The latest transethnic genome wide association study on A1C identified 22 loci that modify A1C independently of glycemia. These loci overlap genes implicated in erythrocyte phenotypes that vary in prevalence across populations. We used TOPMed WGS data to estimate ancestral differences in associations with A1C at these loci and 23 additional erythrocyte genes not previously known to be related to A1C.

We conducted WGS association analyses of A1C in 5224 nondiabetic individuals [2662 European ancestry (EA): Framingham Heart Study and Amish; 2562 African ancestry (AA): Jackson Heart Study] using age and sex-adjusted linear mixed-effect regression, and meta-analyzed cohort-specific results. We used Cochran heterogeneity and Fisher’s exact tests to assess ancestral differences in effect and Minor Allele Frequency (MAF).

We detected single variant associations in 11 genes/loci (P < 0.001; α = 0.05/45; ≥ 1 cohort; Table). Variants had ancestral differences in MAF (P < 1%) and ancestry-specific signals (AA: G6PD, HBB, HBA1; EA: ANK1, PIEZO1, SPTA1, SPTB, HBA2).

Genetic variation at erythrocyte genes exhibit ancestral differences in A1C effect and MAF. These variants may differ in their contributions to inter-individual A1C variation, which may impact glucose estimation and diabetes diagnosis by A1C, particularly in minority populations.


C. Sarnowski: None. A. Leong: None. L. Raffield: None.

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