Introduction and Objective: Second-line glucose-lowering medications for T2D vary in glycemic and metabolic effects due in part to genetic factors. We previously conducted a Cox proportional hazards genome-wide association study (GWAS), identifying variants associated with glycemic response. We hypothesized that an alternative whole-genome regression including dominant (full effect by one allele copy) and recessive (only homozygous have an effect) models would increase statistical power. Methods: The GRADE Genetics Study examined 4,538 participants on metformin and randomized to glargine, glimepiride, liraglutide, or sitagliptin. We performed a time-to-event GWAS of treatment failure (HbA1c ≥7%). We used REGENIE-v4.1 to run additive, dominant, and recessive models, adjusted for baseline age, sex, HbA1c, BMI, and the first 10 principal components. Results: We found twelve additive and eleven non-additive signals associated with glycemic response across the four treatments (p5×10-8). rs113801264 had improved response to liraglutide (HR=0.52, p=2.4×10-8) and greater weight loss (β=-0.96kg, p=0.04). rs181359782 had improved response to glargine (HR=0.35, p=2.4×10-8). X-chromosome variant rs5969895 had improved response to liraglutide in hemizygous males (HR = 0.16, p = 7.7×10-9). Conclusion: To sum up, we identified novel loci associated with treatment response, which may support T2D personalized treatment. Disclosure T.Y. Wangden: None. L. Szczerbinski: Research Support; Current; Novo Nordisk. Consultant; Current; Eli Lilly and Company. M.T. Tripputi: None. A. Huerta: None. A. Kretowski: None. S. Kahn: Advisory Panel; Current; AltPep, Amgen Inc., Congruence Therapeutics, Eli Lilly and Company, General Medicines, Kayothera, Merck Ended; Jubilant Therapeutics, Inc. J.C. Florez: Research Support; Current; Novo Nordisk. Consultant; Current; Alveus Therapeutics. J. Mercader: None.
WANGDEN et al. (Fri,) studied this question.