2410-P: Lean Body Mass Polygenic Score Predicts Longitudinal Muscle Loss: Evidence for Faster Decline in Adults with Diabetes

Introduction and Objective: Type 2 diabetes is a well-established risk factor that accelerates age-related muscle decline, predisposing individuals to sarcopenia. However, the interaction between genetic predisposition and the longitudinal trajectory of muscle mass remains unexplored. We assessed whether lean body mass polygenic scores (PS) contribute to accelerated muscle loss in individuals with diabetes. Methods: We analyzed 6,597 participants from the Ansan-Ansung cohort who had repeated measurements of BMI and muscle mass (estimated via bioelectrical impedence analysis) over 14 years. PS was calculated using approximately 1 million variants from lean body mass genome-wide association study from pan-UK Biobank Project using Bayesian regression using continuous shrinkage priors (PRS-CS). Participants were categorized into low (1st tertile), intermediate (2nd tertile) and high (3rd tertile) genetic scores. Results: Total of 1,377 East Asian participants were diagnosed with diabetes during a median follow-up of 13 years. Based on linear mixed model analysis adjusting baseline age, sex and physical activity status, participants with diabetes had a faster decline in BMI (-0.085 vs -0.002; P < 2×10-16) and muscle mass (-0.278 vs -0.168; P < 2×10-16) per year. Among individuals with diabetes, lean body mass PS was associated with higher baseline BMI (Beta = 0.32, P = 1.48×10-4) and muscle mass (Beta = 0.60, P = 1.16×10-5). However, a 1-SD increase in lean body mass PS showed a significant interaction with the longitudinal decline of both BMI (Beta = -0.014, P = 0.014) and muscle mass (Beta = -0.026, P = 0.005). Notably, individuals in the high PS category showed a faster decline in muscle mass than those in the low PS category (-0.296 vs -0.272; P = 0.029). Conclusion: High genetic predisposition to increased muscle mass was paradoxically associated with accelerated muscle loss in people with diabetes. Further validation and mechanistic investigation are warranted to confirm these findings and elucidate the underlying biology. Disclosure J. Choi: None. H. Lee: None. J. Park: None. J. Lee: None. Y. Jo: None. S. Lee: None. S. Kwak: None. Funding National Human Genome Research Institute (U01HG011723), National Research Foundation of Korea grant funded by the Korean Ministry of Science and ICT (RS-2023-00262002), Korea Ministry of Food and Drug Safety grant (23212MFDS202)