Causal relationship between smoking status, smoking frequency and bladder cancer: a Mendelian randomization study

Background Smoking is a well-established risk factor for bladder cancer. However, it remained unclear that whether smoke status and smoke frequency increase bladder cancer. Objective We aim to explore the causal relationship between smoking status, smoking frequency and the risk of bladder cancer by Mendelian randomization. Methods Large sample size of the genome-wide association(GWAS) database of smoking status, smoking frequency and bladder cancer were obtained. Smoking status included never, previous and current whereas smoking frequency included cigarettes smoked per day, number of cigarettes currently smoked daily and pack years of smoking. Six sets of instrumental variables and 78 related single nucleotide polymorphic(SNP) loci were identified (P < 5 x 10-8. Linkage disequilibrium R2 < 0.001). The causal relationship between smoking status and bladder tumor was studied by inverse variance weighted (IVW), weighted median and MR-Egger regression. Sensitivity analysis were also performed. Results There is no causal effect from smoke status on bladder cancer risk while significantly positive relationship between smoking frequency on bladder cancer risk were found. IVW results showed that cigarettes smoked per day, number of cigarettes currently smoked daily and pack years of smoking increase bladder cancer (OR 1.001, 95% CI 1.000-1.002, P = 0.047; OR 1.003, 95% CI 1.000-1.005, P = 0.028; OR 1.004, 95% CI 1.001-1.006, P = 0.003). Sensitivity analysis showed that genetic pleiotropy did not bias the results. Conclusion The results of two sample Mendelian randomization analysis show that there is a positive causal relationship between smoking frequency and the risk of bladder cancer.