Muscle strength, genetic susceptibility, and cardiometabolic diseases

Abstract

Poor muscle strength has been increasingly recognized as a key risk factor for cardiometabolic diseases. To advance the current understanding of the associations between muscle strength and cardiometabolic health, this dissertation aims to incorporate genetic susceptibility to cardiometabolic health and explore the interplay between muscle strength, genetic susceptibility, and the risk of common cardiometabolic diseases. This dissertation utilized data from a large cohort study, UK Biobank. Muscle strength was expressed as the relative value of grip strength (measured by hand dynamometer) to fat-free mass. Genetic susceptibility to each cardiometabolic condition was quantified as polygenic risk score based on published genetic variants. Cox regression models with age as the underlying timescale were used to estimate hazard ratios (HR) and 95% confidence intervals (CI).

The first study (Chapter 2) evaluated the interplay of muscle strength and genetic susceptibility to high blood pressure (BP) with cardiovascular disease (CVD) mortality, incident coronary heart disease (CHD), and stroke. Low muscle strength was associated with higher hazards of CVD mortality (HR:1.51, 95%CI:1.43-1.59), incident CHD (HR:1.16, 95%CI:1.11-1.21), and stroke (HR:1.20, 95%CI:1.14-1.27), independently of genetic predisposition to high BP, compared with high muscle strength. The estimated 10-year absolute risks of each outcome were lower for high muscle strength - high genetic risk of high BP, compared with low muscle strength combined with low or medium genetic risk.

The second study (Chapter 3) investigated the prospective associations between muscle strength, genetic risk of type 2 diabetes (T2D), and incident T2D. High muscle strength was associated with a 44% lower hazard of T2D (95%CI:0.52-0.60), compared with low muscle strength, after adjustment for genetic risk. The estimated 8-year absolute risk of T2D was lower for high genetic risk - high muscle strength, compared with low or medium genetic risk combined with low muscle strength.

The third study (Chapter 4) explored the prospective associations between muscle strength, genetic susceptibility to atherosclerosis cardiovascular disease (ASCVD), and incident ASCVD outcomes among individuals with diabetes. High muscle strength was associated with up to 33% lower hazards of incident ASCVD, compared with low muscle strength, after adjustment for genetic risk, among individuals with diabetes. The inverse associations of relative risk between muscle strength and ASCVD outcomes were only found in individuals at low and medium genetic risk, but not in those at high genetic risk. However, within each genetic risk stratum (including high genetic risk), estimates of the 10-year absolute risk of each ASCVD outcome were lower for individuals with diabetes who had high muscle strength compared to those who had low muscle strength.

Collectively, this dissertation demonstrated the potential role that high muscle strength could play in the prevention of cardiometabolic diseases not only in the general population but also in at-risk individuals including those at high genetic risk of cardiometabolic disease and/or those with diabetes. The findings from this dissertation inform future preventive medicine initiatives and clinical trials aimed at preventing cardiometabolic diseases through maintaining or improving muscle strength among the general population or individuals with diabetes at high genetic risk of cardiometabolic conditions.