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Association of G6PD variants with hemoglobin A1c and impact on diabetes diagnosis in East Asian individuals
  1. Aaron Leong1,2,
  2. Victor Jun Yu Lim3,
  3. Chaolong Wang4,5,
  4. Jin-Fang Chai3,
  5. Rajkumar Dorajoo5,
  6. Chew-Kiat Heng6,7,
  7. Rob M van Dam3,
  8. Woon-Puay Koh8,
  9. Jian-Min Yuan9,10,
  10. Jost B Jonas11,12,
  11. Ya Xing Wang12,
  12. Wen-Bin Wei13,
  13. Jianjun Liu5,14,
  14. Dermot F Reilly15,
  15. Tien-Yin Wong16,17,
  16. Ching-Yu Cheng16,17,
  17. Xueling Sim3
  1. 1Department of Medicine, Massachusetts General Hospital, Boston, Massachusetts, USA
  2. 2Harvard Medical School, Boston, Massachusetts, USA
  3. 3Saw Swee Hock School of Public Health, National University of Singapore, Singapore
  4. 4Department of Epidemiology and Biostatistics, Key Laboratory for Environment and Health, School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China
  5. 5Genome Institute of Singapore, Agency for Science, Technology and Research, Singapore
  6. 6Department of Paediatrics, Yong Loo Lin School of Medicine, National University of Singapore, Singapore
  7. 7Khoo Teck Puat–National University Children’s Medical Institute, National University Health System, Singapore
  8. 8Health Services and Systems Research, Duke NUS Medical School, Singapore
  9. 9Division of Cancer Control and Population Sciences, UPMC Hillman Cancer Center, University of Pittsburgh, Pittsburgh, Pennsylvania, USA
  10. 10Department of Epidemiology, Graduate School of Public Health, University of Pittsburgh, Pittsburgh, Pennsylvania, USA
  11. 11Department of Ophthalmology, Medical Faculty Mannheim, University of Heidelberg, Heidelberg, Baden-Württemberg, Germany
  12. 12Ophthalmology and Visual Sciences Key Laboratory, Beijing Institute of Ophthalmology, Beijing Tongren Hospital, Capital Medical University, Beijing, China
  13. 13Beijing Key Laboratory of Intraocular Tumor Diagnosis and Treatment, Beijing Tongren Eye Center, Beijing Tongren Hospital, Capital Medical University, Beijing, China
  14. 14Department of Medicine, Yong Loo Lin School of Medicine, National University of Singapore, Singapore
  15. 15Genetics, Merck Sharp and Dohme IA, Kenilworth, New Jersey, USA
  16. 16Singapore Eye Research Institute, Singapore National Eye Centre, Singapore
  17. 17Ophthalmology and Visual Sciences Academic Clinical Program (Eye ACP), Duke–NUS Medical School, Singapore
  1. Correspondence to Dr Xueling Sim; ephsx{at}; Dr Aaron Leong; asleong{at}


Objective Hemoglobin A1c (HbA1c) accuracy is important for diabetes diagnosis and estimation of overall glycemia. The G6PD-Asahi variant which causes glucose-6-phosphate dehydrogenase (G6PD) deficiency has been shown to lower HbA1c independently of glycemia in African ancestry populations. As different G6PD variants occur in Asian ancestry, we sought to identify Asian-specific G6PD variants associated with HbA1c.

Research design and methods In eight Asian population-based cohorts, we performed imputation on the X chromosome using the 1000 Genomes reference panel and tested for association with HbA1c (10 005 East Asians and 2051 South Asians). Results were meta-analyzed across studies. We compared the proportion of individuals classified as having diabetes/pre-diabetes by fasting glucose ≥100 mg/dL or HbA1c ≥5.7% units among carriers and non-carriers of HbA1c-associated variants.

Results The strongest association was a missense variant (G6PD-Canton, rs72554665, minor allele frequency=2.2%, effect in men=−0.76% unit, 95% CI −0.88 to −0.64, p=1.25×10−27, n=2844). Conditional analyses identified a secondary distinct signal, missense variant (G6PD-Kaiping, rs72554664, minor allele frequency=1.6%, effect in men=−1.12 % unit, 95% CI −1.32 to −0.92, p=3.12×10−15, pconditional_Canton=7.57×10−11). Adjusting for glucose did not attenuate their effects. The proportion of individuals with fasting glucose ≥100 mg/dL did not differ by carrier status of G6PD-Canton (p=0.21). Whereas the proportion of individuals with HbA1c ≥5.7% units was lower in carriers (5%) compared with non-carriers of G6PD-Canton (30%, p=0.03).

Conclusions We identified two G6PD variants in East Asian men associated with non-glycemic lowering of HbA1c. Carriers of these variants are more likely to be underdiagnosed for diabetes or pre-diabetes than non-carriers if screened by HbA1c without confirmation by direct glucose measurements.

  • A1C
  • diagnostic criteria
  • Asian
  • genetic association

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  • AL and VJYL contributed equally.

  • Contributors AL, VJYL, and XS conceptualized, planned and conducted the study, interpreted the results, and wrote the manuscript. VJYL, CW, RD, and JFC performed the data analyses. CKH, RMvD, WPK, JMY, JBJ, YXW, WBW, JL, DFR, TYW, and CYC were involved in the study design, sample collection and data generation (phenotype, genotype). All authors reviewed and approved the manuscript for submission. XS and AL had full access to all the data in the study and had final responsibility for the decision to submit for publication. XS and AL are the guarantors of the work.

  • Funding The Diabetic Cohort (DC), Multi-Ethnic Cohort (MEC) and Living Biobank was supported by grants from the Ministry of Health, Singapore, the National University of Singapore and the National University Health System, Singapore. In addition, genotyping for Living Biobank was funded by the Agency for Science, Technology and Research, Singapore, and Merck Sharp & Dohme Corp., Whitehouse Station, NJ, USA. The Singapore Prospective Study Program (SP2) were supported by the individual research grant and clinician scientist award schemes from the National Medical Research Council (NMRC) and the Biomedical Research Council (BMRC) of Singapore. The Singapore Chinese Eye Study (SCES) and the Singapore Malay Eye Study (SiMES) are supported by the National Medical Research Council (NMRC), Singapore (grants 0796/2003, 1176/2008, 1149/2008, STaR/0003/2008, 1249/2010, CG/SERI/2010, CIRG/1371/2013, and CIRG/1417/2015), and Biomedical Research Council (BMRC), Singapore (08/1/35/19/550 and 09/1/35/19/616). The Singapore Chinese Health Study was supported by the National Institutes of Health, USA (RO1 CA144034 and UM1 CA182876), the nested case–control study of myocardial infarction by the Singapore National Medical Research Council (NMRC 1270/2010) and genotyping by the HUJ-CREATE Programme of the National Research Foundation, Singapore (Project No 370062002). The Beijing Eye Study (BES) was funded by the National Natural Science Foundation of China (NSFC, No 81170890 and 81570835).

  • Competing interests None declared.

  • Patient consent for publication Not required.

  • Ethics approval This study was approved by the National University of Singapore International Review Board (08-013) and conducted according to the Declaration of Helsinki.

  • Provenance and peer review Not commissioned; externally peer reviewed.

  • Data availability statement Summary-level statistics will be publicly available at

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