Hemoglobin A1c Genetics and Disparities in Risk of Diabetic Retinopathy in Individuals of Genetically Inferred African-American/African-British and European Ancestries

Objective: Individuals with diabetes who carry genetic variants that lower hemoglobin A1c (HbA1c) independently of glycemia may have higher real, but undetected, hyperglycemia compared to those without these variants despite achieving similar HbA1c targets, potentially placing them at greater risk for diabetes-related complications. We sought to determine whether these genetic variants, aggregated in a polygenic score, and the large-effect African-ancestry specific missense variant in G6PD (rs1050828) that lower HbA1c were associated with higher retinopathy risk.

Research Design and Methods: Using data from 29,828 type 2 diabetes cases of genetically inferred African-American/African-British and European ancestries, we calculated ancestry-specific nonglycemic HbA1c polygenic scores (ngA1cPS) composed of 122 variants associated with HbA1c at genome-wide significance, but not with glucose. We tested the association of the ngA1cPS and the G6PD variant with retinopathy, adjusting for measured HbA1c and retinopathy risk factors.

Results: Participants in the bottom quintile of the ngA1cPS showed between 20 to 50% higher retinopathy prevalence, compared to those above this quintile, despite similar levels of measured HbA1c. The adjusted meta-analytic odds ratio for the bottom quintile was 1.31 (95% CI 1.0, 1.73; p=0.05) in African ancestry and 1.31 (95% CI 1.15, 1.50; p=6.5x10-5) in European ancestry. Among individuals of African ancestry with HbA1c below 7%-units, retinopathy prevalence was higher in individuals below, compared to above, the 50th percentile of the ngA1cPS regardless of sex or G6PD carrier status

Conclusions: Genetic effects need to be considered to personalize HbA1c targets and improve outcomes of people with diabetes from diverse ancestries.