Abstract
BACKGROUND: Clear cell renal cell carcinoma (ccRCC) presents significant clinical challenges. This study investigates the causal relationship between telomere length (TL) and ccRCC risk using a comprehensive multicohort genetic approach. METHODS: We conducted a rigorous two-sample Mendelian randomization (MR) analysis using independent discovery (UK Biobank, n = 472,174) and validation (genome-wide association studies [GWAS] Catalog, n = 438,351) cohorts. Multivariable MR (MVMR) adjusted for chronic kidney disease (CKD), hypertension, and smoking. Colocalization analysis and single-cell RNA sequencing (scRNA-seq) were employed to validate genetic associations and explore cellular mechanisms. RESULTS: In the discovery cohort, inverse variance weighted (IVW) MR analysis revealed a significant positive association between TL and ccRCC risk (odds ratio [OR]: 1.604, 95% confidence interval [CI]: 1.358-1.895, p < 0.001). The validation cohort consistently confirmed these findings (OR: 1.470, 95% CI: 1.290-1.674, p < 0.001). MVMR analysis using IVW method, adjusting for key risk factors, demonstrated a significant association (OR: 2.072, 95% CI: 1.724-2.491, p < 0.001). Colocalization analysis showed strong evidence of shared causal variants (posterior probability > 98% in both discovery and validation sets). scRNA-seq revealed that proximal tubule cells (PTCs) with telomerase-associated genes NOP10 and NHP2 exhibited complex senescence dynamics, characterizing distinct cellular communication patterns in the tumor microenvironment. CONCLUSION: Our comprehensive multiomics study provides robust evidence of a causal relationship between TL and ccRCC risk. By integrating genetic epidemiology and single-cell transcriptomics, we unveil novel molecular mechanisms underlying ccRCC pathogenesis and identify potential therapeutic targets.