Influence of genetically predicted stair-climbing frequency on the risk of lung cancer:a Mendelian randomization study
Objective To explore the causal relationship between the frequency of stair climbing(FSC)and the risk of lung cancer(LC)using Mendelian randomization(MR).Methods Firstly,the relevant genome-wide association study(GWAS)data for FSC,LC risk factors,and LC risk were obtained from the IEU OpenGWAS database.Secondly,the causal relationship between FSC,LC risk factors,and LC risk was analyzed by MR,and the proportions of the effects of body mass index(BMI),chronic obstructive pulmonary disease(COPD),and smoking behavior on the relationship between FSC and LC risk were analyzed.Subsequently,this relationship was further validated through linkage disequilibrium score regression.Finally,the molecular mechanisms that may influence the reduc-tion of LC risk by FSC were explored using Bayesian colocalization methods.Results The results of inverse-variance weighting(IVW)in MR analysis indicated a significant negative causal relationship between the predicted FSC based on GWAS and LC risk(IVW:OR 0.611,95%CI 0.503-0.743,P=0.011).In different types of lung cancer,FSC demonstrated significant negative causal relationships with lung squamous cell carcinoma(LUSC)risk(IVW:OR0.506,95%CI 0.370-0.693,P=0.030),small cell lung cancer(SCLC)risk(IVW:OR 0.380,95%CI 0.248-0.583,P=0.023),and smoker's lung cancer risk(IVW:OR 0.599,95%CI 0.485-0.739,P=0.015).Furthermore,BMI(IVW:OR 1.218,95%CI 1.144-1.298,P=0.001),COPD(IVW:OR 2.003,95%CI 1.652-2.430,P<0.001),and ever smoking(IVW:OR 2.139,95%CI 1.731-2.644,P<0.001)were significantly positively associated with LC risk,while never smoking showed a significant negative causal relationship with LC risk(IVW:OR 0.382,95%CI 0.317-0.462,P<0.001).FSC also exhibited significant negative causal relationships with BMI(IVW:OR 0.740,95%CI 0.683-0.802,P<0.001),COPD(IVW:OR 1.173,95%CI 1.034-1.331,P=0.001),and ever smoking(IVW:OR 0.951,95%CI 0.932-0.970,P=0.021),and a significant positive causal relationship with never smoking(IVW:OR 1.094,95%CI 1.072-1.116,P<0.001).The mediation proportion of BMI,COPD,ever smoking,and never smoking in the relationship between FSC and LC risk was 2.2%,78.7%,5.7%,and 15.2%,respectively.Linkage disequilibrium score regression confirmed the genetic correlation between FSC and LC,LUSC,SCLC,and smoker's lung cancer.Bayesian colocalization analysis indicated that the effect of FSC on LC risk may be mediated through genes such as KPC1,UBA7,CTD-2330K9.3,GNAT1,MARK3,RPL10AP1,and ERCC8.Conclusion Mendelian randomization studies suggest that an increase in FSC may potentially decrease the risk of LC,and this relationship is partially mediated by BMI,COPD,and smoking.