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; Aaron Leong; Ching-Ti Liu; Marie-France Hivert; Rona J Strawbridge; Clara Podmore; Man Li; Jie Yao; Xueling Sim; Jaeyoung Hong; Audrey Y Chu; Weihua Zhang; Xu Wang; Peng Chen; Nisa M Maruthur; Bianca C Porneala; Stephen J Sharp; Yucheng Jia; Edmond K Kabagambe; Li-Ching Chang; Wei-Min Chen; Cathy E Elks; Daniel S Evans; Qiao Fan; Franco Giulianini; Min Jin Go; Jouke-Jan Hottenga; Yao Hu; Anne U Jackson; Stavroula Kanoni; Young Jin Kim; Marcus E Kleber; Claes Ladenvall; Cecile Lecoeur; Sing-Hui Lim; Yingchang Lu; Anubha Mahajan; Carola Marzi; Mike A Nalls; Pau Navarro; Ilja M Nolte; Lynda M Rose; Denis V Rybin; Serena Sanna; Yuan Shi; Daniel O Stram; Fumihiko Takeuchi; Shu Pei Tan; Peter J van der Most; Jana V Van Vliet-Ostaptchouk; Andrew Wong; Loic Yengo; Wanting Zhao; Anuj Goel; Maria Teresa Martinez Larrad; Dörte Radke; Perttu Salo; Toshiko Tanaka; Erik P A van Iperen; Goncalo Abecasis; Saima Afaq; Behrooz Z Alizadeh; Alain G Bertoni; Amelie Bonnefond; Yvonne Böttcher; Erwin P Bottinger; Harry Campbell; Olga D Carlson; Chien-Hsiun Chen; Yoon Shin Cho; W Timothy Garvey; Christian Gieger; Mark O Goodarzi; Harald Grallert; Anders Hamsten; Catharina A Hartman; Christian Herder; Chao Agnes Hsiung; Jie Huang; Michiya Igase; Masato Isono; Tomohiro Katsuya; Chiea-Chuen Khor; Wieland Kiess; Katsuhiko Kohara; Peter Kovacs; Juyoung Lee; Wen-Jane Lee; Benjamin Lehne; Huaixing Li; Jianjun Liu; Stephane Lobbens; Jian'an Luan; Valeriya Lyssenko; Thomas Meitinger; Tetsuro Miki; Iva Miljkovic; Sanghoon Moon; Antonella Mulas; Gabriele Müller; Martina Müller-Nurasyid; Ramaiah Nagaraja; Matthias Nauck; James S Pankow; Ozren Polasek; Inga Prokopenko; Paula S Ramos; Laura Rasmussen-Torvik; Wolfgang Rathmann; Stephen S Rich; Neil R Robertson; Michael Roden; Ronan Roussel; Igor Rudan; Robert A Scott; William R Scott; Bengt Sennblad; David S Siscovick; Konstantin Strauch; Liang Sun; Morris Swertz; Salman M Tajuddin; Kent D Taylor; Yik-Ying Teo; Yih Chung Tham; Anke Tönjes; Nicholas J Wareham; Gonneke Willemsen; Tom Wilsgaard; Aroon D Hingorani; Josephine Egan; Luigi Ferrucci; G Kees Hovingh; Antti Jula; Mika Kivimaki; Meena Kumari; Inger Njølstad; Colin N A Palmer; Manuel Serrano Ríos; Michael Stumvoll; Hugh Watkins; Tin Aung; Matthias Blüher; Michael Boehnke; Dorret I Boomsma; Stefan R Bornstein; John C Chambers; Daniel I Chasman; Yii-Der Ida Chen; Yduan-Tsong Chen; Ching-Yu Cheng; Francesco Cucca; Eco J C de Geus; Panos Deloukas; Michele K Evans; Myriam Fornage; Yechiel Friedlander; Philippe Froguel; Leif Groop; Myron D Gross; Tamara B Harris; Caroline Hayward; Chew-Kiat Heng; Erik Ingelsson; Norihiro Kato; Bong-Jo Kim; Woon-Puay Koh; Jaspal S Kooner; Antje Körner; Diana Kuh; Johanna Kuusisto; Markku Laakso; Xu Lin; Yongmei Liu; Ruth J F Loos; Patrik K E Magnusson; Winfried März; Mark I McCarthy; Albertine J Oldehinkel; Ken K Ong; Nancy L Pedersen; Mark A Pereira; Annette Peters; Paul M Ridker; Charumathi Sabanayagam; Michele Sale; Danish Saleheen; Juha Saltevo; Peter Eh Schwarz; Wayne H H Sheu; Harold Snieder; Timothy D Spector; Yasuharu Tabara; Jaakko Tuomilehto; Rob M van Dam; James G Wilson; James F Wilson; Bruce H R Wolffenbuttel; Tien Yin Wong; Jer-Yuarn Wu; Jian-Min Yuan; Alan B Zonderman; Nicole Soranzo; Xiuqing Guo; David J Roberts; Jose C Florez; Robert Sladek; Josée Dupuis; Andrew P Morris; E-Shyong Tai; Elizabeth Selvin; Jerome I Rotter; Claudia Langenberg; Inês Barroso; James B Meigs; EPIC-CVD Consortium

doi:10.1371/journal.pmed.1002383

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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

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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, Aaron Leong, Ching-Ti Liu, Marie-France Hivert, Rona J Strawbridge, Clara Podmore, Man Li, Jie Yao, Xueling Sim, Jaeyoung Hong, …

PLoS medicine, Vol.14(9), pp.e1002383-e1002383

12/09/2017

DOI: https://doi.org/10.1371/journal.pmed.1002383

PMID: 28898252

Abstract

Diabetes Mellitus, Type 2 - diagnosis

Diabetes Mellitus, Type 2 - epidemiology

Diabetes Mellitus, Type 2 - genetics

Genetic Variation

Genome-Wide Association Study

Glycated Hemoglobin A - genetics

Glycated Hemoglobin A - metabolism

Humans

Phenotype

Risk

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. 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. 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.

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Title: 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
Creators - without role: Eleanor Wheeler - Wellcome Sanger Institute
Aaron Leong - Harvard University
Ching-Ti Liu - Boston University
Marie-France Hivert - Harvard University
Rona J Strawbridge - Karolinska Institutet
Clara Podmore - University of Cambridge
Man Li - Johns Hopkins University
Jie Yao - Ronald Reagan UCLA Medical Center
Xueling Sim - National University of Singapore
Jaeyoung Hong - Boston University
Audrey Y Chu - Brigham and Women's Hospital
Weihua Zhang - Imperial College London
Xu Wang - Duke-NUS Medical School
Peng Chen - Jilin University
Nisa M Maruthur - Johns Hopkins University
Bianca C Porneala - Harvard University
Stephen J Sharp - University of Cambridge
Yucheng Jia - Ronald Reagan UCLA Medical Center
Edmond K Kabagambe - Vanderbilt University Medical Center
Li-Ching Chang - Academia Sinica
Wei-Min Chen - University of Virginia
Cathy E Elks - University of Cambridge
Daniel S Evans - California Pacific Medical Center
Qiao Fan - Duke-NUS Medical School
Franco Giulianini - Brigham and Women's Hospital
Min Jin Go - Genomics
Jouke-Jan Hottenga - Vrije Universiteit Amsterdam
Yao Hu - Chinese Academy of Sciences
Anne U Jackson - University of Michigan–Ann Arbor
Stavroula Kanoni - Queen Mary University of London
Young Jin Kim - Genomics
Marcus E Kleber - Heidelberg University
Claes Ladenvall - Lund University
Cecile Lecoeur - University of Lille
Sing-Hui Lim - Singapore Eye Research Institute
Yingchang Lu - Icahn School of Medicine at Mount Sinai
Anubha Mahajan - Wellcome Centre for Human Genetics
Carola Marzi - German Center for Diabetes Research
Mike A Nalls - National Institutes of Health
Pau Navarro - Western General Hospital
Ilja M Nolte - University Medical Center Groningen
Lynda M Rose - Brigham and Women's Hospital
Denis V Rybin - Boston University
Serena Sanna - GeneTiCA
Yuan Shi - Singapore Eye Research Institute
Daniel O Stram - University of Southern California
Fumihiko Takeuchi - Gene
Shu Pei Tan - Singapore Eye Research Institute
Peter J van der Most - University Medical Center Groningen
Jana V Van Vliet-Ostaptchouk - University Medical Center Groningen
Andrew Wong - Massachusetts Rehabilitation Commission
Loic Yengo - University of Lille
Wanting Zhao - Singapore Eye Research Institute
Anuj Goel - University of Oxford
Maria Teresa Martinez Larrad - Instituto de Investigación Sanitaria del Hospital Clínico San Carlos
Dörte Radke - Greifswald University Hospital
Perttu Salo - University of Helsinki
Toshiko Tanaka - National Institutes of Health
Erik P A van Iperen - University of Amsterdam
Goncalo Abecasis - University of Michigan–Ann Arbor
Saima Afaq - Imperial College London
Behrooz Z Alizadeh - University Medical Center Groningen
Alain G Bertoni - Wake Forest University
Amelie Bonnefond - University of Lille
Yvonne Böttcher - Leipzig University
Erwin P Bottinger - Icahn School of Medicine at Mount Sinai
Harry Campbell - University of Edinburgh
Olga D Carlson - National Institutes of Health
Chien-Hsiun Chen - Academia Sinica
Yoon Shin Cho - Hallym University
W Timothy Garvey - University of Alabama at Birmingham
Christian Gieger - Helmholtz Zentrum München
Mark O Goodarzi - Cedars-Sinai Medical Center
Harald Grallert - German Center for Diabetes Research
Anders Hamsten - Karolinska Institutet
Catharina A Hartman - University Medical Center Groningen
Christian Herder - Heinrich Heine University Düsseldorf
Chao Agnes Hsiung - The Ohio State University
Jie Huang - Boston VA Research Institute
Michiya Igase - Ehime University
Masato Isono - Gene
Tomohiro Katsuya - Osaka University
Chiea-Chuen Khor - Agency for Science, Technology and Research
Wieland Kiess - Leipzig University
Katsuhiko Kohara - Ehime University
Peter Kovacs - Leipzig University
Juyoung Lee - Genomics
Wen-Jane Lee - Taichung Veterans General Hospital
Benjamin Lehne - Imperial College London
Huaixing Li - Chinese Academy of Sciences
Jianjun Liu - Agency for Science, Technology and Research
Stephane Lobbens - University of Lille
Jian'an Luan - University of Cambridge
Valeriya Lyssenko - Lund University
Thomas Meitinger - Technical University of Munich
Tetsuro Miki - Ehime University
Iva Miljkovic - University of Pittsburgh
Sanghoon Moon - Genomics
Antonella Mulas - GeneTiCA
Gabriele Müller - TU Dresden
Martina Müller-Nurasyid - DZHK (German Centre for Cardiovascular Research), partner site Munich Heart Alliance, Munich, Germany
Ramaiah Nagaraja - National Institute on Aging
Matthias Nauck - Institute for Clinical Chemistry and Laboratory Medicine, University Medicine Greifswald, Greifswald, Germany
James S Pankow - University of Minnesota
Ozren Polasek - University of Edinburgh
Inga Prokopenko - Imperial College London
Paula S Ramos - Medical University of South Carolina
Laura Rasmussen-Torvik - Department of Preventive Medicine, Northwestern University Feinberg School of Medicine, Chicago, IL, United States of America
Wolfgang Rathmann - German Center for Diabetes Research
Stephen S Rich - University of Virginia
Neil R Robertson - University of Oxford
Michael Roden - Department of Endocrinology and Diabetology, University Hospital Düsseldorf, Düsseldorf, Germany
Ronan Roussel - Assistance Publique – Hôpitaux de Paris
Igor Rudan - University of Edinburgh
Robert A Scott - University of Cambridge
William R Scott - Ealing Hospital NHS Trust
Bengt Sennblad - Karolinska Institutet
David S Siscovick - The New York Academy of Medicine, New York, NY, United States of America
Konstantin Strauch - Institute of Medical Informatics, Biometry and Epidemiology, Ludwig-Maximilians-Universität, Munich, Germany
Liang Sun - 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
Morris Swertz - University Medical Center Groningen
Salman M Tajuddin - National Institute on Aging
Kent D Taylor - Harbor–UCLA Medical Center
Yik-Ying Teo - Duke-NUS Medical School
Yih Chung Tham - Singapore Eye Research Institute
Anke Tönjes
Nicholas J Wareham - University of Cambridge
Gonneke Willemsen - Vrije Universiteit Amsterdam
Tom Wilsgaard - Faculty
Aroon D Hingorani - Institute of Cardiovascular Science, University College London, London, United Kingdom
Josephine Egan - National Institute on Aging
Luigi Ferrucci - National Institute on Aging
G Kees Hovingh - Academic Medical Center
Antti Jula - National Institute for Health and Welfare (THL), Helsinki, Finland
Mika Kivimaki - UCL Australia
Meena Kumari - University of Essex
Inger Njølstad - Faculty
Colin N A Palmer - Ninewells Hospital
Manuel Serrano Ríos - Instituto de Investigación Sanitaria del Hospital Clínico San Carlos
Michael Stumvoll
Hugh Watkins - University of Oxford
Tin Aung - Singapore National Eye Centre, Singapore, Singapore
Matthias Blüher
Michael Boehnke - University of Michigan–Ann Arbor
Dorret I Boomsma - Vrije Universiteit Amsterdam
Stefan R Bornstein - Faculty
John C Chambers - Imperial College Healthcare NHS Trust
Daniel I Chasman - Broad Institute
Yii-Der Ida Chen - Harbor–UCLA Medical Center
Yduan-Tsong Chen - Institute of Biomedical Sciences, Academia Sinica
Ching-Yu Cheng - Singapore National Eye Centre, Singapore, Singapore
Francesco Cucca - Dipartimento di Scienze Biomediche, Università di Sassari, Italy
Eco J C de Geus - Vrije Universiteit Amsterdam
Panos Deloukas - King Abdulaziz University
Michele K Evans - National Institute on Aging
Myriam Fornage - The University of Texas Health Science Center at Houston
Yechiel Friedlander - Hadassah Medical Center
Philippe Froguel - CNRS 8199-Lille University, France
Leif Groop - Finnish Institute for Molecular Medicine (FIMM), Helsinki, Finland
Myron D Gross - University of Minnesota
Tamara B Harris - National Institute on Aging
Caroline Hayward - University of Edinburgh
Chew-Kiat Heng - Khoo Teck Puat-National University Children's Medical Institute, National University Health System, Singapore, Singapore
Erik Ingelsson - Stanford University School of Medicine
Norihiro Kato - Gene
Bong-Jo Kim - Genomics
Woon-Puay Koh - Duke-NUS Medical School
Jaspal S Kooner - Imperial College London
Antje Körner - LIFE Child, LIFE Leipzig Research Center for Civilization Diseases, University of Leipzig, Leipzig, Germany
Diana Kuh - Massachusetts Rehabilitation Commission
Johanna Kuusisto - University of Eastern Finland
Markku Laakso - University of Eastern Finland
Xu Lin - 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
Yongmei Liu - Wake Forest University
Ruth J F Loos - Icahn School of Medicine at Mount Sinai
Patrik K E Magnusson - Department of Medical Epidemiology and Biostatistics, Karolinska Insitutet, Stockholm, Sweden
Winfried März - Synlab
Mark I McCarthy - University of Oxford
Albertine J Oldehinkel - University Medical Center Groningen
Ken K Ong - University of Cambridge
Nancy L Pedersen - Department of Medical Epidemiology and Biostatistics, Karolinska Insitutet, Stockholm, Sweden
Mark A Pereira - University of Minnesota
Annette Peters - Helmholtz Zentrum München
Paul M Ridker - Brigham and Women's Hospital
Charumathi Sabanayagam - Duke-NUS Medical School
Michele Sale - University of Virginia
Danish Saleheen - Center for Non-Communicable Diseases
Juha Saltevo - Department of Medicine, Central Hospital, Central Finland, Jyväskylä, Finland
Peter Eh Schwarz - Faculty
Wayne H H Sheu - National Defense Medical Center
Harold Snieder - University Medical Center Groningen
Timothy D Spector - King's College London
Yasuharu Tabara - Kyoto University
Jaakko Tuomilehto - King Abdulaziz University
Rob M van Dam - Duke-NUS Medical School
James G Wilson - University of Mississippi Medical Center
James F Wilson - University of Edinburgh
Bruce H R Wolffenbuttel - University Medical Center Groningen
Tien Yin Wong - Singapore National Eye Centre, Singapore, Singapore
Jer-Yuarn Wu - School of Chinese Medicine, China Medical University, Taichung City, Taiwan
Jian-Min Yuan - UPMC Hillman Cancer Center
Alan B Zonderman - National Institute on Aging
Nicole Soranzo - University of Cambridge
Xiuqing Guo - Harbor–UCLA Medical Center
David J Roberts - NHS Blood and Transplant
Jose C Florez - Broad Institute
Robert Sladek - McGill University
Josée Dupuis - National Heart Lung and Blood Institute
Andrew P Morris - University of Liverpool
E-Shyong Tai - Duke-NUS Medical School
Elizabeth Selvin - Johns Hopkins University
Jerome I Rotter - Harbor–UCLA Medical Center
Claudia Langenberg - University of Cambridge
Inês Barroso - University of Cambridge
James B Meigs - Broad Institute
EPIC-CVD Consortium
Publication Details: PLoS medicine, Vol.14(9), pp.e1002383-e1002383
Grant note: U01 DK078616 / NIDDK NIH HHS UL1 TR001881 / NCATS NIH HHS S10 OD018522 / NIH HHS P30 DK079626 / NIDDK NIH HHS P30 DK020541 / NIDDK NIH HHS R01 DK106236 / NIDDK NIH HHS UM1 CA182913 / NCI NIH HHS MR/K002414/1 / Medical Research Council R01 DK089174 / NIDDK NIH HHS UL1 TR000124 / NCATS NIH HHS G0601261 / Medical Research Council K24 DK080140 / NIDDK NIH HHS U54 GM115428 / NIGMS NIH HHS U01 HG007417 / NHGRI NIH HHS MC_UU_12015/1 / Medical Research Council MC_UU_12019/1 / Medical Research Council R01 HL105756 / NHLBI NIH HHS MC_UU_12015/2 / Medical Research Council MR/K013351/1 / Medical Research Council U01 DK062370 / NIDDK NIH HHS P30 DK020572 / NIDDK NIH HHS MC_PC_U127561128 / Medical Research Council RG/14/5/30893 / British Heart Foundation K24 DK106414 / NIDDK NIH HHS P30 DK063491 / NIDDK NIH HHS RG/10/12/28456 / British Heart Foundation
Identifiers: 9938342108331
Academic Unit: King Abdulaziz University
Language: English
Resource Type: Journal article