ObjectiveHemoglobin 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 methodsIn 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.ResultsThe 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=1.25x10(-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=3.12x10(-15), p(conditional_Canton)=7.57x10(-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).ConclusionsWe 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.