotion of Science and by Grants-in-Aid on Priority Areas ‘Comprehensive Genomics’ and ‘Applied Genomics’, from the Ministry of Education, Culture, Sports, Science and Technology of Japan. CAGE-Vietnam. The CAGE-Vietnam study was supported by Grants for International Health Research (17C-1 and 20S-6) from the Ministry of Health, Labour and Welfare of Japan, grants for the National Center for Global Health and Medicine (22S-10 and 25S-1) and the Manpei Suzuki Diabetes Foundation. We acknowledge the following investigators and institutions for their substantial contribution to the current study: T. Sasazuki, M. Noda, N. Kato, S. Kanagawa, T. Mizoue, H. Ohara and Y. Takahashi (Japanese investigators); T. Quy, N. Lan Viet, P. Thi Hong Hoa, N. Hoa Dieu Van, N. Thi Lam, L. Bach Mai, N. Quang Bay, P. Thi Phuong Thuy and B. Minh Duc (Vietnamese investigators); the National Center for Global Health and Medicine (Japan), Bach Mai Hospital (Vietnam), the Vietnam National Institute of Nutrition and the NCGM-BMH Medical Collaboration Center. Cilento. We thank the populations of Cilento, Italy, for their participation in the study. This work was supported by grants from the Italian Ministry of Universities (FIRB-RBNE08NKH7, Interomics Flag project), the Assessorato Ricerca Regione Campania, the Fondazione con il SUD (2011-PDR-13) and the Fondazione Banco di Napoli to M.C. CLHNS. We thank the Office of Population Studies Foundation research and data collection teams for the Cebu Longitudinal Health and Nutrition Survey. This work was supported by National Institutes of Health grants DK078150, TW05596, HL085144 and TW008288 and pilot funds from RR20649, ES10126 and DK56350. DIABNORD. We are grateful to the study participants who dedicated their time and samples to these studies. We also thank the VHS, the Swedish Diabetes Registry and the Umeå Medical Biobank staff for biomedical data and DNA extraction. We also thank M. Sterner, M. Juhas and P. Storm for their expert technical assistance with genotyping and genotype data preparation. The current study was funded by Novo Nordisk, the Swedish Research Council, Påhlssons Foundation, the Swedish Heart Lung Foundation and the Skåne Regional Health Authority (all to P.W.F.). EGCUT. EGCUT received targeted financing from the Estonian government (SF0180142s08), the Center of Excellence in Genomics (EXCEGEN) and the University of Tartu (SP1GVARENG). We acknowledge EGCUT technical personnel, especially V. Soo and S. Smit. Data analyses were carried out in part at the High-Performance Computing Center of the University of Tartu. FINCAVAS. This work was supported by Competitive Research Funding from Tampere University Hospital (grants 9M048 and 9N035), the Finnish Cultural Foundation, the Finnish Foundation for Cardiovascular Research, the Emil Aaltonen Foundation, Finland, and the Tampere Tuberculosis Foundation. The authors thank the staff of the Department of Clinical Physiology for collecting the exercise test data. GEMS. This work was partially supported by US NIH grants R01CA107431 and P42ES10349 to H. Ahsan. We would like to thank the study participants, as well as the staff of UChicago Research Bangladesh. GeneBank. The Cleveland Clinic GeneBank study is supported by National Heart, Lung, and Blood Institute grants P01HL098055, P01HL076491, R01HL103866, P20HL113452 and R01HL103931. H. Allayee was supported by grant R01ES021801 from the National Institute of Environmental Health Sciences. GenSalt. The Genetic Epidemiology Network of Salt Sensitivity is supported by research grants (U01HL072507, R01HL087263 and R01HL090682) from the National Heart, Lung, and Blood Institute, US NIH. GLACIER-exome. We are indebted to the study participants who dedicated their time and samples to these studies. We thank J. Hutiainen and Å. Ågren (Umeå Medical Biobank) for data organization and K. Enquist and T. Johansson (Västerbottens County Council) for technical assistance with DNA extraction. We also thank M. Sterner, M. Juhas and P. Storm for their expert technical assistance with genotyping and genotype data preparation. The current study was funded by Novo Nordisk, the Swedish Research Council, Påhlssons Foundation, the Swedish Heart Lung Foundation and the Skåne Regional Health Authority (all to P.W.F.). GLACIER Metabochip. We are indebted to the study participants who dedicated their time and samples to these studies. We also thank the VIP and Umeå Medical

Funding Information:
InterAct. We are grateful to all participants who gave their time and effort to the study. We are also extremely grateful to all persons who contributed to the data collection across the study sites. This study was supported by funding from the European Union (integrated project LSHM-CT-2006-037197 in the Sixth Framework Programme of the European Community) and the Medical Research Council, UK. JMGP. The JMGP study group is composed of the following individuals; JMGP-Ohasama: T. Ohkubo, M. Satoh, R. Inoue, T. Hirose, H. Metoki, M. Kikuya and Y. Imai; JMGP-Yokohama: N. Hirawa, K. Yatsu, T. Shiwa, M. Ogawa and S. Umemura; JMGP-Shigaraki and Takashima: Y. Kita, Y. Nakamura, N. Takashima and H. Ueshima; and JMGP-Nomura: Y. Tabara, R. Kawamoto, K. Kohara and T. Miki (chairperson). This work was supported by Grants-in-Aid for Scientific Research (Priority Areas ‘Medical Genome Science (Millennium Genome Project)’ and ‘Applied Genomics’), the Leading Project for Personalized Medicine and Scientific Research (20390185, 21390099, 19659163, 16790336, 12204008, 15790293, 16590433, 17790381, 17790381, 18390192, 18590265, 18590587, 18590811, 19590929, 19650188, 19790423, 17390186, 20390184 and 21390223) from the Ministry of Education, Culture, Sports, Science and Technology of Japan; Grants-in-Aid (H15-Longevity-005, H17-Longevity-003, H16-Kenko-001, H18-Longevity (kokusai), H11-Longevity-020, H17-Kenkou-007, H17-Pharmaco-common-003, H18-Junkankitou[Seishuu]-Ippan-012 and H20-Junkankitou[Seishuu]-Ippan-009, 013) from the Ministry of Health, Labor and Welfare of Japan, Health and Labor Sciences Research Grants, Japan; a Science and Technology Incubation Program in Advanced Regions, the Japanese Science and Technology Agency; Grants-in-Aid from Japanese Society for the Promotion of Science fellows (16.54041, 18.54042, 19.7152, 20.7198, 20.7477 and 20.54043); Health Science Research Grants and Medical Technology Evaluation Research Grants from the Ministry of Health, Labour and Welfare of Japan; the Japanese Atherosclerosis Prevention Fund; the Uehara Memorial Foundation; the Takeda Medical Research Foundation; National Cardiovascular Research Grants; Biomedical Innovation Grants; and the Japanese Research Foundation for Clinical Pharmacology. KARE. This work was supported by grants from the Korean Centers for Disease Control and Prevention (4845-301, 4851-302 and 4851-307) and an intramural grant from the Korean National Institute of Health (2012-N73002-00), Republic of Korea. KORA. KORA was initiated and financed by the Helmholtz Zentrum München– German Research Center for Environmental Health and supported by grants from the German Federal Ministry of Education and Research (BMBF), the Federal Ministry of Health and the Munich Center of Health Sciences (MC Health) as part of LMUinnovativ. This research was supported by a grant from the German-Israeli Foundation for Scientific Research and Development, by the European Union’s Seventh Framework Programme (FP7-HEALTH-F5-2012) under grant agreement 305280 (MIMOmics), by Helmholtz-Russia Joint Research Group (HRJRG) 310 and by the German Center for Diabetes Research (DZD). We thank all members of the field staff who were involved in the planning and conduct of the MONICA/KORA Augsburg studies. The funders had no role in study design, data collection and analysis, decision to publish or preparation of the manuscript. C.G. is supported by EU-FP7-HEALTH grant 602936: CARTARDIS–Identification and Validation of Novel Pharmaceutical Drug Targets for Cardiovascular Disease and BMBF e:Med project e:AtheroSysMed–Systems Medicine of Myocardial Infarction and Stroke. LBC1921. We thank the cohort participants and team members who contributed to these studies. Phenotype collection was supported by the UK Biotechnology and Biological Sciences Research Council (BBSRC), the Royal Society and the Chief Scientist Office of the Scottish government. Genotyping was funded by the BBSRC. The work was undertaken by the University of Edinburgh Centre for Cognitive Ageing and Cognitive Epidemiology, part of the cross-council Lifelong Health and Wellbeing Initiative (MR/K026992/1). Funding from the BBSRC and Medical Research Council, UK, is gratefully acknowledged. LBC1936. We thank the cohort participants and team members who contributed to these studies. Phenotype collection was supported by Age UK (The Disconnected Mind project). Genotyping was funded by the BBSRC. The work was undertaken by the University of Edinburgh Centre for Cognitive Ageing and Cognitive Epidemiology, part of the cross-council Lifelong Health and Wellbeing Initiative (MR/K026992/1). Funding from the BBSRC and Medical Research Council, UK, is gratefully acknowledged. LifeLines. The LifeLines Cohort Study and the generation and management of GWAS genotype data for the LifeLines Cohort Study are supported by the Netherlands Organization for Scientific Research (NWO; grant 175.010.2007.006), the Economic Structure-Enhancing Fund (FES) of the Dutch government, the Ministry of Economic Affairs, the Ministry of Education, Culture and Science, the Ministry for Health, Welfare and Sports, the Northern Netherlands Collaboration of Provinces (SNN), the province of Groningen, University Medical

Funding Information:
SWHS. This research was supported by US NIH research grant R37CA70867. The authors thank the participants and staff members of SWHS for their important contributions. TWSC. We gratefully acknowledge the members of the Translational Resource Center (TRC) (NSC102-2325-B-001-040) and the National Center for Genome Medicine (NSC102-2319-B-001-001) at Academia Sinica for their support in subject recruitment, genotyping and statistical analysis. The TWSC study was supported by the Academia Sinica Genomic Medicine Multicenter Study, Taiwan (40-05-GMM). WHII. The WHII study is supported by grants from the Medical Research Council, UK (G0902037), the British Heart Foundation (RG/07/008/23674), the Stroke Association, the National Heart, Lung, and Blood Institute (5RO1HL036310), the National Institute on Aging (5RO1AG13196), the Agency for Health Care Policy Research (HS06516) and the John D. and Catherine T. MacArthur Foundation Research Networks on Successful Midlife Development and Socio-Economic Status and Health. YFS. The Young Finns Study has been financially supported by the Academy of Finland through grants 286284 (T.L.), 134309 (Eye), 126925, 121584, 124282, 129378 (Salve), 117787 (Gendi) and 41071 (Skidi); the Social Insurance Institution of Finland; Kuopio, Tampere and Turku University Hospital Medical Funds (grant X51001 for T.L.); the Juho Vainio Foundation; the Paavo Nurmi Foundation; the Finnish Foundation of Cardiovascular Research (T.L.); the Finnish Cultural Foundation; the Tampere Tuberculosis Foundation (T.L.); the Emil Aaltonen Foundation (T.L.); and the Yrjö Jahnsson Foundation (T.L.).

Funding Information:
Biobank staff for biomedical data collection and preparation. We specifically thank J. Hutiainen, Å. Ågren and S. Nilsson (Umeå Medical Biobank) for data organization, K. Enquist and T. Johansson (Västerbottens County Council) for expert technical assistance with DNA preparation, and D. Hunter, P. Soule and H. Ranu (Harvard School of Public Health) for expert assistance with planning and undertaking genotyping of GLACIER samples. The current study was funded by Novo Nordisk, the Swedish Research Council, Påhlssons Foundation, the Swedish Heart Lung Foundation and the Skåne Regional Health Authority (all to P.W.F.). Health2006. The Health2006 study was financially supported by grants from the Velux Foundation; the Danish Medical Research Council, Danish Agency for Science, Technology and Innovation; the Aase and Ejner Danielsens Foundation; and ALK-Abello (Hørsholm, Denmark), Timber Merchant Vilhelm Bangs Foundation, MEKOS Laboratories Denmark and Research Centre for Prevention and Health, the Capital Region of Denmark. This project was also funded by the Lundbeck Foundation and produced by the Lundbeck Foundation Centre for Applied Medical Genomics in Personalised Disease Prediction, Prevention and Care (LuCamp; http://www.lucamp.org/). The Novo Nordisk Foundation Centre for Basic Metabolic Research is an independent Research Centre at the University of Copenhagen partially funded by an unrestricted donation from the Novo Nordisk Foundation (http://www.metabol.ku.dk/). HEXA. This work was supported by grants from the Korean Centers for Disease Control and Prevention (4845-301, 4851-302 and 4851-307) and an intramural grant from the Korean National Institute of Health (2012-N73002-00), Republic of Korea. HPS. The Heart Protection Study (ISRCTN48489393) was funded by the UK Medical Research Council, the British Heart Foundation, Merck & Co., and Roche Vitamins, Ltd. Genotyping and analysis were supported by a grant to the University of Oxford and the Centre National de Génotypage from Merck & Co. and the Oxford British Heart Foundation Centre of Research Excellence. J.C.H. acknowledges support from the British Heart Foundation (FS/14/55/30806). GOYA. This study was conducted as part of the activities of the Gene-Diet Interactions in Obesity project (GENDINOB; http://www.gendinob.dk/) and the Medical Research Council Centre for Causal Analyses in Translational Epidemiology (MRC CAiTE). We thank the staff of the Copenhagen City Heart Study for their skillful examination of the study subjects in the collection of baseline and follow-up data. T.S.A. was also funded by the GENDINOB project and acknowledges the same. GUSTO. The GUSTO study group includes P. Agarwal, A. Biswas, C. Looi Bong, B.F.P. Broekman, S. Cai, J.K.Y. Chan, Y.H. Chan, C.Y.I. Chee, H.Y.H. Chen, Y.B. Cheung, A. Chia, A. Chinnadurai, C.K. Chng, M.F.-F. Chong, S.C. Chong, M.C. Chua, C.M. Ding, E.A. Finkelstein, D. Fok, M. Fortier, A.E.N. Goh, Y.T.D. Goh, J.J. Gooley, W.M. Han, M. Hanson, C.J. Henry, C.-Y. Hsu, H. Inskip, J. Kapur, K. Kwek, I.Y.-M. Lau, B.W. Lee, N. Lek, S.B. Lim, Y.-L. Low, I. Magiati, L. Mary Daniel, C. Ngo, K. Naiduvaje, W.W. Pang, A. Qiu, B.L. Quah, V.S. Rajadurai, M. Rauff, S.A. Rebello, J.L. Richmond, A. Rifkin-Graboi, L.P.-C. Shek, A. Sheppard, B. Shuter, L. Singh, W. Stunkel, L.L. Su, O.H. Teoh, H.P.S. van Bever, R.M. van Dam, I.B.Y. Wong, P.C. Wong and G.S.H. Yeo. This research is supported by the Singapore National Research Foundation under its Translational and Clinical Research (TCR) Flagship Programme and administered by the Singapore Ministry of Health’s National Medical Research Council (NMRC), Singapore-NMRC/TCR/012-NUHS/2014. Additional funding is provided by the Singapore Institute for Clinical Sciences, A*STAR, Singapore. INGI-VB. The research was supported by funds from Compagnia di San Paolo (Torino, Italy); Fondazione Cariplo, Italy, and the Ministry of Health, Ricerca Finalizzata 2008 and CCM 2010, and Telethon, Italy, to D.T. The funders had no role in study design, data collection and analysis, decision to publish or preparation of the manuscript. We thank the inhabitants of Val Borbera who made this study possible, the local administrations, the Tortona and Genova archdioceses, and the ASL-22, Novi Ligure (Al), for support. We also thank C. Camaschella for the supervision of data collection and organization of the clinical data collection, F. Viganò for technical help, and C. Masciullo and M. Cocca for building the analysis platform. Inter99. Inter99 was initiated by T.J. (principal investigator), K. Borch-Johnsen (co-principal investigator), H. Ibsen and T.F. Thomsen. The steering committee comprises the first two and C. Pisinger. The study was financially supported by research grants from the Danish Research Council, the Danish Centre for Health Technology Assessment, Novo Nordisk, the Research Foundation of Copenhagen County, the Ministry of Internal Affairs and Health, the Danish Heart Foundation, the Danish Pharmaceutical Association, the Augustinus Foundation, the Ib Henriksen Foundation, the Becket Foundation and the Danish Diabetes Association. This project was also funded by the Lundbeck Foundation and produced by LuCamp (http://www.lucamp.org/). The Novo Nordisk Foundation Centre for Basic Metabolic Research is an independent Research Centre at the University of Copenhagen partially funded by an unrestricted donation from the Novo Nordisk Foundation (http://www.metabol.ku.dk/).

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