PT - JOURNAL ARTICLE AU - Aaron Leong AU - Victor Jun Yu Lim AU - Chaolong Wang AU - Jin-Fang Chai AU - Rajkumar Dorajoo AU - Chew-Kiat Heng AU - Rob M van Dam AU - Woon-Puay Koh AU - Jian-Min Yuan AU - Jost B Jonas AU - Ya Xing Wang AU - Wen-Bin Wei AU - Jianjun Liu AU - Dermot F Reilly AU - Tien-Yin Wong AU - Ching-Yu Cheng AU - Xueling Sim TI - Association of <em>G6PD</em> variants with hemoglobin A1c and impact on diabetes diagnosis in East Asian individuals AID - 10.1136/bmjdrc-2019-001091 DP - 2020 Mar 01 TA - BMJ Open Diabetes Research &amp; Care PG - e001091 VI - 8 IP - 1 4099 - http://drc.bmj.com/content/8/1/e001091.short 4100 - http://drc.bmj.com/content/8/1/e001091.full SO - BMJ Open Diab Res Care2020 Mar 01; 8 AB - 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.