Date Published: September 12, 2017
Publisher: Public Library of Science
Author(s): 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, Ed Gregg
Abstract: BackgroundGlycated 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 & findingsUsing 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.ConclusionsAs 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.
Partial Text: Type 2 diabetes (T2D) is a health scourge rising unabated worldwide, escaping all past and current control measures, in part because only half of prevalent T2D worldwide has been clinically diagnosed . Glycated hemoglobin (HbA1c) is an accepted diagnostic test for T2D and a principal clinical measure of glycemic control in individuals with diabetes. T2D arises from the environment interacting with genetics. Studies investigating genetic contributions to HbA1c in individuals of European [2–4] and Asian ancestry [5–7] have identified 18 loci influencing HbA1c through glycemic and nonglycemic pathways, the latter primarily reflecting erythrocytic biology. Alterations in HbA1c that are due to genetic variation acting through nonglycemic pathways may not accurately reflect ambient glycemia or T2D risk and could affect the validity of HbA1c as a diagnostic test and measure of glycemic control in some individuals or populations. Some genetic variants (e.g., the sickle cell variant HbS) that vary in frequency across ancestries can interfere with the accuracy of certain assays . Further, certain hematologic conditions associated with shortened erythrocyte lifespan (e.g., hemolytic anemias) lower HbA1c values irrespective of the assay performed. HbA1c values in such patients may no longer accurately reflect ambient glycemia .
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In a very large transancestry GWAS of HbA1c, we identified 42 novel and 18 known genetic variants associated with HbA1c, explaining 4%–14% of the trait variance. Genetic variants influencing HbA1c through erythrocytic pathways did not predict future T2D, and adjusting for their contribution to HbA1c led to a moderate misclassification of T2D by adjusted HbA1c. Notably, we detected strong ancestral differences in the contribution of genetic variants to HbA1c that substantially altered the performance of HbA1c as a diagnostic test for T2D in African Americans compared with Europeans and East Asians.