Genetic Liability to Higher Muscle Strength Associates with a Lower Risk of Cardiovascular Disease Mortality in Men Irrespective of Physical Activity in Adulthood: A Longitudinal Cohort Study

Background Low muscle strength predicts premature mortality. We determined whether genetic liability to muscle strength is associated with mortality and whether this association is influenced by long-term leisure-time physical activity (PA). Methods and Results We estimated the effects of a polygenic score for hand grip strength (PGS HGS) on all-cause and cardiovascular disease (CVD) mortality risk in the older Finnish Twin Cohort (N=8815, 53% women). National registries provided dates and causes of death. PA volume was assessed longitudinally in 1975, 1981, and 1990 using validated questionnaires. During the 16.9-year median follow-up time (143,723 person-years), 2896 deaths occurred, of which 1089 were due to CVD. We found a significant interaction between sex and PGS HGS ( P =0.016) for predicting all-cause mortality. In men, one standard deviation increase in the PGS HGS was associated with a decreased risk both of all-cause (hazard ratio, HR [95% confidence interval, CI]): 0.93 [0.89–0.98] and CVD mortality (HR 0.88 [0.81–0.96]). Associations persisted after adjusting for PA, but only with CVD mortality after adjusting for other lifestyle covariates (HR 0.85 [0.76–0.96]). The cumulative incidence rates by age 75 years were 4.3% lower for all-cause mortality and 2.1% lower for CVD mortality in the highest PGS HGS quintile compared to the lowest quintile. No PGS HGS×PA interactions were found. PGS HGS was not associated with mortality in women. Conclusions Higher PGS HGS was associated with a decreased risk of all-cause and CVD mortality in men; however, long-term PA in adulthood did not potentiate this association. Clinical Perspective What Is New? To the best of our knowledge, this is the first study to use a genome-wide polygenic score for hand grip strength to investigate whether the association between genetic liability to muscle strength and lifespan is affected by physical activity. Our results suggest that individuals with a genetic predisposition for higher muscle strength have a modest decreased risk of cardiovascular disease mortality, independent of their lifestyle. What Are the Clinical Implications? Polygenic scores for muscle strength require further development but may help identify individuals who represent extreme ends of genetic predisposition and vulnerability to premature death.