Methods & Findings: Using genome-wide association meta-analyses in up to 159,940 individuals from 82 cohorts of European, African, East 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 multi-ethnic 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=3×10-29 250 ); 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 253 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 ~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 multi-ethnic 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.
- Diabetes Mellitus, Type 2
- Genetic Variation
- Genome-Wide Association Study
- Hemoglobin A, Glycosylated