Integrative analysis prioritizes proteins associated with renal cell carcinoma and its risk factors

Renal cell carcinoma (RCC), the predominant form of kidney cancer, is influenced by several risk factors (RFs) including obesity, hypertension, and smoking. However, the molecular mechanisms linking these RFs to RCC remain unclear. We investigated plasma proteins (PP) as potential intermediates of the effects of RFs on RCC using two-step Mendelian randomization (TSMR). In step 1, we identified PPs influenced by each RF, leveraging GWAS summary-statistics from the UK Biobank Proteomics (N = 34,557) for PPs and 19 RFs encompassing anthropometric traits, blood pressure, smoking behavior, blood cell, and kidney function. In step 2, we evaluated the effects of these RF-associated PPs on RCC, using the largest-to-date RCC GWAS (cases=29,020). Proteins significantly associated with both RFs and RCC were further prioritized through convergent evidence from multiple downstream analyses. Among 2,940 PPs, 2,339 were significantly associated (P < 1.7E-05) with at least one of the 19 RFs. Of these, 33 showed a significant effect on RCC (FDR<5%) with 28 mapping outside RCC GWAS loci. Using multivariable MR, we estimated mediation effects of associated PPs, finding that proteins such as APOL1 mediated 2.76% of white blood cell's effect. Convergent evidence from multiple downstream analyses prioritized TYMP, UMOD, and USP28 as key protein intermediaries of the RF effects on RCC. TYMP and USP28, both inversely associated with RCC risk, showed immune-related and tumor-suppressive effects, while UMOD was positively associated, potentially linking renal dysfunction to carcinogenesis. Our analysis highlights PPs as intermediates of the effect of distinct RFs on RCC, thereby nominating molecular targets for further investigation.