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PLoS Med. 2017 Sep 12;14(9):e1002383. doi: 10.1371/journal.pmed.1002383. eCollection 2017 Sep.

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.

Wheeler E1, Leong A2,3, Liu CT4, Hivert MF5,6, Strawbridge RJ7,8, Podmore C9,10, Li M11,12,13, Yao J14, Sim X15, Hong J4, Chu AY16,17, Zhang W18,19, Wang X20, Chen P15,21,22,23, Maruthur NM11,24,25, Porneala BC2, Sharp SJ9, Jia Y14, Kabagambe EK26, Chang LC27, Chen WM28, Elks CE9,29, Evans DS30, Fan Q31, Giulianini F17, Go MJ32, Hottenga JJ33, Hu Y34, Jackson AU35, Kanoni S36, Kim YJ32, Kleber ME37, Ladenvall C38,39, Lecoeur C40, Lim SH41, Lu Y42,43, Mahajan A44, Marzi C45,46, Nalls MA47,48, Navarro P49, Nolte IM50, Rose LM17, Rybin DV4,51, Sanna S52, Shi Y41, Stram DO53, Takeuchi F54, Tan SP41, van der Most PJ50, Van Vliet-Ostaptchouk JV50,55, Wong A56, Yengo L40, Zhao W41, Goel A44,57, Martinez Larrad MT58, Radke D59, Salo P60,61, Tanaka T62, van Iperen EPA63,64, Abecasis G35, Afaq S18, Alizadeh BZ50, Bertoni AG65, Bonnefond A40, Böttcher Y66, Bottinger EP42, Campbell H67, Carlson OD68, Chen CH27,69, Cho YS32,70, Garvey WT71, Gieger C45, Goodarzi MO72, Grallert H45,46, Hamsten A7,8, Hartman CA73, Herder C74,75, Hsiung CA76, Huang J77, Igase M78, Isono M54, Katsuya T79,80, Khor CC81, Kiess W82,83, Kohara K84, Kovacs P66, Lee J32, Lee WJ85, Lehne B18, Li H34, Liu J15,81, Lobbens S40, Luan J9, Lyssenko V39, Meitinger T86,87,88, Miki T78, Miljkovic I89, Moon S32, Mulas A52, Müller G90, Müller-Nurasyid M91,92,93, Nagaraja R94, Nauck M95, Pankow JS96, Polasek O97,98, Prokopenko I44,99,100, Ramos PS101, Rasmussen-Torvik L102, Rathmann W75, Rich SS103, Robertson NR99,104, Roden M74,75,105, Roussel R106,107,108, Rudan I109, Scott RA9, Scott WR18,19, Sennblad B7,8,110, Siscovick DS111, Strauch K91,112, Sun L34, Swertz M113, Tajuddin SM114, Taylor KD14, Teo YY15,20,81,115,116, Tham YC41, Tönjes A117, Wareham NJ9, Willemsen G33, Wilsgaard T118, Hingorani AD119; EPIC-CVD Consortium; EPIC-InterAct Consortium; Lifelines Cohort Study, Egan J68, Ferrucci L68, Hovingh GK120, Jula A60, Kivimaki M121, Kumari M121,122, Njølstad I118, Palmer CNA123, Serrano Ríos M58, Stumvoll M117, Watkins H44,57, Aung T41,124,125,126, Blüher M117, Boehnke M35, Boomsma DI33, Bornstein SR127, Chambers JC18,19,128, Chasman DI17,129,130, Chen YI14, Chen YT27, Cheng CY41,124,125,126, Cucca F52,131, de Geus EJC33, Deloukas P36,132, Evans MK114, Fornage M133, Friedlander Y134, Froguel P100,135, Groop L39,136, Gross MD137, Harris TB138, Hayward C139, Heng CK140,141, Ingelsson E142,143, Kato N54, Kim BJ32, Koh WP15,144, Kooner JS19,128,145, Körner A82,83, Kuh D56, Kuusisto J146, Laakso M146, Lin X34, Liu Y147, Loos RJF42,43,148, Magnusson PKE149, März W37,150,151, McCarthy MI99,104,152, Oldehinkel AJ73, Ong KK9, Pedersen NL149, Pereira MA96, Peters A45, Ridker PM17,153, Sabanayagam C41,124, Sale M103, Saleheen D154,155, Saltevo J156, Schwarz PE127, Sheu WHH157,158,159, Snieder H50, Spector TD160, Tabara Y161, Tuomilehto J162,163,164,165, van Dam RM15, Wilson JG166, Wilson JF49,67, Wolffenbuttel BHR55, Wong TY41,124,125,126, Wu JY27,69, Yuan JM89,167, Zonderman AB168, Soranzo N1,169,170, Guo X14, Roberts DJ171,172, Florez JC3,173,174, Sladek R175, Dupuis J4,16, Morris AP104,176, Tai ES15,144,177, Selvin E11,24,25, Rotter JI14, Langenberg C9, Barroso I1,178, Meigs JB2,3,174.

Author information

1
Department of Human Genetics, Wellcome Trust Sanger Institute, Genome Campus, Hinxton, Cambridge, United Kingdom.
2
Division of General Internal Medicine, Massachusetts General Hospital, Boston, MA, United States of America.
3
Harvard Medical School, Boston, MA, United States of America.
4
Department of Biostatistics, Boston University School of Public Health, Boston, MA, United States of America.
5
Department of Population Medicine, Harvard Medical School, Harvard Pilgrim Health Care Institute, Boston, MA, United States of America.
6
Massachusetts General Hospital, Boston, MA, United States of America.
7
Cardiovascular Medicine Unit, Department of Medicine Solna, Karolinska Institutet, Stockholm, Sweden.
8
Centre for Molecular Medicine, Karolinska Universitetsjukhuset, Solna, Sweden.
9
MRC Epidemiology Unit, Institute of Metabolic Science, University of Cambridge School of Clinical Medicine, Cambridge, United Kingdom.
10
Department of Internal Medicine, Lausanne University Hospital (CHUV), Lausanne, Switzerland.
11
Department of Epidemiology, The Johns Hopkins Bloomberg School of Public Health, Baltimore, MD, United States of America.
12
Division of Nephrology, University of Utah, Salt Lake City, UT, United States of America.
13
Department of Human Genetics, University of Utah, Salt Lake City, UT, United States of America.
14
Institute for Translational Genomics and Population Sciences, Department of Pediatrics, LABioMed at Harbor-UCLA Medical Center, Torrance, CA, United States of America.
15
Saw Swee Hock School of Public Health, National University of Singapore, Singapore, Singapore.
16
National Heart, Lung, and Blood Institute's Framingham Heart Study, Framingham, MA, United States of America.
17
Division of Preventive Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, United States of America.
18
Department of Epidemiology and Biostatistics, School of Public Health, Imperial College London, London, United Kingdom.
19
Department of Cardiology, Ealing Hospital NHS Trust, Southall, Middlesex, United Kingdom.
20
Life Sciences Institute, National University of Singapore, Singapore, Singapore.
21
Phoenix Epidemiology and Clinical Research Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Phoenix, AZ, United States of America.
22
Key Laboratory of Pathobiology, Ministry of Education, Jilin University, Changchun, Jilin, China.
23
College of Basic Medical Sciences, Jilin University, Changchun, Jilin, China.
24
Division of General Internal Medicine, The Johns Hopkins University School of Medicine, Baltimore, MD, United States of America.
25
Welch Center for Prevention, Epidemiology and Clinical Research, The Johns Hopkins University, Baltimore, MD, United States of America.
26
Division of Epidemiology, Department of Medicine, Vanderbilt University Medical Center, Nashville, TN, United States of America.
27
Institute of Biomedical Sciences, Academia Sinica, Taipei, Taiwan.
28
University of Virginia Center for Public Health Genomics, Charlottesville, VA, United States of America.
29
Personalised Healthcare & Biomarkers, Innovative Medicines and Early Development Biotech Unit, AstraZeneca, Cambridge, United Kingdom.
30
California Pacific Medical Center Research Institute, San Francisco, CA, United States of America.
31
Centre for Quantitative Medicine, Duke-NUS Medical School, Singapore, Singapore.
32
Division of Structural and Functional Genomics, Center for Genome Science, Korean National Institute of Health, Osong, Chungchungbuk-do, South Korea.
33
Biological Psychology, Vrije Universiteit Amsterdam, Amsterdam, Netherlands.
34
The 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.
35
Department of Biostatistics and Center for Statistical Genetics, University of Michigan, Ann Arbor, MI, United States of America.
36
William Harvey Research Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London, United Kingdom.
37
Vth Department of Medicine, Medical Faculty Mannheim, University of Heidelberg, Mannheim, Germany.
38
Department of Immunology, Genetics and Pathology, Science for Life Laboratory, Uppsala University, Uppsala, Sweden.
39
Lund University Diabetes Centre, Lund University, Lund, Sweden.
40
University of Lille, CNRS, Institut Pasteur of Lille, UMR 8199-EGID, Lille, France.
41
Singapore Eye Research Institute, The Academia Level 6, Discovery Tower, Singapore, Singapore.
42
The Charles Bronfman Institute for Personalized Medicine, The Icahn School of Medicine at Mount Sinai, New York, NY, United States of America.
43
The Genetics of Obesity and Related Metabolic Traits Program, The Icahn School of Medicine at Mount Sinai, New York, NY, United States of America.
44
Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, United Kingdom.
45
Institute of Epidemiology II, Research Unit of Molecular Epidemiology, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany.
46
German Center for Diabetes Research (DZD e.V.), Partner Munich, Munich, Germany.
47
Data Tecnica International, Glen Echo, MD, United States of America.
48
Laboratory of Neurogenetics, National Institute on Aging, Bethesda, MD, United States of America.
49
MRC Human Genetics Unit, Institute of Genetics and Molecular Medicine, University of Edinburgh, Western General Hospital, Edinburgh, Scotland.
50
Department of Epidemiology, University of Groningen, University Medical Center Groningen, Groningen, Netherlands.
51
Data Coordinating Center, Boston University School of Public Health, Boston, MA, United States of America.
52
Istituto di Ricerca Genetica e Biomedica (IRGB), CNR, Monserrato, Italy.
53
Department of Preventive Medicine, University of Southern California, Los Angeles, CA, United States of America.
54
Department of Gene Diagnostics and Therapeutics, Research Institute, National Center for Global Health and Medicine, Tokyo, Japan.
55
Department of Endocrinology, University of Groningen, University Medical Center Groningen, Groningen, Netherlands.
56
MRC Unit for Lifelong Health & Ageing, London, United Kingdom.
57
Division of Cardiovascular Medicine, Radcliffe Department of Medicine, University of Oxford, Oxford, United Kingdom.
58
Spanish Biomedical Research Centre in Diabetes and Associated Metabolic Disorders (CIBERDEM), Instituto de Investigación Sanitaria del Hospital Clínico San Carlos (IdISSC), Madrid, Spain.
59
Institute for Community Medicine, University Medicine Greifswald, Greifswald, Germany.
60
National Institute for Health and Welfare (THL), Helsinki, Finland.
61
University of Helsinki, Institute for Molecular Medicine, Finland (FIMM) and Diabetes and Obesity Research Program, Helsinki, Finland.
62
Translational Gerontology Branch, National Institute on Aging, Baltimore, MD, United States of America.
63
Department of Clinical Epidemiology, Biostatistics and Bioinformatics, Academic Medical Center, University of Amsterdam, Amsterdam, Netherlands.
64
Durrer Center for Cardiogenetic Research, ICIN-Netherlands Heart Institute, Utrecht, Netherlands.
65
Department of Epidemiology and Prevention, Wake Forest School of Medicine, Winston-Salem, NC, United States of America.
66
Integrated Research and Treatment (IFB) Center Adiposity Diseases, University of Leipzig, Leipzig, Germany.
67
Centre for Global Health Research, Usher Institute of Population Health Sciences and Informatics, University of Edinburgh, Edinburgh, Scotland.
68
Laboratory of Clinical Investigation, National Institute on Aging, Baltimore, MD, United States of America.
69
School of Chinese Medicine, China Medical University, Taichung City, Taiwan.
70
Department of Biomedical Science, Hallym University, Chuncheon, Gangwon-do, South Korea.
71
Department of Nutrition Sciences, University of Alabama at Birmingham and the Birmingham Veterans Affairs Medical Center, Birmingham, AL, United States of America.
72
Division of Endocrinology, Diabetes, and Metabolism, Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, CA, United States of America.
73
Department of Psychiatry, University of Groningen, University Medical Center Groningen, Groningen, Netherlands.
74
Institute for Clinical Diabetology, German Diabetes Center, Leibniz Institute for Diabetes Research at Heinrich Heine University Düsseldorf, Düsseldorf, Germany.
75
German Center for Diabetes Research (DZD), München-Neuherberg, Germany.
76
Division of Endocrinology, Diabetes, Metabolism, Department of Internal Medicine, Wexner Medical Center, The Ohio State University, Columbus, OH, United States of America.
77
Boston VA Research Institute, Inc., Boston, MA, United States of America.
78
Department of Geriatric Medicine, Ehime University Graduate School of Medicine, Ehime, Japan.
79
Department of Clinical Gene Therapy, Osaka University Graduate School of Medicine, Suita, Japan.
80
Department of Geriatric Medicine and Nephrology, Osaka University Graduate School of Medicine, Suita, Japan.
81
Genome Institute of Singapore, Agency for Science Technology and Research, Singapore, Singapore.
82
Center of Pediatric Research, University Hospital for Children & Adolescents, Dept. of Women's & Child Health, University of Leipzig, Leipzig, Germany.
83
LIFE Child, LIFE Leipzig Research Center for Civilization Diseases, University of Leipzig, Leipzig, Germany.
84
Faculty of Collaborative Regional Innovation, Ehime University, Ehime, Japan.
85
Department of Medical Research, Taichung Veterans General Hospital, Taichung, Taiwan.
86
Institute of Human Genetics, Technische Universität München, Munich, Germany.
87
Institute of Human Genetics, Helmholtz Zentrum München, Neuherberg, Germany.
88
Munich Cluster for Systems Neurology (SyNergy), Munich, Germany.
89
Department of Epidemiology, Graduate School of Public Health, University of Pittsburgh, Pittsburgh, PA, United States of America.
90
Center for Evidence-based Healthcare, University Hospital and Medical Faculty Carl Gustav Carus, Dresden, Germany.
91
Institute of Genetic Epidemiology, Helmholtz Zentrum München-German Research Center for Environmental Health, Neuherberg, Germany.
92
Department of Medicine I, University Hospital Grosshadern, Ludwig-Maximilians-Universität, Munich, Germany.
93
DZHK (German Centre for Cardiovascular Research), partner site Munich Heart Alliance, Munich, Germany.
94
Laboratory of Genetics, National Institute on Aging, Baltimore, MD, United States of America.
95
Institute for Clinical Chemistry and Laboratory Medicine, University Medicine Greifswald, Greifswald, Germany.
96
Division of Epidemiology and Community Health, University of Minnesota, Minneapolis, MN, United States of America.
97
University of Split, Split, Croatia.
98
Centre for Population Health Sciences, University of Edinburgh, Edinburgh, United Kingdom.
99
Oxford Centre for Diabetes, Endocrinology and Metabolism, Radcliffe Department of Medicine, University of Oxford, Oxford, United Kingdom.
100
Department of Genomics of Common Disease, School of Public Health, Imperial College London, London, United Kingdom.
101
Department of Medicine, Medical University of South Carolina, Charleston, SC, United States of America.
102
Department of Preventive Medicine, Northwestern University Feinberg School of Medicine, Chicago, IL, United States of America.
103
Center for Public Health Genomics, University of Virginia School of Medicine, Charlottesville, VA, United States of America.
104
Wellcome Trust Centre for Human Genetics, Nuffield Department of Medicine, University of Oxford, Oxford, United Kingdom.
105
Department of Endocrinology and Diabetology, University Hospital Düsseldorf, Düsseldorf, Germany.
106
INSERM, UMR_S 1138, Centre de Recherche des Cordelier, Paris, France.
107
Université Paris Diderot, Sorbonne Paris Cité, UFR de Médecine, Paris, France.
108
Assistance Publique Hôpitaux de Paris, Bichat Hospital, DHU FIRE, Department of Diabetology, Endocrinology and Nutrition, Paris, France.
109
University of Edinburgh, Edinburgh, United Kingdom.
110
Science for life laboratory, Karolinska Institutet, Solna, Sweden.
111
The New York Academy of Medicine, New York, NY, United States of America.
112
Institute of Medical Informatics, Biometry and Epidemiology, Ludwig-Maximilians-Universität, Munich, Germany.
113
Department of Genetics, University of Groningen, University Medical Center Groningen, Groningen, Netherlands.
114
Health Disparities Unit, National Institute on Aging, National Institutes of Health, Baltimore, MD, United States of America.
115
Department of Statistics and Applied Probability, National University of Singapore, Singapore, Singapore.
116
NUS Graduate School for Integrative Science and Engineering, National University of Singapore, Singapore, Singapore.
117
Department of Medicine; University of Leipzig, Leipzig, Germany.
118
Dept of Community Medicine, Faculty of Health Sciences, University of Tromsø, Tromsø, Norway.
119
Institute of Cardiovascular Science, University College London, London, United Kingdom.
120
Department of Vascular Medicine, Academic Medical Center, Amsterdam, Netherlands.
121
Department of Epidemiology and Public Health, University College London, London, United Kingdom.
122
Institute for Social and Economic Research, University of Essex, Colchester, United Kingdom.
123
Pat Macpherson Centre for Pharmacogenetics and Pharmacogenomics, Medical Research Institute, Ninewells Hospital and Medical School, Dundee, United Kingdom.
124
Ophthalmology and Visual Sciences Academic Clinical Program (Eye ACP), Duke-NUS Medical School, Singapore, Singapore.
125
Department of Ophthalmology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore.
126
Singapore National Eye Centre, Singapore, Singapore.
127
Dept of Medicine III, University of Dresden, Medical Faculty Carl Gustav Carus, Dresden, Germany.
128
Imperial College Healthcare NHS Trust, London, United Kingdom.
129
Division of Genetics, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, United States of America.
130
Broad Institute of MIT and Harvard, Cambridge, MA, United States of America.
131
Dipartimento di Scienze Biomediche, Università di Sassari, Italy.
132
Princess Al-Jawhara Al-Brahim Centre of Excellence in Research of Hereditary Disorders (PACER-HD), King Abdulaziz University, Jeddah, Saudi Arabia.
133
Brown 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.
134
Braun School of Public Health, Hebrew University-Hadassah Medical Center, Jerusalem, Israel.
135
CNRS 8199-Lille University, France.
136
Finnish Institute for Molecular Medicine (FIMM), Helsinki, Finland.
137
Department of Laboratory Medicine and Pathology, University of Minnesota, Minneapolis, MN, United States of America.
138
National Institute on Aging, Bethesda, MD, United States of America.
139
Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh, United Kingdom.
140
Department of Paediatrics, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore.
141
Khoo Teck Puat-National University Children's Medical Institute, National University Health System, Singapore, Singapore.
142
Department of Medical Sciences, Molecular Epidemiology and Science for Life Laboratory, Uppsala University, Uppsala, Sweden.
143
Department of Medicine, Division of Cardiovascular Medicine, Stanford University School of Medicine, Stanford, CA, United States of America.
144
Duke-NUS Medical School Singapore, Singapore.
145
National Heart and Lung Institute, Imperial College London, Hammersmith Hospital Campus, London, United Kingdom.
146
Institute of Clinical Medicine, Internal Medicine, University of Eastern Finland and Kuopio University Hospital, Kuopio, Finland.
147
Department of Epidemiology and Prevention, Division of Public Health Sciences, Wake Forest University, Winston-Salem, NC, United States of America.
148
The Mindich Child Health Development Institute, The Icahn School of Medicine at Mount Sinai, New York, NY, United States of America.
149
Department of Medical Epidemiology and Biostatistics, Karolinska Insitutet, Stockholm, Sweden.
150
Clinical Institute of Medical and Chemical Laboratory Diagnostics, Medical University of Graz, Graz, Austria.
151
Synlab Academy, Synlab Services GmbH, Mannheim, Germany.
152
Oxford NIHR Biomedical Research Centre, Oxford University Hospitals Trust, Oxford, United Kingdom.
153
Division of Cardiovascular Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, United States of America.
154
Department of Biostatistics and Epidemiology, University of Pennsylvania, Philadelphia, PA, United States of America.
155
Center for Non-Communicable Diseases, Karachi, Pakistan.
156
Department of Medicine, Central Hospital, Central Finland, Jyväskylä, Finland.
157
Division of Endocrine and Metabolism, Department of Internal Medicine, Taichung Veterans General Hospital, Taichung, Taiwan.
158
School of Medicine, National Yang-Ming University, Taipei, Taiwan.
159
School of Medicine, National Defense Medical Center, Taipei, Taiwan.
160
Department of Twin Research and Genetic Epidemiology, King's College London, London, United Kingdom.
161
Center for Genomic Medicine, Kyoto University Graduate School of Medicine, Kyoto, Japan.
162
Chronic Disease Prevention Unit, National Institute for Health and Welfare, Helsinki, Finland.
163
Dasman Diabetes Institute, Dasman, Kuwait.
164
Centre for Vascular Prevention, Danube-University Krems, Krems, Austria.
165
Saudi Diabetes Research Group, King Abdulaziz University, Fahd Medical Research Center, Jeddah, Saudi Arabia.
166
Department of Physiology and Biophysics, University of Mississippi Medical Center, Jackson, MS, United States of America.
167
Division of Cancer Control and Population Sciences,University of Pittsburgh Cancer Institute, Pittsburgh, PA, United States of America.
168
Laboratory of Epidemiology & Population Sciences, National Institute on Aging, National Institutes of Health, Baltimore, MD, United States of America.
169
Department of Haematology, University of Cambridge, Cambridge, United Kingdom.
170
The National Institute for Health Research Blood and Transplant Unit (NIHR BTRU) in Donor Health and Genomics at the University of Cambridge, United Kingdom.
171
Biomedical Research Centre Oxford Haematology Theme and Radcliffe Department of Medicine, University of Oxford, John Radcliffe Hospital, Headley Way, Headington, Oxford, United Kingdom.
172
NHS Blood and Transplant, Headington, Oxford, United Kingdom.
173
Diabetes Unit and Center for Human Genetic Research, Massachusetts General Hospital, Boston, MA, United States of America.
174
Programs in Metabolism and Medical & Population Genetics, Broad Institute, Cambridge, MA, United States of America.
175
Department of Medicine, McGill University, Montreal, Quebec, Canada.
176
Department of Biostatistics, University of Liverpool, Liverpool, United Kingdom.
177
Department of Medicine, Yong Loo Lin School of Medicine, National University of Singapore, Singapore.
178
Institute 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.

PMID:
28898252
PMCID:
PMC5595282
DOI:
10.1371/journal.pmed.1002383
[Indexed for MEDLINE]
Free PMC Article

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