Introduction Cyclooxygenase 2 (COX-2) inhibitors have less upper gastrointestinal toxicity than traditional non-steroidal anti-inflammatory drugs (NSAIDs). However, both COX-2 inhibitors and traditional NSAIDs may be associated with adverse cardiovascular side effects. Data from randomised and observational studies suggest that celecoxib has similar cardiovascular toxicity to traditional NSAIDs. The overall safety balance of a strategy of celecoxib therapy versus traditional NSAID therapy is unknown. The European Medicines Agency requested studies of the cardiovascular safety of celecoxib within Europe. The Standard care versus Celecoxib Outcome Trial (SCOT) compares the cardiovascular safety of celecoxib with traditional NSAID therapy in the setting of the European Union healthcare system. Methods and analysis SCOT is a large streamlined safety study conducted in Scotland, England, Denmark and the Netherlands using the Prospective Randomised Open Blinded Endpoint design. Patients aged over 60 years with osteoarthritis or rheumatoid arthritis, free from established cardiovascular disease and requiring chronic NSAID therapy, are randomised to celecoxib or their previous traditional NSAID. They are then followed up for events by record-linkage within their normal healthcare setting. The hypothesis is non-inferiority with a confidence limit of 1.4. The primary endpoint is the first occurrence of hospitalisation or death for the Anti-Platelet Trialists' Collaboration (APTC) cardiovascular endpoint of non-fatal myocardial infarction, non-fatal stroke or cardiovascular death. Secondary endpoints are (1) first hospitalisation or death for upper gastrointestinal ulcer complications (bleeding, perforation or obstruction); (2) first occurrence of hospitalised upper gastrointestinal ulcer complications or APTC endpoint; (3) first hospitalisation for heart failure; (4) first hospitalisation for APTC endpoint plus heart failure; (5) all-cause mortality and (6) first hospitalisation for new or worsening renal failure. Ethics and dissemination SCOT has been approved by the relevant ethics committees. The trial results will be published in a peer-reviewed scientific journal.
Published ; Journal Article ; Meta-Analysis ; Research Support, N.I.H., Extramural ; Research Support, N.I.H., Intramural ; Research Support, Non-U.S. Gov't ; Research Support, U.S. Gov't, Non-P.H.S. ; Thyroid hormone is essential for normal metabolism and development, and overt abnormalities in thyroid function lead to common endocrine disorders affecting approximately 10% of individuals over their life span. In addition, even mild alterations in thyroid function are associated with weight changes, atrial fibrillation, osteoporosis, and psychiatric disorders. To identify novel variants underlying thyroid function, we performed a large meta-analysis of genome-wide association studies for serum levels of the highly heritable thyroid function markers TSH and FT4, in up to 26,420 and 17,520 euthyroid subjects, respectively. Here we report 26 independent associations, including several novel loci for TSH (PDE10A, VEGFA, IGFBP5, NFIA, SOX9, PRDM11, FGF7, INSR, ABO, MIR1179, NRG1, MBIP, ITPK1, SASH1, GLIS3) and FT4 (LHX3, FOXE1, AADAT, NETO1/FBXO15, LPCAT2/CAPNS2). Notably, only limited overlap was detected between TSH and FT4 associated signals, in spite of the feedback regulation of their circulating levels by the hypothalamic-pituitary-thyroid axis. Five of the reported loci (PDE8B, PDE10A, MAF/LOC440389, NETO1/FBXO15, and LPCAT2/CAPNS2) show strong gender-specific differences, which offer clues for the known sexual dimorphism in thyroid function and related pathologies. Importantly, the TSH-associated loci contribute not only to variation within the normal range, but also to TSH values outside the reference range, suggesting that they may be involved in thyroid dysfunction. Overall, our findings explain, respectively, 5.64% and 2.30% of total TSH and FT4 trait variance, and they improve the current knowledge of the regulation of hypothalamic-pituitary-thyroid axis function and the consequences of genetic variation for hypo- or hyperthyroidism. ; Intramural Research Program of the NIH ; NCRR ; NHLBI ; MedStar Research Institute ; NINDS ; National Center of Advancing Translational Technologies CTSI ; National Institute of Diabetes and Digestive and Kidney Diseases ; Robert Dawson Evans Endowment ; Italian Ministry of Health ; University and Research of the Autonomous Province of Bolzano ; European Union's Seventh Framework Programme ; ENGAGE project ; EPIGENESYS ; BLUEPRINT ; Dutch Innovation-Oriented Research Program on Genomics ; Netherlands Organization for Scientific Research (NWO) ; South Tyrolean Sparkasse Foundation ; Radboud University Nijmegen Medical Centre ; University of Maryland General Clinical Research Center ; Johns Hopkins University General Clinical Research Center ; Baltimore Veterans Administration Geriatric Research and Education Clinical Center (GRECC) ; Netherlands Research Institute for Diseases in the Elderly ; Erasmus Medical Center and Erasmus University, Rotterdam ; Netherlands Organization for the Health Research and Development (ZonMw) ; Dutch Ministry for Health, Welfare and Sports ; European Commission ; Municipality of Rotterdam ; German Bundesministerium fuer Forschung und Technology ; Wellcome Trust ; English Department of Health, National Institute for Health Research (NIHR) Comprehensive Biomedical Research Centre ; Canadian Institutes of Health Research, Canadian Foundation for Innovation ; Fonds de la Recherche en Santé Québec, Ministère du Développement Économique, de l'Innovation et de l'Exportation ; Lady Davis Institute of the Jewish General Hospital (JBR) ; Australian National Health and Medical Research Council ; Sir Charles Gairdner Hospital Research Fund ; Italian "Compagnia di San Paolo" ; Italian "Fondazione Cariplo" ; Leiden University Medical Centre ; Dutch Arthritis Association ; Pfizer, Groton, CT, USA ; Dutch Centre of Medical System Biology ; Netherlands Genomics Initiative (NGI), Netherlands Consortium of Healthy Aging ; Academy of Finland ; Finnish Diabetes Research Society ; Folkhälsan Research Foundation ; Novo Nordisk Foundation ; Finska Läkaresällskapet, Signe and Ane Gyllenberg Foundation ; University of Helsinki ; European Science Foundation (EUROSTRESS) ; Finnish Ministry of Education ; Ahokas Foundation ; Emil Aaltonen Foundation ; Juho Vainio Foundation ; BBSRC ; EPSRC ; ESRC ; MRC ; AXA Research Fund ; Help the Aged/Research Into Ageing (Disconnected Mind) ; Economic Structure Enhancing Fund (FES) of the Dutch government ; Dutch Ministry of Economic Affairs ; Dutch Ministry of Education, Culture and Science ; Northern Netherlands Collaboration of Provinces (SNN) ; Province of Groningen ; University of Groningen ; Dutch Kidney Foundation ; Dutch Diabetes Research Foundation ; Bristol-Myers Squibb ; Netherlands Heart Foundation ; National Computing Facilities Foundation (NCF), Netherlands ; Endocrine Research Fund
BACKGROUND: Genome-wide association studies have so far identified 56 loci associated with risk of coronary artery disease (CAD). Many CAD loci show pleiotropy; that is, they are also associated with other diseases or traits. OBJECTIVES: This study sought to systematically test if genetic variants identified for non-CAD diseases/traits also associate with CAD and to undertake a comprehensive analysis of the extent of pleiotropy of all CAD loci. METHODS: In discovery analyses involving 42,335 CAD cases and 78,240 control subjects we tested the association of 29,383 common (minor allele frequency >5%) single nucleotide polymorphisms available on the exome array, which included a substantial proportion of known or suspected single nucleotide polymorphisms associated with common diseases or traits as of 2011. Suggestive association signals were replicated in an additional 30,533 cases and 42,530 control subjects. To evaluate pleiotropy, we tested CAD loci for association with cardiovascular risk factors (lipid traits, blood pressure phenotypes, body mass index, diabetes, and smoking behavior), as well as with other diseases/traits through interrogation of currently available genome-wide association study catalogs. RESULTS: We identified 6 new loci associated with CAD at genome-wide significance: on 2q37 (KCNJ13-GIGYF2), 6p21 (C2), 11p15 (MRVI1-CTR9), 12q13 (LRP1), 12q24 (SCARB1), and 16q13 (CETP). Risk allele frequencies ranged from 0.15 to 0.86, and odds ratio per copy of the risk allele ranged from 1.04 to 1.09. Of 62 new and known CAD loci, 24 (38.7%) showed statistical association with a traditional cardiovascular risk factor, with some showing multiple associations, and 29 (47%) showed associations at p < 1 × 10(-4) with a range of other diseases/traits. CONCLUSIONS: We identified 6 loci associated with CAD at genome-wide significance. Several CAD loci show substantial pleiotropy, which may help us understand the mechanisms by which these loci affect CAD risk. ; Drs. Akinsanya, Wu, Yin, and Reilly are employees of Merck Sharp & Dohme; and Dr. Vogt was an employee of Merck when aspects of this research was conducted, but is now retired from Merck. A cholesteryl ester transfer protein inhibitor, Anacetrapib (MK-0859), is currently undergoing clinical investigation in the REVEAL outcome trial sponsored by Merck Sharp & Dohme. Dr. Schick is an employee of Recombine. Dr. Dube has equity in DalCor Pharmaceuticals. Dr. McCarthy is a member of advisory boards for Pfizer and Novo Nordisk; has received honoraria from Pfizer, Novo Nordisk, and Eli Lilly; and has received research funding provided by Pfizer, Novo Nordisk, Eli Lilly, Servier, Sanofi-Aventis, Janssen, Roche, Boehringer-Ingelheim, Takeda, Merck, and AstraZeneca. Dr. Ferrieres has received grants from Merck Sharp & Dohme, Amgen, and Sanofi. Dr. Sattar has served as a consultant for Amgen and Sanofi. Dr. Butterworth has received grants from Pfizer and Merck. Dr. Danesh has served as a consultant for Takeda; has served on the Novartis Cardiovascular & Metabolic Advisory Board and International Cardiovascular and Metabolism Research and Development Portfolio Committee of Novartis; has served on the UK Atherosclerosis Advisory Board of Merck Sharp & Dohme; has served on the advisory board of Sanofi; has served on the Pfizer Population Research Advisory Panel; and has financial relationships with the British Heart Foundation, BUPA Foundation, diaDexus, European Research Council, European Union, Evelyn Trust, Fogarty International Centre, GlaxoSmithKline, Merck, National Heart, Lung, and Blood Institute, National Health Service Blood and Transplant, National Institute for Health Research, National Institute of Neurological Disorders and Stroke, Novartis, Pfizer, Roche, Sanofi, Takeda, The Wellcome Trust, UK Biobank, University of British Columbia, and UK Medical Research Council. Dr. Tardif has received research grants from Amarin, AstraZeneca, Merck, Pfizer, Eli Lilly, Sanofi, Servier, and DalCor; has received honoraria from Pfizer (to his institution), Servier, DalCor, and Sanofi (to his institution); and has received modest equity interest from DalCor. Dr. Kathiresan has financial/other relationships with Regeneron, Bayer, Catabasis, Merck, Celera, Genomics PLC, San Therapeutics, Novartis, Sanofi, AstraZeneca, Alnylam, Eli Lilly, Leerink Partners, and Noble Insights. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose. A full list of acknowledgments and funding sources is included in the Online Appendix.
This is the final version. Available on open access from Nature Research via the DOI in this record. ; Data availability: GWAS summary statistics for FG/FI analyses presented in this manuscript are deposited on https://www.magicinvestigators.org/downloads/ and will be also be available through the NHGRI-EBI GWAS Catalog https://www.ebi.ac.uk/gwas/downloads/summary-statistics. Raw files for RNA-seq mRNA expression in islet donors have been deposited in NCBI GEO database with the accession code GSE50398. Summary-level GWAS results for genetic correlation analysis with glycemic traits were downloaded from the LDHub database (http://ldsc.broadinstitute.org/ldhub/). Islets from 89 cadaver donors were provided by the Nordic Islet Transplantation Programme (http://www.medscinet.com/nordicislets/). The dexseq_count python script for RNA sequencing analysis in human pancreatic islets was downloaded from http://www-huber.embl.de/pub/DEXSeq/analysis/scripts/. Raw files for RNA-seq mRNA expression in islet donors have been deposited in NCBI GEO database with the accession code GSE50398. ; Differences between sexes contribute to variation in the levels of fasting glucose and insulin. Epidemiological studies established a higher prevalence of impaired fasting glucose in men and impaired glucose tolerance in women, however, the genetic component underlying this phenomenon is not established. We assess sex-dimorphic (73,089/50,404 women and 67,506/47,806 men) and sex-combined (151,188/105,056 individuals) fasting glucose/fasting insulin genetic effects via genome-wide association study meta-analyses in individuals of European descent without diabetes. Here we report sex dimorphism in allelic effects on fasting insulin at IRS1 and ZNF12 loci, the latter showing higher RNA expression in whole blood in women compared to men. We also observe sex-homogeneous effects on fasting glucose at seven novel loci. Fasting insulin in women shows stronger genetic correlations than in men with waist-to-hip ratio and anorexia nervosa. Furthermore, waist-to-hip ratio is causally related to insulin resistance in women, but not in men. These results position dissection of metabolic and glycemic health sex dimorphism as a steppingstone for understanding differences in genetic effects between women and men in related phenotypes. ; Academy of Finland ; ADA ; Biotechnology and Biological Sciences Research Council (BBSRC) ; BHF ; Clinical Translational Science Institute ; Croatian Ministry of Science ; Directorate C - Public Health and Risk Assessment, Health & Consumer Protection ; Dutch Kidney Foundation ; Estonian Research Council ; European Research Council (ERC) ; European Regional Development Fund (ERDF) ; European Union Horizon 2020 ; Federal Ministry of Education and Research (BMBF), Germany ; Finnish Funding Agency for Technology and Innovation ; German Research Foundation ; Greek General Secretary of Research and Technology ; Icelandic National Bioethics Committee ; IFB Adiposity Diseases ; IngaBritt och Arne Lundberg's Research Foundation ; Italian Ministry of Health ; Knut & Alice Wallenberg foundation ; Kuopio University Hospital from Ministry of Health and Social Affairs ; Affymetrix, Inc ; Lundberg Foundation ; Medical Research Council (MRC) ; Mid-Atlantic Nutrition Obesity Research Center ; Ministry of Education and Culture of Finland ; MRC-GSK pilot programme ; NHLBI ; NIA ; NIH ; Nordic Centre of Excellence on Systems biology in controlled dietary interventions and cohort studies, SYSDIET ; Novo Nordisk Foundation ; NWO/ZonMW ; Spinozapremie ; Rutgers University Cell and DNA Repository ; Stockholm County Council ; Swedish Foundation for Strategic Research ; Swedish Heart-Lung Foundation ; Swedish Research Council ; Swiss National Science Foundation ; TEKES ; Torsten och Ragnar Söderbergs Stiftelser ; Wellcome Trust ; Yrjö Jahnsson Foundation ; Note that the full list of funders and grant numbers is available in the online article and in the PDF in this record
Funding for this study was provided by the Aase and Ejner Danielsens Foundation; Academy of Finland (41071, 77299, 102318, 110413, 117787, 121584, 123885, 124243, 124282, 126925, 129378, 134309, 286284); Accare Center for Child and Adolescent Psychiatry; Action on Hearing Loss (G51); Agence Nationale de la 359 Recherche; Agency for Health Care Policy Research (HS06516); ALF/LUA research grant in Gothenburg; ALFEDIAM; ALK-Abello´ A/S; Althingi; American Heart Association (13POST16500011); Amgen; Andrea and Charles Bronfman Philanthropies; Ardix Medical; Arthritis Research UK; Association Diabe`te Risque Vasculaire; Australian National Health and Medical Research Council (241944, 339462, 389875, 389891, 389892, 389927, 389938, 442915, 442981, 496739, 552485, 552498); Avera Institute; Bayer Diagnostics; Becton Dickinson; BHF (RG/14/5/30893); Boston Obesity Nutrition Research Center (DK46200), Bristol-Myers Squibb; British Heart Foundation (RG/10/12/ 28456, RG2008/08, RG2008/014, SP/04/002); Medical Research Council of Canada; Canadian Institutes for Health Research (FRCN-CCT-83028); Cancer Research UK; Cardionics; Cavadis B.V., Center for Medical Systems Biology; Center of Excellence in Genomics; CFI; CIHR; City of Kuopio; CNAMTS; Cohortes Sante´ TGIR; Contrat de Projets E´tat-Re´gion; Croatian Science Foundation (8875); Danish Agency for Science, Technology and Innovation; Danish Council for Independent Research (DFF-1333- 00124, DFF-1331-00730B); County Council of Dalarna; Dalarna University; Danish Council for Strategic Research; Danish Diabetes Academy; Danish Medical Research Council; Department of Health, UK; Development Fund from the University of Tartu (SP1GVARENG); Diabetes Hilfs- und Forschungsfonds Deutschland; Diabetes UK; Diabetes Research and Wellness Foundation Fellowship; Donald W. Reynolds Foundation; Dr Robert Pfleger-Stiftung; Dutch Brain Foundation; Dutch Diabetes Research Foundation; Dutch Inter University Cardiology Institute; Dutch Kidney Foundation (E033); Dutch Ministry of Justice; the DynaHEALTH action No. 633595, Economic Structure Enhancing Fund of the Dutch Government; Else Kro¨ner-Fresenius-Stiftung (2012_A147, P48/08//A11/08); Emil Aaltonen Foundation; Erasmus University Medical Center Rotterdam; Erasmus MC and Erasmus University Rotterdam; the Municipality of Rotterdam; Estonian Government (IUT20-60, IUT24-6); Estonian Research Roadmap through the Estonian Ministry of Education and Research (3.2.0304.11-0312); European Research Council (ERC Starting Grant and 323195:SZ-245 50371-GLUCOSEGENESFP7-IDEAS-ERC); European Regional Development Fund; European Science Foundation (EU/QLRT-2001-01254); European Commission (018947, 018996, 201668, 223004, 230374, 279143, 284167, 305739, BBMRI-LPC-313010, HEALTH-2011.2.4.2-2-EUMASCARA, HEALTH-2011-278913, HEALTH-2011-294713-EPLORE, HEALTH-F2- 2008-201865-GEFOS, HEALTH-F2-2013-601456, HEALTH-F4-2007-201413, HEALTH-F4-2007-201550-HYPERGENES, HEALTH-F7-305507 HOMAGE, IMI/ 115006, LSHG-CT-2006-018947, LSHG-CT-2006-01947, LSHM-CT-2004-005272, LSHM-CT-2006-037697, LSHM-CT-2007-037273, QLG1-CT-2002-00896, QLG2-CT2002-01254); Faculty of Biology and Medicine of Lausanne; Federal Ministry of Education and Research (01ZZ0103, 01ZZ0403, 01ZZ9603, 03IS2061A, 03ZIK012); Federal State of Mecklenburg-West Pomerania; Fe´de´ration Franc¸aise de Cardiologie; Finnish Cultural Foundation; Finnish Diabetes Association; Finnish Foundation of Cardiovascular Research; Finnish Heart Association; Fondation Leducq; Food Standards Agency; Foundation for Strategic Research; French Ministry of Research; FRSQ; Genetic Association Information Network (GAIN) of the Foundation for the NIH; German Federal Ministry of Education and Research (BMBF, 01ER1206, 01ER1507); GlaxoSmithKline; Greek General Secretary of Research and Technology; Go¨teborg Medical Society; Health and Safety Executive; Healthcare NHS Trust; Healthway; Western Australia; Heart Foundation of Northern Sweden; Helmholtz Zentrum Mu¨nchen—German Research Center for Environmental Health; Hjartavernd; Ingrid Thurings Foundation; INSERM; InterOmics (PB05 MIUR-CNR); INTERREG IV Oberrhein Program (A28); Interuniversity Cardiology Institute of the Netherlands (ICIN, 09.001); Italian Ministry of Health (ICS110.1/RF97.71); Italian Ministry of Economy and Finance (FaReBio di Qualita`); Marianne and Marcus Wallenberg Foundation; the Ministry of Health, Welfare and Sports, the Netherlands; J.D.E. and Catherine T, MacArthur Foundation Research Networks on Successful Midlife Development and Socioeconomic Status and Health; Juho Vainio Foundation; Juvenile Diabetes Research Foundation International; KfH Stiftung Pra¨ventivmedizin e.V.; King's College London; Knut and Alice Wallenberg Foundation; Kuopio University Hospital; Kuopio, Tampere and Turku University Hospital Medical Funds (X51001); La Fondation de France; Leenaards Foundation; Lilly; LMUinnovativ; Lundberg Foundation; Magnus Bergvall Foundation; MDEIE; Medical Research Council UK (G0000934, G0601966, G0700931, MC_U106179471, MC_UU_12019/1); MEKOS Laboratories; Merck Sante´; Ministry for Health, Welfare and Sports, The Netherlands; Ministry of Cultural Affairs of Mecklenburg-West Pomerania; Ministry of Economic Affairs, The Netherlands; Ministry of Education and Culture of Finland (627;2004-2011); Ministry of Education, Culture and Science, The Netherlands; Ministry of Science, Education and Sport in the Republic of Croatia (108-1080315-0302); MRC centre for Causal Analyses in Translational Epidemiology; MRC Human Genetics Unit; MRC-GlaxoSmithKline pilot programme (G0701863); MSD Stipend Diabetes; National Institute for Health Research; Netherlands Brain Foundation (F2013(1)-28); Netherlands CardioVascular Research Initiative (CVON2011-19); Netherlands Genomics Initiative (050-060-810); Netherlands Heart Foundation (2001 D 032, NHS2010B280); Netherlands Organization for Scientific Research (NWO) and Netherlands Organisation for Health Research and Development (ZonMW) (56-464- 14192, 60-60600-97-118, 100-001-004, 261-98-710, 400-05-717, 480-04-004, 480-05-003, 481-08-013, 904-61-090, 904-61-193, 911-11-025, 985-10-002, Addiction-31160008, BBMRI–NL 184.021.007, GB-MaGW 452-04-314, GB-MaGW 452-06-004, GB-MaGW 480-01-006, GB-MaGW 480-07-001, GB-MW 940-38-011, Middelgroot-911-09-032, NBIC/BioAssist/RK 2008.024, Spinozapremie 175.010.2003.005, 175.010.2007.006); NATURE COMMUNICATIONS | DOI:10.1038/ncomms14977 ARTICLE NATURE COMMUNICATIONS | 8:14977 | DOI:10.1038/ncomms14977 | www.nature.com/naturecommunications 13 Neuroscience Campus Amsterdam; NHS Foundation Trust; National Institutes of Health (1RC2MH089951, 1Z01HG000024, 24152, 263MD9164, 263MD821336, 2R01LM010098, 32100-2, 32122, 32108, 5K99HL130580-02, AA07535, AA10248, AA11998, AA13320, AA13321, AA13326, AA14041, AA17688, AG13196, CA047988, DA12854, DK56350, DK063491, DK078150, DK091718, DK100383, DK078616, ES10126, HG004790, HHSN268200625226C, HHSN268200800007C, HHSN268201200036C, HHSN268201500001I, HHSN268201100046C, HHSN268201100001C, HHSN268201100002C, HHSN268201100003C, HHSN268201100004C, HHSN271201100004C, HL043851, HL45670, HL080467, HL085144, HL087660, HL054457, HL119443, HL118305, HL071981, HL034594, HL126024, HL130114, KL2TR001109, MH66206, MH081802, N01AG12100, N01HC55015, N01HC55016, N01C55018, N01HC55019, N01HC55020, N01HC55021, N01HC55022, N01HC85079, N01HC85080, N01HC85081, N01HC85082, N01HC85083, N01HC85086, N01HC95159, N01HC95160, N01HC95161, N01HC95162, N01HC95163, N01HC95164, N01HC95165, N01HC95166, N01HC95167, N01HC95168, N01HC95169, N01HG65403, N01WH22110, N02HL6-4278, N01-HC-25195, P01CA33619, R01HD057194, R01HD057194, R01AG023629, R01CA63, R01D004215701A, R01DK075787, R01DK062370, R01DK072193, R01DK075787, R01DK089256, R01HL53353, R01HL59367, R01HL086694, R01HL087641, R01HL087652, R01HL103612, R01HL105756, R01HL117078, R01HL120393, R03 AG046389, R37CA54281, RC2AG036495, RC4AG039029, RPPG040710371, RR20649, TW008288, TW05596, U01AG009740, U01CA98758, U01CA136792, U01DK062418, U01HG004402, U01HG004802, U01HG007376, U01HL080295, UL1RR025005, UL1TR000040, UL1TR000124, UL1TR001079, 2T32HL007055-36, T32GM074905, HG002651, HL084729, N01-HC25195, UM1CA182913); NIH, National Institute on Aging (Intramural funding, NO1-AG-1-2109); Northern Netherlands Collaboration of Provinces; Novartis Pharma; Novo Nordisk; Novo Nordisk Foundation; Nutricia Research Foundation (2016-T1); ONIVINS; Parnassia Bavo group; Pierre Fabre; Province of Groningen; Pa¨ivikki and Sakari Sohlberg Foundation; Påhlssons Foundation; Paavo Nurmi Foundation; Radboud Medical Center Nijmegen; Research Centre for Prevention and Health, the Capital Region of Denmark; the Research Institute for Diseases in the Elderly; Research into Ageing; Robert Dawson Evans Endowment of the Department of Medicine at Boston University School of Medicine and Boston Medical Center; Roche; Royal Society; Russian Foundation for Basic Research (NWO-RFBR 047.017.043); Rutgers University Cell and DNA Repository (NIMH U24 MH068457-06); Sanofi-Aventis; Scottish Government Health Directorates, Chief Scientist Office (CZD/16/6); Siemens Healthcare; Social Insurance Institution of Finland (4/26/2010); Social Ministry of the Federal State of Mecklenburg-West Pomerania; Socie´te´ Francophone du 358 Diabe`te; State of Bavaria; Stiftelsen fo¨r Gamla Tja¨narinnor; Stockholm County Council (560183, 592229); Strategic Cardiovascular and Diabetes Programmes of Karolinska Institutet and Stockholm County Council; Stroke Association; Swedish Diabetes Association; Swedish Diabetes Foundation (2013-024); Swedish Foundation for Strategic Research; Swedish Heart-Lung Foundation (20120197, 20150711); Swedish Research Council (0593, 8691, 2012-1397, 2012-1727, and 2012-2215); Swedish Society for Medical Research; Swiss Institute of Bioinformatics; Swiss National Science Foundation (3100AO-116323/1, 31003A-143914, 33CSCO-122661, 33CS30-139468, 33CS30-148401, 51RTP0_151019); Tampere Tuberculosis Foundation; Technology Foundation STW (11679); The Fonds voor Wetenschappelijk Onderzoek Vlaanderen, Ministry of the Flemish Community (G.0880.13, G.0881.13); The Great Wine Estates of the Margaret River Region of Western Australia; Timber Merchant Vilhelm Bangs Foundation; Topcon; Tore Nilsson Foundation; Torsten and Ragnar So¨derberg's Foundation; United States – Israel Binational Science Foundation (Grant 2011036), Umeå University; University Hospital of Regensburg; University of Groningen; University Medical Center Groningen; University of Michigan; University of Utrecht; Uppsala Multidisciplinary Center for Advanced Computational Science (UPPMAX) (b2011036); Velux Foundation; VU University's Institute for Health and Care Research; Va¨stra Go¨taland Foundation; Wellcome Trust (068545, 076113, 079895, 084723, 088869, WT064890, WT086596, WT098017, WT090532, WT098051, 098381); Wissenschaftsoffensive TMO; Yrjo¨ Jahnsson Foundation; and Åke Wiberg Foundation
