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

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.

Christian Gieger | Sanghoon Moon | Tien Yin Wong | Morris Swertz | Thomas Meitinger | Jie Huang | Inês Barroso | Xu Lin | Bengt Sennblad | Philippe Froguel | Peng Chen | Luigi Ferrucci | Meena Kumari | Tin Aung | Perttu Salo | Nicole Soranzo | Ching-Yu Cheng | Juyoung Lee | Igor Rudan | Matthias Nauck | Marie-France Hivert | Josée Dupuis | Tamara B Harris | Martina Müller-Nurasyid | Wei-Min Chen | Harald Grallert | Andrew P Morris | Anubha Mahajan | Mark I McCarthy | Colin N A Palmer | Johanna Kuusisto | Harry Campbell | Carola Marzi | Ramaiah Nagaraja | Francesco Cucca | Nicholas J Wareham | Michael Stumvoll | Wolfgang Rathmann | Danish Saleheen | Jie Yao | Caroline Hayward | Michael Boehnke | Yingchang Lu | Man Li | Saima Afaq | Bong-Jo Kim | Peter Kovacs | Elizabeth Selvin | Panos Deloukas | Claudia Langenberg | Konstantin Strauch | Matthias Blüher | Erik Ingelsson | Anuj Goel | Paula S Ramos | Leif Groop | Daniel O Stram | Inga Prokopenko | Harold Snieder | Diana Kuh | Anke Tönjes | Jose C Florez | Katsuhiko Kohara | Josephine Egan | Annette Peters | Stefan R Bornstein | Xiuqing Guo | Min Jin Go | Yoon Shin Cho | Antonella Mulas | Michele Sale | Young Jin Kim | E-Shyong Tai | Chew-Kiat Heng | James S Pankow | Yasuharu Tabara | Franco Giulianini | Winfried März | Goncalo Abecasis | Dorret I Boomsma | Gonneke Willemsen | Eco J C de Geus | Myriam Fornage | Nancy L Pedersen | Serena Sanna | Li-Ching Chang | Jouke-Jan Hottenga | Stavroula Kanoni | Fumihiko Takeuchi | Loic Yengo | Woon-Puay Koh | Mika Kivimaki | Ronan Roussel | Benjamin Lehne | John C Chambers | Y. J. Kim | Jaakko Tuomilehto | Ozren Polasek | Tom Wilsgaard | Christian Herder | Norihiro Kato | Jaeyoung Hong | Stephen S Rich | Laura Rasmussen-Torvik | Claes Ladenvall | Daniel I Chasman | Paul M Ridker | Anders Hamsten | Michael Roden | Xueling Sim | William R Scott | Tomohiro Katsuya | Yvonne Böttcher | Eleanor Wheeler | Bruce H R Wolffenbuttel | Robert A Scott | Pau Navarro | Audrey Y. Chu | Jian'an Luan | Wieland Kiess | Dörte Radke | Yih Chung Tham | Jianjun Liu | M. Fornage | Toshiko Tanaka | M. Nalls | C. Gieger | W. Rathmann | T. Spector | A. Peters | J. Pankow | L. Ferrucci | M. McCarthy | P. Deloukas | A. Morris | G. Abecasis | L. Groop | M. Laakso | Mark A Pereira | K. Strauch | M. Boehnke | P. Ridker | D. Chasman | Y. Teo | W. Sheu | T. Wong | A. Hingorani | A. Zonderman | M. Evans | E. Tai | T. Meitinger | A. Mulas | Yongmei Liu | D. Siscovick | G. Willemsen | H. Snieder | D. Stram | E. Ingelsson | A. Jackson | J. Tuomilehto | V. Lyssenko | J. Florez | K. Taylor | J. 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