Causal linkage of tobacco smoking with ageing traits: a Mendelian randomization analysis towards telomere attrition and frailty

Abstract

Background: Ageing traits and frailty are important health issues in modern medicine. Evidence supporting the causal effects from tobacco smoking on various ageing traits is warranted. Methods: This Mendelian randomization (MR) analysis instrumented 377 genetic variants associated with being an ever smoker in a genome-wide significant level to test the causal estimates from tobacco smoking. The outcome data included 337,318 white British ancestry UK Biobank participants. Leukocyte telomere length, appendicular lean mass index, subjective walking pace, handgrip strength, and wristband accelerometry determined physical activity degree were collected as ageing related outcomes. Summary-level MR by inverse variance weighted method and pleiotropy-robust MR methods, including weighted median and MR-Egger, was performed. Results: Summary-level MR analysis indicated that higher genetic predisposition for tobacco smoking was significantly associated with shorter leukocyte telomere length [2-fold prevalence increase in smoking towards standardized Z-score, -0.041 (-0.054, -0.028)], lower appendicular lean mass index [-0.007 (-0.010, -0.005)], slower walking pace [ordinal category, -0.047 (-0.054, -0.033)], and lower time spent on moderate-to-vigorous physical activity [hours per week, -0.39 (-0.56, -0.23). The causal estimates were nonsignificant towards handgrip strength phenotype [kg, 0.074 (-0.055, 0.204)]. Pleiotropy-robust MR results generally supported the main causal estimates. Conclusion: Genetically predicted tobacco smoking is significantly associated with worse ageing phenotypes. Healthcare providers may continue to reduce tobacco use which may be helpful to reduce the burden related to ageing and frailty.