Genetic predisposition to smoking in relation to the risk of frailty in ageing

Frailty causes emerging global health burden due to its high prevalence and mortality. In this study, we used Mendelian randomization (MR) approach to examine the potential causal relationship between smoking and frailty in ageing. Using inverse-variance weighted (IVW) method, genetically predicted smoking initiation was associated with an increased risk of frailty in ageing (odd ratio (OR) 1.23, 95% confidence interval (CI) 1.19-1.27, P = 3.21 × 10^-39). Similarly, per year increase in age of initiation of regular smoking was associated with a 25% decrease in the risk of frailty (95% CI 7-39%, P = 7.79 × 10^-3, per year), while higher number of cigarettes per day was associated with a 12% increased risk (95% CI 4-20%, P = 1.76 × 10^-3). Compared with former smokers, current smokers were associated with an increased risk of frailty (OR 1.12, 95% CI 1.02-1.22, P = 0.01). Lifetime smoking was associated with a 46% higher risk of frailty (95% CI 37-56%, P = 2.63 × 10^-29). Sensitivity analysis using alternative MR methods yielded similar results. Our study indicates that genetic predisposition to smoking is associated with the risk of frailty in ageing. Further studies are warranted to examine the exact role of smoking in the development of frailty.