Assessment of causal effects of visceral adipose tissue on risk of cancers:a Mendelian randomization study

BACKGROUND: Despite the established association between obesity and cancer risk, it remains unclear whether visceral obesity is causally related to cancer risk and whether it is more pro-oncogenic than total body fat.METHODS: We conducted two-sample Mendelian randomization (MR) analysis to assess the causal effects of visceral adipose tissue (VAT) on six common cancers. For exposure data, 221 genetic variants associated with the predicted volume of VAT in 325 153 Europeans from UK Biobank were used as instrumental variables. Genetic association data of six common cancers (breast, lung, colorectal, ovarian, pancreatic and prostate cancers) were obtained from large-scale consortia with an average of 19 576 cases and 43 272 controls. We performed univariable MR with five MR methods [inverse-variance weighted (IVW), MR-Egger regression, weighted median, MR-Pleiotropy Residual Sum and Outlier (MR-PRESSO) and Radial MR] and multivariable MR to estimate the effect of VAT independent of body mass index (BMI). Finally, we performed a series of sensitivity analyses as validation of primary MR results.RESULTS: Two associations survived the false discovery rate correction for multiple testing (q-value < 0.05): in IVW, the odds ratios (95% CIs) per unit increase in genetically determined VAT were 1.65 (1.03 to 2.62) for pancreatic cancer and 1.47 (1.20 to 1.82) for lung squamous-cell carcinoma, respectively, which showed the same directions and overlapped confidence intervals with MR-Egger regression and weighted median results. There were no outlier variants identified by MR-PRESSO and no evidence supporting the presence of heterogeneity and pleiotropy in sensitivity analyses, although with wider confidence intervals that included the null, multivariable MR results for these two cancers showed the same directions and similar effect sizes as in IVW, which were independent of the effect from BMI. There was no evidence for a causal effect of VAT on the risk of other types of cancer.CONCLUSION: Our findings suggest that lifelong exposure to elevated volumes of VAT might increase the risk of pancreatic cancer and lung squamous-cell carcinoma, highlighting the importance of revealing the underlying mechanisms for intervention targets.