Polygenic risk score for lower limb skeletal muscle mass and its interaction with protein and vitamin D intake in older adults.

Lower limb skeletal muscle mass is essential for maintaining physical function in older adults and serves as an early indicator of sarcopenia. This study aimed to characterize the polygenic architecture of low-lower limb skeletal muscle index (low-LSMI), identify underlying biological mechanisms, and develop a polygenic risk score (PRS). A genome-wide association study was conducted using UK Biobank data from 93,402 participants aged ≥65 y with bioelectrical impedance analysis results, including 14 076 with low-LSMI. Low-LSMI was defined as <5.7 kg/m² for men and <4.9 kg/m² for women based on EWGSOP2 (European Working Group on Sarcopenia in Older People 2) criteria. Secondary analyses included gene set enrichment analysis and tissue-specific expression profiling. A PRS was developed using generalized multifactor dimensionality reduction, and molecular docking analysis evaluated nutrient-protein binding. Low-LSMI prevalence was higher in men than in women (18.5% vs. 11.8%), and was associated with elevated inflammatory markers (Hs-CRP: 3.43 vs. 2.73 mg/dL in men; P < 0.001), lower serum vitamin D (49.7 vs. 53.3 ng/mL in men; P < 0.001), and paradoxically lower metabolic syndrome prevalence. The strongest genetic association was rs77530409 in IL5RA (odds ratio [OR] = 1.97, P = 6.16 × 10⁻¹⁷). An optimal 4-single-nucleotide polymorphism (SNP) PRS model (FTO rs3751814, ADAMTSL3 rs4842838, CYP4F2 rs3093198, and DPP8 rs66993805) achieved an area under the curve of 0.852. Significant gene-lifestyle interactions were observed for high-risk individuals with low protein intake (OR = 1.35), low vitamin D (OR = 1.66), high alcohol consumption (OR = 1.54), or low physical activity (OR = 1.52). Molecular docking showed reduced binding affinity of vitamin D3 to the ADAMTSL3-mutated variant (661Leu; -8.7 kcal/mol) relative to the wild-type (Val661; -9.3 kcal/mol). The 4-SNP PRS, combined with lifestyle assessment through gene-lifestyle interaction analysis, provides a tool for early risk stratification of muscle loss in older adults, with molecular evidence supporting personalized nutritional interventions.