Genetic Variants That Lower Hemoglobin A1c Independently of Glycemia Are Associated with Higher Diabetic Retinopathy Risk in Diverse Ancestries

Introduction: People with type 2 diabetes (T2D) who carry genetic variants that lower hemoglobin A1c (A1c) independently of glycemia may have higher real, but undetected, hyperglycemia compared to those who do not despite achieving similar A1c targets, placing them at greater risk for complications. Methods: Using data from 39,199 T2D cases of European ancestry (EA) and African ancestry (AA) in UK Biobank and All of Us, we calculated a nonglycemic A1c polygenic score (ngA1cPS) composed of 123 variants previously associated with A1c at genome-wide significance, but not with glucose. We tested the association of the ngA1cPS with DR (n = 3,859), adjusting for A1c and known DR risk factors (T2D duration, kidney disease, hypertension, lipids, smoking). Results: Participants at the bottom ngA1cPS quintile showed 25-50% higher DR prevalence vs. the rest despite having lower measured A1c (6.6 vs 6.7%). Odds ratios were 1.28 in EA and 1.37 in AA (Fig. 1). Among carriers of the African-specific G6PD variant rs1050828 known to lower A1c, DR prevalence was 27% higher among those with ngA1cPS below the median vs. above the median. Conclusions: The aggregate effect of variants that lower A1c independently of glycemia is associated with a higher DR risk in both EA and AA. Genetic effects need to be considered to define personalized A1c targets to improve the outcomes of patients with T2D. Disclosure P.H.Schroeder: None. R.Mandla: None. J.C.Florez: Consultant; AstraZeneca, Novo Nordisk, Other Relationship; AstraZeneca, Merck & Co., Inc. J.M.Mercader: None. A.Leong: Other Relationship; Merck & Co., Inc. Funding Doris Duke Charitable Foundation (2020096)