MON-437 Germline VHL-gene Alterations Are Associated With An Increased Risk Of Cardiovascular Disease - A Large Population Study

Abstract R. Halperin: None. A. Tirosh: None. Introduction: Von Hippel-Lindau (VHL) is an autosomal dominant disease associated with increased risk for developing hemangioblastomas of the central nervous system and retina, renal cell carcinoma (RCC), pancreatic neuroendocrine tumors (PNET), adrenal pheochromocytomas and paraganglioma (PPGL). Loss of function VHL alterations lead to pseudohypoxia and, consequently, to angiogenesis and metabolic derangements (e.g., increased glucose uptake). Little is known about the systemic effects of VHL alterations on the cardiometabolic system. Aim Study whether VHL gene variants are associated with increased cardiometabolic risk. Methods: Data were extracted from the UK Biobank database, including demographic and anthropometric parameters, medical history, and lab testing. Whole exome sequencing data were available for all patients, and a focused variant calling and annotation of the VHL gene region was performed on the DNA-nexus platform. A composite of major adverse cardiovascular events (MACE) per patient consisted of ischemic heart disease (IHD), cerebrovascular accident (CVA), and peripheral artery disease (PVD). VHL variant severity was sub-categorized into low (silent or missense), intermediate (in-frame insertion or deletion and 5’ UTR variants), and high-risk (nonsense or frameshift). Results: Data from 460,430 participants were analyzed (45.8% males, age at inclusion 73.6±8.1 years). IHD, CVA, and PVD rates were 11.5%, 3.0%, and 1.8%, respectively. Germline VHL variants were detected in 2594 participants (0.45%), with 2073 low- (242 silent, 1830 missense), 505 intermediate- (18 in-frame deletion and 23 in-frame insertion and 464 5' UTR variants), and 16 high-risk (3 frameshift insertions, one frameshift deletion, and 12 nonsense) VHL variants. In the multivariable logistic regression analysis, harboring a high-risk VHL variant was associated with an 11-fold increased risk of MACE (odds ratio [OR] 11.1, 95% confidence interval 1.5-54.1, p=0.006), after adjustment for age at inclusion, age at diagnosis with cancer, sex, kidney function, c-reactive protein plasma levels, and diagnosis status with diabetes mellitus, hypertension, dyslipidemia, obesity, and RCC. Conclusions and discussion: VHL gene alterations are associated with an increased cardiometabolic risk. Metabolic changes or enhanced drive for angiogenesis might contribute to this association. Further research is needed to verify these results and to assess a possible benefit from early intervention in this population. Monday, June 3, 2024