Abstract Clonal hematopoiesis (CH) has been implicated in both cancer and cardiovascular disease, but a shared germline architecture connecting renal cell carcinoma (RCC), coronary artery disease (CAD), and hematopoietic traits remains unclear. We aimed to map shared germline architecture across RCC, CAD, and hematopoietic traits using an unbiased genome-wide-to-locus workflow, and to prioritize biological pathways for follow-up based on convergent signals. We performed genome-wide genetic correlation (high-definition likelihood, HDL) across RCC, CAD and hematopoietic phenotypes (CH of indeterminate potential CHIP, loss of Y, loss of X, mosaic chromosomal alterations, and telomere length TL), followed by linkage disequilibrium (LD) -aware Bayesian colocalization (coloc and SuSiE-coloc) using harmonized GRCh38/rsID-aligned summary statistics from previously published genome-wide association studies (GWAS). Prompted by robust TERT-promoter colocalization, we conducted secondary, hypothesis-generating, cis-Mendelian randomization (MR) restricted to the TERT promoter window (chr5: 1, 258, 437-1, 358, 437; 2- and 4-SNP instruments based on shared credible-set variants). Significant genetic correlations were observed for RCC-CAD (rg=0. 125, P=1. 20×10-4), RCC-TL (rg=0. 093, P=1. 42×10-2), RCC-CHIP (rg=0. 182, P=2. 30×10-2), and CAD-TL (rg=-0. 173, P=1. 03×10-11, false-discovery rate FDR10%). Colocalization identified a promoter-proximal TERT haplotype (chr5: 1. 28-1. 29 Mb) with strong support for a shared causal signal across TL-RCC, TL-CHIP, CHIP-RCC, and TL-CAD (PP4∼1. 00), with shared lead variants including rs1282204A, rs1282989C, rs1283931C, rs1286401A, and rs1296371G. Additional high-confidence TL-RCC colocalizations were observed at telomere-maintenance loci including TERC (3q26. 2), OBFC1/STN1 (10q24. 33), and CTC1 (17p13. 1). In TERT-restricted MR, TL-increasing alleles were associated with increased CHIP risk (OR=1. 13 per unit TL, P=3. 03×10-27), increased RCC risk (OR=1. 96 per SD TL, P=8. 36×10-11), and decreased CAD risk (OR=0. 75 per unit TL, P=1. 70×10-14). When CHIP was treated as the exposure (TERT-restricted instruments, OR per 10% increase in CHIP odds), CHIP-raising alleles at TERT were also associated with increased RCC risk (OR: 1. 66, P0. 001) and decreased CAD risk (OR=0. 80, P0. 001). Genome-wide correlation and multi-trait colocalization nominate a shared regulatory haplotype at the TERT promoter and convergent telomere maintenance loci, as a germline axis linking TL, CH, and RCC, with divergent effects on CAD. The MR analyses supported these directional effects, but should be interpreted as secondary as they relied on a small number of variants. These findings motivate mechanistic follow-up of TERT-mediated telomere regulation in tumor-hematopoietic systems, and if validated, may help refine how CH is interpreted in patients with RCC by suggesting that CH subtypes tied to telomere/TERT biology could have distinct cardiovascular risk profiles. Citation Format: Maxine Sun, Weiwei Bian, Marc Machaalani, Mustafa Jamal Saleh, David Braun, Rana McKay, Alexander Gusev, Toni K. Choueiri. Shared germline architecture across renal cell carcinoma, coronary artery disease, and clonal hematopoiesis implicates a regulatory haplotype at the TERT promoter abstract. In: Proceedings of the AACR Special Conference in Cancer Research: Innovations in Kidney Cancer Research: From Molecular Insights to Therapeutic Breakthroughs; 2026 Mar 13-16; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2026;86 (5Suppl₂): Abstract nr PR014.
Sun et al. (Fri,) studied this question.