72-OR: Higher Genetic Risk for Type 2 Diabetes Is Associated with Faster Decline of Beta-Cell Function

Abstract

Objective: Polygenic risk score (PRS) for type 2 diabetes (T2D) has been reported to be associated with beta cell function, but whether it is also associated with the longitudinal change of beta cell function is largely unknown. We aimed to evaluate the association of PRS and the trajectory of beta cell function in a community based prospective cohort. Method: We analyzed 6,323 participants without T2D at baseline from Ansan-Ansung cohort with 75-g 2-hour oral glucose tolerance tests taken biennially for 14 years. Disposition index (DI), derived from insulinogenic index at 60 minutes and Matsuda index, was used as a marker for beta cell function. PRS was calculated using 1.2 million variants from trans-ancestry T2D genome-wide association study using Bayesian regression (PRS-CSx). Participants were stratified into low (1st quintile), intermediate (2nd to 4th quintiles) and high genetic risk (5th quintile). Lifestyle was categorized as unfavorable, intermediate and favorable lifestyle according to Life’s Essential 8. Linear mixed model was applied. Result: During a median follow-up of 13 years, 379 (30.6%), 875 (23.0%) and 171 (13.4%) participants developed T2D in high, intermediate and low genetic risk group, respectively. Participants in high genetic risk group, compared to low genetic risk group, had a 33% lower DI at baseline (53 [95% CI 50, 56] vs 79 [74, 84]; P = 7.9×10-15), and a 1.7-fold faster rate of decline in log2(DI) per year (-0.035 [-0.028, -0.042] vs -0.020 [-0.013, -0.027]; P = 0.0026). Notably, we found significant interaction between the rate of decline in DI and T2D PRS (P = 8.5×10-5). Healthy lifestyle was associated with decreased rate of decline in DI across all genetic risk group. Conclusion: Having a high genetic risk for T2D was associated with not only a lower DI at baseline, but also a faster rate of decline in DI. Genetic information could be used to identify those at risk for rapid decline of beta cell function and emphasize lifestyle modification. Disclosure H.Lee: None. J.Choi: None. H.Son: None. K.Park: None. N.H.Cho: None. S.Kwak: None. Funding Ministry of Health & Welfare, Republic of Korea