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

## TL;DR

This study identifies obesity-related factors like fasting insulin and blood pressure that may explain how excess body fat increases the risk of kidney cancer.

## Contribution

The study combines longitudinal cohort data and Mendelian randomization to systematically assess obesity-related mediators of renal cancer risk.

## Key findings

- Fasting insulin, triglycerides, and diastolic blood pressure are positively associated with renal cancer risk.
- High-density lipoprotein cholesterol and sex-hormone binding globulin are inversely associated with renal cancer risk.
- The findings suggest these factors mediate the relationship between obesity and kidney cancer.

## Abstract

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.

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.

Our study highlights roles for fasting insulin, HDL cholesterol, DBP, triglycerides and SHBG in mediating the relationship between body adiposity and renal cancer risk.

The importance of excess body adiposity and renal caner etiology is well established, but the underlying mechanisms mediating this relationship are unclear.

We used two complementary observational approaches to evaluate 20 potential obesity-related risk factors in relation to renal cancer risk, including

direct risk factor assessment in longitudinal cohorts, and

genetically proxied risk factor assessment through Mendelian randomization (MR) in large genome-wide association studies.

We found consistent evidence for associations with renal cancer risk for fasting insulin, diastolic blood pressure (DBP), high-density lipoprotein (HDL) cholesterol, triglycerides and sex-hormone binding globulin (SHBG).

Our findings highlighted important roles for fasting insulin, HDL cholesterol, DBP, triglycerides and SHBG in mediating the relationship between body adiposity and renal cancer risk.

Limitations of our study include a relatively small sample size for the risk analysis of fasting insulin, and an incomplete assessment of sex hormones.

This study advances our understanding of obesity in renal cancer etiology.

Using evidence from both observational and Mendelian randomization analyses, Karine Alcala and colleagues systematically assess obesity‑related risk factors as potential mediators in the development of renal cancer.