Impact of common genetic determinants of Hemoglobin A1c on type 2 diabetes risk and diagnosis in ancestrally diverse populations: A transethnic genome-wide meta-analysis
Eleanor Wheeler 1, Aaron Leong 2 3, Ching-Ti Liu 4, Marie-France Hivert 5 6, Rona J Strawbridge 7 8, Clara Podmore 9 10, Man Li 11 12 13, Jie Yao 14, Xueling Sim 15, Jaeyoung Hong 4, Audrey Y Chu 16 17, Weihua Zhang 18 19, Xu Wang 20, Peng Chen 15 21 22 23, Nisa M Maruthur 11 24 25, Bianca C Porneala 2, Stephen J Sharp 9, Yucheng Jia 14, Edmond K Kabagambe 26, Li-Ching Chang 27, Wei-Min Chen 28, Cathy E Elks 9 29, Daniel S Evans 30, Qiao Fan 31, Franco Giulianini 17, Min Jin Go 32, Jouke-Jan Hottenga 33, Yao Hu 34, Anne U Jackson 35, Stavroula Kanoni 36, Young Jin Kim 32, Marcus E Kleber 37, Claes Ladenvall 38 39, Cecile Lecoeur 40, Sing-Hui Lim 41, Yingchang Lu 42 43, Anubha Mahajan 44, Carola Marzi 45 46, Mike A Nalls 47 48, Pau Navarro 49, Ilja M Nolte 50, Lynda M Rose 17, Denis V Rybin 4 51, Serena Sanna 52, Yuan Shi 41, Daniel O Stram 53, Fumihiko Takeuchi 54, Shu Pei Tan 41, Peter J van der Most 50, Jana V Van Vliet-Ostaptchouk 50 55, Andrew Wong 56, Loic Yengo 40, Wanting Zhao 41, Anuj Goel 44 57, Maria Teresa Martinez Larrad 58, Dörte Radke 59, Perttu Salo 60 61, Toshiko Tanaka 62, Erik P A van Iperen 63 64, Goncalo Abecasis 35, Saima Afaq 18, Behrooz Z Alizadeh 50, Alain G Bertoni 65, Amelie Bonnefond 40, Yvonne Böttcher 66, Erwin P Bottinger 42, Harry Campbell 67, Olga D Carlson 68, Chien-Hsiun Chen 27 69, Yoon Shin Cho 32 70, W Timothy Garvey 71, Christian Gieger 45, Mark O Goodarzi 72, Harald Grallert 45 46, Anders Hamsten 7 8, Catharina A Hartman 73, Christian Herder 74 75, Chao Agnes Hsiung 76, Jie Huang 77, Michiya Igase 78, Masato Isono 54, Tomohiro Katsuya 79 80, Chiea-Chuen Khor 81, Wieland Kiess 82 83, Katsuhiko Kohara 84, Peter Kovacs 66, Juyoung Lee 32, Wen-Jane Lee 85, Benjamin Lehne 18, Huaixing Li 34, Jianjun Liu 15 81, Stephane Lobbens 40, Jian'an Luan 9, Valeriya Lyssenko 39, Thomas Meitinger 86 87 88, Tetsuro Miki 78, Iva Miljkovic 89, Sanghoon Moon 32, Antonella Mulas 52, Gabriele Müller 90, Martina Müller-Nurasyid 91 92 93, Ramaiah Nagaraja 94, Matthias Nauck 95, James S Pankow 96, Ozren Polasek 97 98, Inga Prokopenko 44 99 100, Paula S Ramos 101, Laura Rasmussen-Torvik 102, Wolfgang Rathmann 75, Stephen S Rich 103, Neil R Robertson 99 104, Michael Roden 74 75 105, Ronan Roussel 106 107 108, Igor Rudan 109, Robert A Scott 9, William R Scott 18 19, Bengt Sennblad 7 8 110, David S Siscovick 111, Konstantin Strauch 91 112, Liang Sun 34, Morris Swertz 113, Salman M Tajuddin 114, Kent D Taylor 14, Yik-Ying Teo 15 20 81 115 116, Yih Chung Tham 41, Anke Tönjes 117, Nicholas J Wareham 9, Gonneke Willemsen 33, Tom Wilsgaard 118, Aroon D Hingorani 119; EPIC-CVD Consortium; EPIC-InterAct Consortium; Lifelines Cohort Study; Josephine Egan 68, Luigi Ferrucci 68, G Kees Hovingh 120, Antti Jula 60, Mika Kivimaki 121, Meena Kumari 121 122, Inger Njølstad 118, Colin N A Palmer 123, Manuel Serrano Ríos 58, Michael Stumvoll 117, Hugh Watkins 44 57, Tin Aung 41 124 125 126, Matthias Blüher 117, Michael Boehnke 35, Dorret I Boomsma 33, Stefan R Bornstein 127, John C Chambers 18 19 128, Daniel I Chasman 17 129 130, Yii-Der Ida Chen 14, Yduan-Tsong Chen 27, Ching-Yu Cheng 41 124 125 126, Francesco Cucca 52 131, Eco J C de Geus 33, Panos Deloukas 36 132, Michele K Evans 114, Myriam Fornage 133, Yechiel Friedlander 134, Philippe Froguel 100 135, Leif Groop 39 136, Myron D Gross 137, Tamara B Harris 138, Caroline Hayward 139, Chew-Kiat Heng 140 141, Erik Ingelsson 142 143, Norihiro Kato 54, Bong-Jo Kim 32, Woon-Puay Koh 15 144, Jaspal S Kooner 19 128 145, Antje Körner 82 83, Diana Kuh 56, Johanna Kuusisto 146, Markku Laakso 146, Xu Lin 34, Yongmei Liu 147, Ruth J F Loos 42 43 148, Patrik K E Magnusson 149, Winfried März 37 150 151, Mark I McCarthy 99 104 152, Albertine J Oldehinkel 73, Ken K Ong 9, Nancy L Pedersen 149, Mark A Pereira 96, Annette Peters 45, Paul M Ridker 17 153, Charumathi Sabanayagam 41 124, Michele Sale 103, Danish Saleheen 154 155, Juha Saltevo 156, Peter Eh Schwarz 127, Wayne H H Sheu 157 158 159, Harold Snieder 50, Timothy D Spector 160, Yasuharu Tabara 161, Jaakko Tuomilehto 162 163 164 165, Rob M van Dam 15, James G Wilson 166, James F Wilson 49 67, Bruce H R Wolffenbuttel 55, Tien Yin Wong 41 124 125 126, Jer-Yuarn Wu 27 69, Jian-Min Yuan 89 167, Alan B Zonderman 168, Nicole Soranzo 1 169 170, Xiuqing Guo 14, David J Roberts 171 172, Jose C Florez 3 173 174, Robert Sladek 175, Josée Dupuis 4 16, Andrew P Morris 104 176, E-Shyong Tai 15 144 177, Elizabeth Selvin 11 24 25, Jerome I Rotter 14, Claudia Langenberg 9, Inês Barroso 1 178, James B Meigs 2 3 174
Affiliations
Affiliations
- 1Department of Human Genetics, Wellcome Trust Sanger Institute, Genome Campus, Hinxton, Cambridge, United Kingdom.
- 2Division of General Internal Medicine, Massachusetts General Hospital, Boston, MA, United States of America.
- 3Harvard Medical School, Boston, MA, United States of America.
- 4Department of Biostatistics, Boston University School of Public Health, Boston, MA, United States of America.
- 5Department of Population Medicine, Harvard Medical School, Harvard Pilgrim Health Care Institute, Boston, MA, United States of America.
- 6Massachusetts General Hospital, Boston, MA, United States of America.
- 7Cardiovascular Medicine Unit, Department of Medicine Solna, Karolinska Institutet, Stockholm, Sweden.
- 8Centre for Molecular Medicine, Karolinska Universitetsjukhuset, Solna, Sweden.
- 9MRC Epidemiology Unit, Institute of Metabolic Science, University of Cambridge School of Clinical Medicine, Cambridge, United Kingdom.
- 10Department of Internal Medicine, Lausanne University Hospital (CHUV), Lausanne, Switzerland.
- 11Department of Epidemiology, The Johns Hopkins Bloomberg School of Public Health, Baltimore, MD, United States of America.
- 12Division of Nephrology, University of Utah, Salt Lake City, UT, United States of America.
- 13Department of Human Genetics, University of Utah, Salt Lake City, UT, United States of America.
- 14Institute for Translational Genomics and Population Sciences, Department of Pediatrics, LABioMed at Harbor-UCLA Medical Center, Torrance, CA, United States of America.
- 15Saw Swee Hock School of Public Health, National University of Singapore, Singapore, Singapore.
- 16National Heart, Lung, and Blood Institute's Framingham Heart Study, Framingham, MA, United States of America.
- 17Division of Preventive Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, United States of America.
- 18Department of Epidemiology and Biostatistics, School of Public Health, Imperial College London, London, United Kingdom.
- 19Department of Cardiology, Ealing Hospital NHS Trust, Southall, Middlesex, United Kingdom.
- 20Life Sciences Institute, National University of Singapore, Singapore, Singapore.
- 21Phoenix Epidemiology and Clinical Research Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Phoenix, AZ, United States of America.
- 22Key Laboratory of Pathobiology, Ministry of Education, Jilin University, Changchun, Jilin, China.
- 23College of Basic Medical Sciences, Jilin University, Changchun, Jilin, China.
- 24Division of General Internal Medicine, The Johns Hopkins University School of Medicine, Baltimore, MD, United States of America.
- 25Welch Center for Prevention, Epidemiology and Clinical Research, The Johns Hopkins University, Baltimore, MD, United States of America.
- 26Division of Epidemiology, Department of Medicine, Vanderbilt University Medical Center, Nashville, TN, United States of America.
- 27Institute of Biomedical Sciences, Academia Sinica, Taipei, Taiwan.
- 28University of Virginia Center for Public Health Genomics, Charlottesville, VA, United States of America.
- 29Personalised Healthcare & Biomarkers, Innovative Medicines and Early Development Biotech Unit, AstraZeneca, Cambridge, United Kingdom.
- 30California Pacific Medical Center Research Institute, San Francisco, CA, United States of America.
- 31Centre for Quantitative Medicine, Duke-NUS Medical School, Singapore, Singapore.
- 32Division of Structural and Functional Genomics, Center for Genome Science, Korean National Institute of Health, Osong, Chungchungbuk-do, South Korea.
- 33Biological Psychology, Vrije Universiteit Amsterdam, Amsterdam, Netherlands.
- 34The Key Laboratory of Nutrition and Metabolism, Institute for Nutritional Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, University of the Chinese Academy of Sciences, Shanghai, People's Republic of China.
- 35Department of Biostatistics and Center for Statistical Genetics, University of Michigan, Ann Arbor, MI, United States of America.
- 36William Harvey Research Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London, United Kingdom.
- 37Vth Department of Medicine, Medical Faculty Mannheim, University of Heidelberg, Mannheim, Germany.
- 38Department of Immunology, Genetics and Pathology, Science for Life Laboratory, Uppsala University, Uppsala, Sweden.
- 39Lund University Diabetes Centre, Lund University, Lund, Sweden.
- 40University of Lille, CNRS, Institut Pasteur of Lille, UMR 8199-EGID, Lille, France.
- 41Singapore Eye Research Institute, The Academia Level 6, Discovery Tower, Singapore, Singapore.
- 42The Charles Bronfman Institute for Personalized Medicine, The Icahn School of Medicine at Mount Sinai, New York, NY, United States of America.
- 43The Genetics of Obesity and Related Metabolic Traits Program, The Icahn School of Medicine at Mount Sinai, New York, NY, United States of America.
- 44Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, United Kingdom.
- 45Institute of Epidemiology II, Research Unit of Molecular Epidemiology, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany.
- 46German Center for Diabetes Research (DZD e.V.), Partner Munich, Munich, Germany.
- 47Data Tecnica International, Glen Echo, MD, United States of America.
- 48Laboratory of Neurogenetics, National Institute on Aging, Bethesda, MD, United States of America.
- 49MRC Human Genetics Unit, Institute of Genetics and Molecular Medicine, University of Edinburgh, Western General Hospital, Edinburgh, Scotland.
- 50Department of Epidemiology, University of Groningen, University Medical Center Groningen, Groningen, Netherlands.
- 51Data Coordinating Center, Boston University School of Public Health, Boston, MA, United States of America.
- 52Istituto di Ricerca Genetica e Biomedica (IRGB), CNR, Monserrato, Italy.
- 53Department of Preventive Medicine, University of Southern California, Los Angeles, CA, United States of America.
- 54Department of Gene Diagnostics and Therapeutics, Research Institute, National Center for Global Health and Medicine, Tokyo, Japan.
- 55Department of Endocrinology, University of Groningen, University Medical Center Groningen, Groningen, Netherlands.
- 56MRC Unit for Lifelong Health & Ageing, London, United Kingdom.
- 57Division of Cardiovascular Medicine, Radcliffe Department of Medicine, University of Oxford, Oxford, United Kingdom.
- 58Spanish Biomedical Research Centre in Diabetes and Associated Metabolic Disorders (CIBERDEM), Instituto de Investigación Sanitaria del Hospital Clínico San Carlos (IdISSC), Madrid, Spain.
- 59Institute for Community Medicine, University Medicine Greifswald, Greifswald, Germany.
- 60National Institute for Health and Welfare (THL), Helsinki, Finland.
- 61University of Helsinki, Institute for Molecular Medicine, Finland (FIMM) and Diabetes and Obesity Research Program, Helsinki, Finland.
- 62Translational Gerontology Branch, National Institute on Aging, Baltimore, MD, United States of America.
- 63Department of Clinical Epidemiology, Biostatistics and Bioinformatics, Academic Medical Center, University of Amsterdam, Amsterdam, Netherlands.
- 64Durrer Center for Cardiogenetic Research, ICIN-Netherlands Heart Institute, Utrecht, Netherlands.
- 65Department of Epidemiology and Prevention, Wake Forest School of Medicine, Winston-Salem, NC, United States of America.
- 66Integrated Research and Treatment (IFB) Center Adiposity Diseases, University of Leipzig, Leipzig, Germany.
- 67Centre for Global Health Research, Usher Institute of Population Health Sciences and Informatics, University of Edinburgh, Edinburgh, Scotland.
- 68Laboratory of Clinical Investigation, National Institute on Aging, Baltimore, MD, United States of America.
- 69School of Chinese Medicine, China Medical University, Taichung City, Taiwan.
- 70Department of Biomedical Science, Hallym University, Chuncheon, Gangwon-do, South Korea.
- 71Department of Nutrition Sciences, University of Alabama at Birmingham and the Birmingham Veterans Affairs Medical Center, Birmingham, AL, United States of America.
- 72Division of Endocrinology, Diabetes, and Metabolism, Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, CA, United States of America.
- 73Department of Psychiatry, University of Groningen, University Medical Center Groningen, Groningen, Netherlands.
- 74Institute for Clinical Diabetology, German Diabetes Center, Leibniz Institute for Diabetes Research at Heinrich Heine University Düsseldorf, Düsseldorf, Germany.
- 75German Center for Diabetes Research (DZD), München-Neuherberg, Germany.
- 76Division of Endocrinology, Diabetes, Metabolism, Department of Internal Medicine, Wexner Medical Center, The Ohio State University, Columbus, OH, United States of America.
- 77Boston VA Research Institute, Inc., Boston, MA, United States of America.
- 78Department of Geriatric Medicine, Ehime University Graduate School of Medicine, Ehime, Japan.
- 79Department of Clinical Gene Therapy, Osaka University Graduate School of Medicine, Suita, Japan.
- 80Department of Geriatric Medicine and Nephrology, Osaka University Graduate School of Medicine, Suita, Japan.
- 81Genome Institute of Singapore, Agency for Science Technology and Research, Singapore, Singapore.
- 82Center of Pediatric Research, University Hospital for Children & Adolescents, Dept. of Women's & Child Health, University of Leipzig, Leipzig, Germany.
- 83LIFE Child, LIFE Leipzig Research Center for Civilization Diseases, University of Leipzig, Leipzig, Germany.
- 84Faculty of Collaborative Regional Innovation, Ehime University, Ehime, Japan.
- 85Department of Medical Research, Taichung Veterans General Hospital, Taichung, Taiwan.
- 86Institute of Human Genetics, Technische Universität München, Munich, Germany.
- 87Institute of Human Genetics, Helmholtz Zentrum München, Neuherberg, Germany.
- 88Munich Cluster for Systems Neurology (SyNergy), Munich, Germany.
- 89Department of Epidemiology, Graduate School of Public Health, University of Pittsburgh, Pittsburgh, PA, United States of America.
- 90Center for Evidence-based Healthcare, University Hospital and Medical Faculty Carl Gustav Carus, Dresden, Germany.
- 91Institute of Genetic Epidemiology, Helmholtz Zentrum München-German Research Center for Environmental Health, Neuherberg, Germany.
- 92Department of Medicine I, University Hospital Grosshadern, Ludwig-Maximilians-Universität, Munich, Germany.
- 93DZHK (German Centre for Cardiovascular Research), partner site Munich Heart Alliance, Munich, Germany.
- 94Laboratory of Genetics, National Institute on Aging, Baltimore, MD, United States of America.
- 95Institute for Clinical Chemistry and Laboratory Medicine, University Medicine Greifswald, Greifswald, Germany.
- 96Division of Epidemiology and Community Health, University of Minnesota, Minneapolis, MN, United States of America.
- 97University of Split, Split, Croatia.
- 98Centre for Population Health Sciences, University of Edinburgh, Edinburgh, United Kingdom.
- 99Oxford Centre for Diabetes, Endocrinology and Metabolism, Radcliffe Department of Medicine, University of Oxford, Oxford, United Kingdom.
- 100Department of Genomics of Common Disease, School of Public Health, Imperial College London, London, United Kingdom.
- 101Department of Medicine, Medical University of South Carolina, Charleston, SC, United States of America.
- 102Department of Preventive Medicine, Northwestern University Feinberg School of Medicine, Chicago, IL, United States of America.
- 103Center for Public Health Genomics, University of Virginia School of Medicine, Charlottesville, VA, United States of America.
- 104Wellcome Trust Centre for Human Genetics, Nuffield Department of Medicine, University of Oxford, Oxford, United Kingdom.
- 105Department of Endocrinology and Diabetology, University Hospital Düsseldorf, Düsseldorf, Germany.
- 106INSERM, UMR_S 1138, Centre de Recherche des Cordelier, Paris, France.
- 107Université Paris Diderot, Sorbonne Paris Cité, UFR de Médecine, Paris, France.
- 108Assistance Publique Hôpitaux de Paris, Bichat Hospital, DHU FIRE, Department of Diabetology, Endocrinology and Nutrition, Paris, France.
- 109University of Edinburgh, Edinburgh, United Kingdom.
- 110Science for life laboratory, Karolinska Institutet, Solna, Sweden.
- 111The New York Academy of Medicine, New York, NY, United States of America.
- 112Institute of Medical Informatics, Biometry and Epidemiology, Ludwig-Maximilians-Universität, Munich, Germany.
- 113Department of Genetics, University of Groningen, University Medical Center Groningen, Groningen, Netherlands.
- 114Health Disparities Unit, National Institute on Aging, National Institutes of Health, Baltimore, MD, United States of America.
- 115Department of Statistics and Applied Probability, National University of Singapore, Singapore, Singapore.
- 116NUS Graduate School for Integrative Science and Engineering, National University of Singapore, Singapore, Singapore.
- 117Department of Medicine; University of Leipzig, Leipzig, Germany.
- 118Dept of Community Medicine, Faculty of Health Sciences, University of Tromsø, Tromsø, Norway.
- 119Institute of Cardiovascular Science, University College London, London, United Kingdom.
- 120Department of Vascular Medicine, Academic Medical Center, Amsterdam, Netherlands.
- 121Department of Epidemiology and Public Health, University College London, London, United Kingdom.
- 122Institute for Social and Economic Research, University of Essex, Colchester, United Kingdom.
- 123Pat Macpherson Centre for Pharmacogenetics and Pharmacogenomics, Medical Research Institute, Ninewells Hospital and Medical School, Dundee, United Kingdom.
- 124Ophthalmology and Visual Sciences Academic Clinical Program (Eye ACP), Duke-NUS Medical School, Singapore, Singapore.
- 125Department of Ophthalmology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore.
- 126Singapore National Eye Centre, Singapore, Singapore.
- 127Dept of Medicine III, University of Dresden, Medical Faculty Carl Gustav Carus, Dresden, Germany.
- 128Imperial College Healthcare NHS Trust, London, United Kingdom.
- 129Division of Genetics, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, United States of America.
- 130Broad Institute of MIT and Harvard, Cambridge, MA, United States of America.
- 131Dipartimento di Scienze Biomediche, Università di Sassari, Italy.
- 132Princess Al-Jawhara Al-Brahim Centre of Excellence in Research of Hereditary Disorders (PACER-HD), King Abdulaziz University, Jeddah, Saudi Arabia.
- 133Brown Foundation Institute of Molecular Medicine, Division of Epidemiology, School of Public Health, University of Texas Health Science Center at Houston, Houston, TX, United States of America.
- 134Braun School of Public Health, Hebrew University-Hadassah Medical Center, Jerusalem, Israel.
- 135CNRS 8199-Lille University, France.
- 136Finnish Institute for Molecular Medicine (FIMM), Helsinki, Finland.
- 137Department of Laboratory Medicine and Pathology, University of Minnesota, Minneapolis, MN, United States of America.
- 138National Institute on Aging, Bethesda, MD, United States of America.
- 139Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh, United Kingdom.
- 140Department of Paediatrics, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore.
- 141Khoo Teck Puat-National University Children's Medical Institute, National University Health System, Singapore, Singapore.
- 142Department of Medical Sciences, Molecular Epidemiology and Science for Life Laboratory, Uppsala University, Uppsala, Sweden.
- 143Department of Medicine, Division of Cardiovascular Medicine, Stanford University School of Medicine, Stanford, CA, United States of America.
- 144Duke-NUS Medical School Singapore, Singapore.
- 145National Heart and Lung Institute, Imperial College London, Hammersmith Hospital Campus, London, United Kingdom.
- 146Institute of Clinical Medicine, Internal Medicine, University of Eastern Finland and Kuopio University Hospital, Kuopio, Finland.
- 147Department of Epidemiology and Prevention, Division of Public Health Sciences, Wake Forest University, Winston-Salem, NC, United States of America.
- 148The Mindich Child Health Development Institute, The Icahn School of Medicine at Mount Sinai, New York, NY, United States of America.
- 149Department of Medical Epidemiology and Biostatistics, Karolinska Insitutet, Stockholm, Sweden.
- 150Clinical Institute of Medical and Chemical Laboratory Diagnostics, Medical University of Graz, Graz, Austria.
- 151Synlab Academy, Synlab Services GmbH, Mannheim, Germany.
- 152Oxford NIHR Biomedical Research Centre, Oxford University Hospitals Trust, Oxford, United Kingdom.
- 153Division of Cardiovascular Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, United States of America.
- 154Department of Biostatistics and Epidemiology, University of Pennsylvania, Philadelphia, PA, United States of America.
- 155Center for Non-Communicable Diseases, Karachi, Pakistan.
- 156Department of Medicine, Central Hospital, Central Finland, Jyväskylä, Finland.
- 157Division of Endocrine and Metabolism, Department of Internal Medicine, Taichung Veterans General Hospital, Taichung, Taiwan.
- 158School of Medicine, National Yang-Ming University, Taipei, Taiwan.
- 159School of Medicine, National Defense Medical Center, Taipei, Taiwan.
- 160Department of Twin Research and Genetic Epidemiology, King's College London, London, United Kingdom.
- 161Center for Genomic Medicine, Kyoto University Graduate School of Medicine, Kyoto, Japan.
- 162Chronic Disease Prevention Unit, National Institute for Health and Welfare, Helsinki, Finland.
- 163Dasman Diabetes Institute, Dasman, Kuwait.
- 164Centre for Vascular Prevention, Danube-University Krems, Krems, Austria.
- 165Saudi Diabetes Research Group, King Abdulaziz University, Fahd Medical Research Center, Jeddah, Saudi Arabia.
- 166Department of Physiology and Biophysics, University of Mississippi Medical Center, Jackson, MS, United States of America.
- 167Division of Cancer Control and Population Sciences,University of Pittsburgh Cancer Institute, Pittsburgh, PA, United States of America.
- 168Laboratory of Epidemiology & Population Sciences, National Institute on Aging, National Institutes of Health, Baltimore, MD, United States of America.
- 169Department of Haematology, University of Cambridge, Cambridge, United Kingdom.
- 170The National Institute for Health Research Blood and Transplant Unit (NIHR BTRU) in Donor Health and Genomics at the University of Cambridge, United Kingdom.
- 171Biomedical Research Centre Oxford Haematology Theme and Radcliffe Department of Medicine, University of Oxford, John Radcliffe Hospital, Headley Way, Headington, Oxford, United Kingdom.
- 172NHS Blood and Transplant, Headington, Oxford, United Kingdom.
- 173Diabetes Unit and Center for Human Genetic Research, Massachusetts General Hospital, Boston, MA, United States of America.
- 174Programs in Metabolism and Medical & Population Genetics, Broad Institute, Cambridge, MA, United States of America.
- 175Department of Medicine, McGill University, Montreal, Quebec, Canada.
- 176Department of Biostatistics, University of Liverpool, Liverpool, United Kingdom.
- 177Department of Medicine, Yong Loo Lin School of Medicine, National University of Singapore, Singapore.
- 178Institute of Metabolic Science, University of Cambridge, Cambridge, United Kingdom.
Abstract
Background: Glycated hemoglobin (HbA1c) is used to diagnose type 2 diabetes (T2D) and assess glycemic control in patients with diabetes. Previous genome-wide association studies (GWAS) have identified 18 HbA1c-associated genetic variants. These variants proved to be classifiable by their likely biological action as erythrocytic (also associated with erythrocyte traits) or glycemic (associated with other glucose-related traits). In this study, we tested the hypotheses that, in a very large scale GWAS, we would identify more genetic variants associated with HbA1c and that HbA1c variants implicated in erythrocytic biology would affect the diagnostic accuracy of HbA1c. We therefore expanded the number of HbA1c-associated loci and tested the effect of genetic risk-scores comprised of erythrocytic or glycemic variants on incident diabetes prediction and on prevalent diabetes screening performance. Throughout this multiancestry study, we kept a focus on interancestry differences in HbA1c genetics performance that might influence race-ancestry differences in health outcomes.
Methods & findings: Using genome-wide association meta-analyses in up to 159,940 individuals from 82 cohorts of European, African, East Asian, and South Asian ancestry, we identified 60 common genetic variants associated with HbA1c. We classified variants as implicated in glycemic, erythrocytic, or unclassified biology and tested whether additive genetic scores of erythrocytic variants (GS-E) or glycemic variants (GS-G) were associated with higher T2D incidence in multiethnic longitudinal cohorts (N = 33,241). Nineteen glycemic and 22 erythrocytic variants were associated with HbA1c at genome-wide significance. GS-G was associated with higher T2D risk (incidence OR = 1.05, 95% CI 1.04-1.06, per HbA1c-raising allele, p = 3 × 10-29); whereas GS-E was not (OR = 1.00, 95% CI 0.99-1.01, p = 0.60). In Europeans and Asians, erythrocytic variants in aggregate had only modest effects on the diagnostic accuracy of HbA1c. Yet, in African Americans, the X-linked G6PD G202A variant (T-allele frequency 11%) was associated with an absolute decrease in HbA1c of 0.81%-units (95% CI 0.66-0.96) per allele in hemizygous men, and 0.68%-units (95% CI 0.38-0.97) in homozygous women. The G6PD variant may cause approximately 2% (N = 0.65 million, 95% CI 0.55-0.74) of African American adults with T2D to remain undiagnosed when screened with HbA1c. Limitations include the smaller sample sizes for non-European ancestries and the inability to classify approximately one-third of the variants. Further studies in large multiethnic cohorts with HbA1c, glycemic, and erythrocytic traits are required to better determine the biological action of the unclassified variants.
Conclusions: As G6PD deficiency can be clinically silent until illness strikes, we recommend investigation of the possible benefits of screening for the G6PD genotype along with using HbA1c to diagnose T2D in populations of African ancestry or groups where G6PD deficiency is common. Screening with direct glucose measurements, or genetically-informed HbA1c diagnostic thresholds in people with G6PD deficiency, may be required to avoid missed or delayed diagnoses.
Conflict of interest statement
We have read the journal's policy and the authors of this manuscript have the following competing interests: AYC is an employee of Merck, however all work for the manuscript was completed before the start of employment. CEE is a current employee of AstraZeneca. CLan receives a stipend as a specialty consulting editor for PLOS Medicine and serves on the journal's editorial board. EI is a scientific advisor for Precision Wellness, Cellink and Olink Proteomics for work unrelated to the present project. GKH declared institution support from Amgen, AstraZeneca, Cerenis, Ionis, Regeneron Pharmaceuticals, Inc. and Sanofi, Synageva. He has served as a consultant and received speaker fees from Aegerion, Amgen, Sanofi, Regeneron Pharmaceuticals, Inc., and Pfizer. IB and spouse own stock in GlaxoSmithKline and Incyte Corporation. JD declared grants from the National Heart, Lung, and Blood Institute (NHLBI) of the National Institute of Health (NIH) during the course of this study. JIR declared funding from NIH grants. MAN consults for Illumina Inc, the Michael J. Fox Foundation and University of California Healthcare among others. MBl receives speaker’s honoraria and/or compensation for participation in advisory boards from: Astra Zeneca, Bayer, Boehringer-Ingelheim, Lilly, Novo Nordisk, Novartis, MSD, Pfizer, Riemser and Sanofi. MIM was a member of the editorial board of PLOS Medicine at the time this manuscript was submitted. RAS is an employee and shareholder in GlaxoSmithKline.
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