1466-P: Genome-Wide Association Studies in the GRADE Study Identify Genetic Variation Influencing the Response to Pharmacotherapy for Type 2 Diabetes

Abstract

Treatment selection for type 2 diabetes (T2D) is largely driven by guidelines based on population-level clinical data and does not incorporate genetics into decision making. To address this gap, we conducted genome-wide association studies in GRADE, a randomized trial comparing the metabolic effects of glargine, glimepiride, liraglutide, or sitagliptin, when added to metformin over a mean follow-up of 5 years. 4,689 participants with T2D from diverse ancestries underwent genome-wide genotyping with the Illumina Infinium GSA 3.0 array, and high-quality imputation was performed with the TOPMed reference panel. We defined cases as meeting the two outcome criteria (primary: HbA1c ≥7%; secondary: HbA1c ≥7.5%) after 1 or 4 years of treatment. Whole-genome logistic regression using an additive model tested for case-control associations for each treatment. Results were filtered to minor allele frequency >0.005 and imputation R2 ≥0.80. We identified four loci associated with glargine response and one with sitagliptin response at standard genome-wide significance (p<5.0×10−8). For glargine, rs116991960 proximal to the RPSAP52 pseudogene region was associated with increased risk of the primary outcome at year 1 (p=2.6×10−8). Interestingly, RPSAP52 interacts with the RNA binding protein IGF2BP2, and genetic variation in IGF2BP2 has been associated with increased T2D risk. Moreover, rs142895019, located in ITPK1, was associated with the secondary outcome for sitagliptin at year 1 (p=9.4×10−9). In a separate Cox proportional hazards survival analysis, C-allele carriers of rs142895019 had an increased risk of treatment failure on sitagliptin (HR 3.6, p=1.0×10−7). In summary, we identified new genetic loci that may be associated with glycemic response in a multi-ancestry clinical trial of common glucose-lowering medications for T2D. These findings require independent validation but have potential utility in guiding therapy selection. Disclosure J.H. Li: None. L. Szczerbinski: None. H. Liu: None. M. Tripputi: None. A. Kretowski: None. S.E. Kahn: Advisory Panel; Anji Pharmaceuticals, Bayer Inc., Boehringer Ingelheim Inc., Eli Lilly and Company, Merck & Co., Inc. Other Relationship; Novo Nordisk. J.M. Lachin: None. N. Younes: None. J.M. Mercader: None. J.C. Florez: Consultant; AstraZeneca. Other Relationship; AstraZeneca, Merck & Co., Inc. Consultant; Novo Nordisk. Funding National Institute of Diabetes and Digestive and Kidney Diseases (U01DK098246, U34DK088043, R01DK123019)