Systematic assessment of obesity-related risk factors in renal cancer etiology: A longitudinal risk and Mendelian randomization analysis

BACKGROUND: Excess body adiposity is an established cause of renal cancer, but underlying molecular pathways mediating this relationship remain unclear. This study aimed to systematically evaluate a panel of obesity-related risk factors as potential mediators in renal cancer etiology. METHODS AND FINDINGS: We used two complementary approaches to evaluate obesity-related risk factors in renal cancer etiology: (i) direct risk factor assessment in longitudinal cohorts and (ii) genetically proxied risk factors through two-sample Mendelian randomization (MR). Direct risk-factor association-analyses (i.e., cohort analyses) were based on the UK Biobank cohort study (472,337 cohort participants, including 1,382 incident renal cancer cases diagnosed during 5,586,414 person years of follow-up) and the Northern Sweden Health and Disease Study (NSHDS) for fasting insulin (204 pairs of cases and controls, ongoing recruitment and follow-up since 1985). We used Cox proportional hazards regression models to evaluate the association between risk factors and renal cancer risk with adjustment for age, sex, center of recruitment, education, smoking and alcohol drinking status. Two-sample MR analyses were based on a genome-wide association study (GWAS) of renal cancer (27,213 cases, 486,846 controls). We used the inverse-variance weighted (IVW) approach to estimate the association between risk factors and renal cancer risk. Mediation analyses were performed for traits displaying directionally consistent associations with renal cancer risk in both the cohort and MR analyses using the product method. We found consistent positive associations with renal cancer risk for fasting insulin (odds ratio per standard deviation increment [ORMR]: 2.24, 95% confidence interval [95% CI]: 1.19, 4.22; p = 0.01; hazard ratio per standard deviation increment [HRcohort]: 1.43, 95% CI: 1.02, 2.00; p = 0.04), triglycerides (ORMR: 1.11, 95% CI: 1.05, 1.17; p < 0.001, HRcohort: 1.23, 95% CI: 1.11, 1.38; p < 0.001), diastolic blood pressure (DBP) (ORMR: 1.14, 95% CI: 1.04, 1.26; p < 0.001, HRcohort: 1.11, 95% CI: 1.05, 1.17; p < 0.001) and consistent inverse associations with renal cancer risk for sex-hormone binding globulin (SHBG) (ORMR: 0.80, 95% CI: 0.70, 0.90; p < 0.001, HRcohort: 0.67, 95% CI: 0.58, 0.76; p < 0.001) and high-density lipoprotein (HDL) cholesterol (ORMR: 0.93, 95% CI: 0.88, 0.98; p < 0.001, HRcohort: 0.72, 95% CI: 0.66, 0.77; p < 0.001). The main limitation of this study was that we had limited statistical power to evaluate some risk factors. CONCLUSIONS: Our study highlights roles for fasting insulin, HDL cholesterol, DBP, triglycerides and SHBG in mediating the relationship between body adiposity and renal cancer risk.