Dataset Information

Association of G6PD variants with hemoglobin A1c and impact on diabetes diagnosis in East Asian individuals.

ABSTRACT: 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.

SUBMITTER: Leong A

PROVIDER: S-EPMC7103857 | biostudies-literature | 2020 Mar

REPOSITORIES: biostudies-literature

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Association of <i>G6PD</i> variants with hemoglobin A1c and impact on diabetes diagnosis in East Asian individuals.

Leong Aaron A Lim Victor Jun Yu VJY Wang Chaolong C Chai Jin-Fang JF Dorajoo Rajkumar R Heng Chew-Kiat CK van Dam Rob M RM Koh Woon-Puay WP Yuan Jian-Min JM Jonas Jost B JB Wang Ya Xing YX Wei Wen-Bin WB Liu Jianjun J Reilly Dermot F DF Wong Tien-Yin TY Cheng Ching-Yu CY Sim Xueling X

BMJ open diabetes research & care 20200301 1

<h4>Objective</h4>Hemoglobin A1c (HbA1c) accuracy is important for diabetes diagnosis and estimation of overall glycemia. The <i>G6PD-</i>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 <i>G6PD</i> variants occur in Asian ancestry, we sought to identify Asian-specific <i>G6PD</i> variants associated with HbA1c.<h4>Research design and methods</h4>In eight Asian popu ...[more]

PMID: 32209585

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Project description: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.

Dataset Information

Association of G6PD variants with hemoglobin A1c and impact on diabetes diagnosis in East Asian individuals.

Publications

Association of <i>G6PD</i> variants with hemoglobin A1c and impact on diabetes diagnosis in East Asian individuals.

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