194-LB: Aggregate Effect of Hemoglobin A1c–Related Genetic Variants on A1c–Glycemia Discordance by Ancestry

Introduction: The aggregate effect of genetic variants reported to lower A1c independently of glycemia by ancestry remains unclear.

Methods: We recalled 177 patients from the Mass General Brigham biobank with genetic data, enriching recruitment for carriers of the African G6PD variant (rs1050828), α thalassemia 3.7kb deletion, and people in the tails of a European polygenic score (PS) composed of variants associated with A1c but not glucose in GWAS. Subjects underwent 14 days of continuous glucose monitoring (CGM). We defined genetic ancestry using principal component analysis, and calculated A1c-glycemia discordance (measured A1c minus estimated A1c by CGM; ADAG study equation).

Results: Measured A1c and mean glucose were correlated in all groups (r2>0.9). Mean A1c-glycemia discordance was 0.4%-unit higher in African vs. European ancestry. In African ancestry, discordance was 0.5%-unit lower in carriers of the G6PD T allele vs. noncarriers. The bottom decile of PS had 0.3%-unit lower discordance vs. top decile (Figure; p<0.01; all comparisons). Discordance was similar regardless of α thalassemia deletion.

Conclusions: While A1c is an excellent proxy for glycemia in all groups, the A1c-glucose relationship differed by genotype and ancestry. Genetic variation should be considered to promote care equity in diverse populations and avoid misestimating glycemia when using A1c in clinical practice.