The association of appendicular lean mass and grip strength with LDL, VLDL and HDL particle diameter: A Mendelian randomization study of the UK Biobank cohort

Background and Aims: Reduced muscle mass and strength is frequently associated with alterations in blood lipids and poorer cardiometabolic outcomes in epidemiological studies, however, a causal association cannot be determined from such observations. Mendelian randomization (MR) was applied to assess the association of genetically determined appendicular lean mass (ALM) and handgrip strength (HGS) with serum lipid particle diameter. Methods: MR was implemented using summary-level data from the largest genome-wide association studies (GWAS) on ALM (n=450,243), HGS (n=461,089) and LDL, VLDL and HDL particle diameters, (n=115,078). Inverse variance weighted method (IVW) was used to estimate the causal estimates. Weighted median (WM)-based method, and MR-Egger, leave-one-out were applied as sensitivity analysis. Results: Increased ALM had a statistically significant positive effect on HDL particle diameter (MR Egger= β:0.055, p=0.081 and IVW= β:0.068, p=6.15x10-7; respectively), and a negative and statistically significant effect on VLDL particle diameter (MR Egger= β:-0.114, p=0.003 and IVW= β:-0.081, p=1.57x10-6, respectively). Increased HGS, had a statistically significant positive effect on HDL particle diameter (MR Egger= β:0.433, SE:0.184, p=0.019 and IVW= β:0.121, SE:0.052, p=0.021), and a negative and statistically significant effect on VLDL particle diameter (MR Egger= β:-0.416, SE:0.163, p=0.011 and IVW= β:-0.122, SE:0.046, p=0.009). There was no significant effect of ALM or HGS on LDL particle diameter. Conclusions: Evidence for a potentially causal association of both increasing ALM and HGS, with both increasing HDL particle size and decreasing VLDL particle size was found, highlighting their potential for improving CVD risk profile.