Chronic inflammation does not mediate the effect of adiposity on grip strength: results from a multivariable Mendelian randomization study

The relationship between adiposity and grip strength (GS) is complex. We investigated whether one pathway through which adiposity affects GS was via chronic inflammation. 367,583 UK Biobank participants had body mass index (BMI), waist-hip-ratio (WHR), C-reactive protein (CRP) and GS data. Univariable Mendelian randomization (MR) and multivariable Mendelian randomization (MVMR) analyses (using inverse variance weighted (IVW) weighted median estimates (WME) and MR-Egger models) estimated total, direct and indirect effects of adiposity traits on GS using genetic instruments for BMI and WHR (exposures) and CRP (mediator). Observational findings suggested higher BMI was associated with stronger grip, e.g., in males, per standard deviation (SD) higher BMI, GS was higher by 0.48 kg (95% confidence interval(CI):0.44,0.51), independent of CRP. For males MR estimates were directionally consistent; for females, estimates were consistent with the null. Observational findings for WHR suggested that higher WHR was associated with weaker grip. In multivariable MR-IVW analyses, effects in males were consistent with the null. In females, there were consistent effects such that higher WHR was associated with stronger grip, e.g., 1-SD higher WHR was associated with 1.25 kg (MVMR-Egger; 95% CI:0.72,1.78) stronger grip, independent of CRP. Across sexes and adiposity indicators, CRP’s mediating role was minor. Greater adiposity may increase GS in early old age, but effects vary by sex and adiposity location. There was no evidence that inflammation mediated these effects.