Genetic evidence for the beneficial effect of greater fat-free mass on cardiometabolic health

BackgroundFat-free mass (FFM), particularly skeletal muscle, is widely considered beneficial for glucose homeostasis and cardiometabolic health. However, its independent role remains uncertain due to confounding by other cardiometabolically relevant anthropometric traits, namely fat mass (FM), fat distribution, and height. Genetic approaches offer a unique opportunity to disentangle these effects and minimize bias. AimWe aimed to assess the independent effects of FFM on glucose and insulin homeostasis, type 2 diabetes (T2D) risk, and cardiovascular risk factors and events using two complementary genetic approaches. MethodsWe first applied multivariable Mendelian randomization (MVMR) to estimate the effect of FFM while accounting for FM, fat distribution, and height. Second, we developed an FFM-specific polygenic score by excluding variants associated with these traits. Genetic instruments for FFM were derived from 1,209 independent genome-wide significant variants among 361,918 UK Biobank participants with bioimpedance data. The polygenic score, comprising 58 of these variants, was validated in an independent sample of 34,540 individuals with DXA data. Cardiometabolic outcome effects were tested using summary statistics from the largest available GWAS meta-analyses and the FinnGen study (combined n up to 1.8 million). ResultsBoth MVMR and the FFM-specific polygenic score indicated a protective effect of higher FFM on postprandial glucose tolerance, insulin sensitivity, and T2D risk (MVMR: OR=0.83, 95%CI 0.76-0.91; Polygenic score: OR=0.81, 95%CI 0.74-0.88 per SD increase in FFM). They also indicated a beneficial effect on cardiometabolic risk markers and risk of stroke (MVMR: OR=0.84, 95%CI 0.77-0.92; Polygenic score: OR=0.79, 95%CI 0.71-0.89), with a more modest reduction observed for myocardial infarction (MVMR: OR=0.89, 95%CI 0.81-0.98; Polygenic score: OR=0.90, 95%CI 0.81-1.01). ConclusionGenetic evidence supports a beneficial effect of greater FFM on cardiometabolic health, underscoring the value of preserving or increasing FFM in T2D and CVD prevention.