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 1Aaron Leong 2 3Ching-Ti Liu 4Marie-France Hivert 5 6Rona J Strawbridge 7 8Clara Podmore 9 10Man Li 11 12 13Jie Yao 14Xueling Sim 15Jaeyoung Hong 4Audrey Y Chu 16 17Weihua Zhang 18 19Xu Wang 20Peng Chen 15 21 22 23Nisa M Maruthur 11 24 25Bianca C Porneala 2Stephen J Sharp 9Yucheng Jia 14Edmond K Kabagambe 26Li-Ching Chang 27Wei-Min Chen 28Cathy E Elks 9 29Daniel S Evans 30Qiao Fan 31Franco Giulianini 17Min Jin Go 32Jouke-Jan Hottenga 33Yao Hu 34Anne U Jackson 35Stavroula Kanoni 36Young Jin Kim 32Marcus E Kleber 37Claes Ladenvall 38 39Cecile Lecoeur 40Sing-Hui Lim 41Yingchang Lu 42 43Anubha Mahajan 44Carola Marzi 45 46Mike A Nalls 47 48Pau Navarro 49Ilja M Nolte 50Lynda M Rose 17Denis V Rybin 4 51Serena Sanna 52Yuan Shi 41Daniel O Stram 53Fumihiko Takeuchi 54Shu Pei Tan 41Peter J van der Most 50Jana V Van Vliet-Ostaptchouk 50 55Andrew Wong 56Loic Yengo 40Wanting Zhao 41Anuj Goel 44 57Maria Teresa Martinez Larrad 58Dörte Radke 59Perttu Salo 60 61Toshiko Tanaka 62Erik P A van Iperen 63 64Goncalo Abecasis 35Saima Afaq 18Behrooz Z Alizadeh 50Alain G Bertoni 65Amelie Bonnefond 40Yvonne Böttcher 66Erwin P Bottinger 42Harry Campbell 67Olga D Carlson 68Chien-Hsiun Chen 27 69Yoon Shin Cho 32 70W Timothy Garvey 71Christian Gieger 45Mark O Goodarzi 72Harald Grallert 45 46Anders Hamsten 7 8Catharina A Hartman 73Christian Herder 74 75Chao Agnes Hsiung 76Jie Huang 77Michiya Igase 78Masato Isono 54Tomohiro Katsuya 79 80Chiea-Chuen Khor 81Wieland Kiess 82 83Katsuhiko Kohara 84Peter Kovacs 66Juyoung Lee 32Wen-Jane Lee 85Benjamin Lehne 18Huaixing Li 34Jianjun Liu 15 81Stephane Lobbens 40Jian'an Luan 9Valeriya Lyssenko 39Thomas Meitinger 86 87 88Tetsuro Miki 78Iva Miljkovic 89Sanghoon Moon 32Antonella Mulas 52Gabriele Müller 90Martina Müller-Nurasyid 91 92 93Ramaiah Nagaraja 94Matthias Nauck 95James S Pankow 96Ozren Polasek 97 98Inga Prokopenko 44 99 100Paula S Ramos 101Laura Rasmussen-Torvik 102Wolfgang Rathmann 75Stephen S Rich 103Neil R Robertson 99 104Michael Roden 74 75 105Ronan Roussel 106 107 108Igor Rudan 109Robert A Scott 9William R Scott 18 19Bengt Sennblad 7 8 110David S Siscovick 111Konstantin Strauch 91 112Liang Sun 34Morris Swertz 113Salman M Tajuddin 114Kent D Taylor 14Yik-Ying Teo 15 20 81 115 116Yih Chung Tham 41Anke Tönjes 117Nicholas J Wareham 9Gonneke Willemsen 33Tom Wilsgaard 118Aroon D Hingorani 119EPIC-CVD ConsortiumEPIC-InterAct ConsortiumLifelines Cohort StudyJosephine Egan 68Luigi Ferrucci 68G Kees Hovingh 120Antti Jula 60Mika Kivimaki 121Meena Kumari 121 122Inger Njølstad 118Colin N A Palmer 123Manuel Serrano Ríos 58Michael Stumvoll 117Hugh Watkins 44 57Tin Aung 41 124 125 126Matthias Blüher 117Michael Boehnke 35Dorret I Boomsma 33Stefan R Bornstein 127John C Chambers 18 19 128Daniel I Chasman 17 129 130Yii-Der Ida Chen 14Yduan-Tsong Chen 27Ching-Yu Cheng 41 124 125 126Francesco Cucca 52 131Eco J C de Geus 33Panos Deloukas 36 132Michele K Evans 114Myriam Fornage 133Yechiel Friedlander 134Philippe Froguel 100 135Leif Groop 39 136Myron D Gross 137Tamara B Harris 138Caroline Hayward 139Chew-Kiat Heng 140 141Erik Ingelsson 142 143Norihiro Kato 54Bong-Jo Kim 32Woon-Puay Koh 15 144Jaspal S Kooner 19 128 145Antje Körner 82 83Diana Kuh 56Johanna Kuusisto 146Markku Laakso 146Xu Lin 34Yongmei Liu 147Ruth J F Loos 42 43 148Patrik K E Magnusson 149Winfried März 37 150 151Mark I McCarthy 99 104 152Albertine J Oldehinkel 73Ken K Ong 9Nancy L Pedersen 149Mark A Pereira 96Annette Peters 45Paul M Ridker 17 153Charumathi Sabanayagam 41 124Michele Sale 103Danish Saleheen 154 155Juha Saltevo 156Peter Eh Schwarz 127Wayne H H Sheu 157 158 159Harold Snieder 50Timothy D Spector 160Yasuharu Tabara 161Jaakko Tuomilehto 162 163 164 165Rob M van Dam 15James G Wilson 166James F Wilson 49 67Bruce H R Wolffenbuttel 55Tien Yin Wong 41 124 125 126Jer-Yuarn Wu 27 69Jian-Min Yuan 89 167Alan B Zonderman 168Nicole Soranzo 1 169 170Xiuqing Guo 14David J Roberts 171 172Jose C Florez 3 173 174Robert Sladek 175Josée Dupuis 4 16Andrew P Morris 104 176E-Shyong Tai 15 144 177Elizabeth Selvin 11 24 25Jerome I Rotter 14Claudia Langenberg 9Inês Barroso 1 178James B Meigs 2 3 174

Affiliations

12 September 2017

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doi: 10.1371/journal.pmed.1002383


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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