Association of varicose veins with rare protein-truncating variants in PIEZO1 identified by exome sequencing of a large clinical population

• Published in: Journal of vascular surgery. Venous and lymphatic disorders (New York, NY) NY), 2022-03, Vol.10 (2), p.382-389.e2
• Main Authors: Smelser, Diane T., Haley, Jeremy S., Ryer, Evan J., Elmore, James R., Cook, Adam M., Carey, David J.
• Format: Article
• Language: English
• Subjects: Adult; Aged; DNA Mutational Analysis; Electronic Health Records; Exome; Female; Frameshift Mutation; Genetic Association Studies; Genetic Predisposition to Disease; Humans; Ion Channels - genetics; Male; Middle Aged; Phenotype; Predictive Value of Tests; Prognosis; Retrospective Studies; Risk factors; Varicose veins; Varicose Veins - diagnostic imaging; Varicose Veins - surgery; Varicose Veins - therapy; Whole Exome Sequencing
• ISSN: 2213-333X; 2213-3348
• DOI: 10.1016/j.jvsv.2021.07.007

The present study sought to determine whether protein-truncating variants (PTVs) in PIEZO1 and CASZ1 genes, previously shown to be associated with varicose veins, were associated with an altered risk of varicose veins. An exome sequence database of 131,918 participants from the Geisinger MyCode Community Health Initiative was used to identify individuals with genetic variants in the PIEZO1 or CASZ1 gene. Clinical phenotypes, including varicose vein diagnoses, were determined by analysis of the electronic health record data. We identified 12,531 individuals (9.5%) with a diagnosis of varicose veins. Exome sequence data identified 92 PIEZO1 PTVs in 305 heterozygous carriers. PIEZO1 PTVs were significantly enriched in those with varicose vein (0.37% of cases vs 0.22% of controls; odds ratio [OR], 1.7; P = .0010). Nearly all varicose vein cases were associated with frameshift or stop-gain PTVs (OR, 3.0 for stop-gain [P = .0001]; OR, 2.9 for frameshift variants [P < .0001]). In the varicose vein cases, the PTV carriers were more likely to have an encounter with a vascular surgeon (62.5% for PTV carriers; 36.9% for noncarriers; P = .0003) and more likely to have received vein ablation therapy (OR, 6.9; P < .0001). No association was found between PIEZO1 PTVs and lymphedema, and no association was found for rare missense variants in PIEZO1 with varicose veins. PTVs in CASZ1 were extremely rare (16 total carriers), with none identified in those with varicose vein. Rare PTVs in PIEZO1 but not CASZ1 were associated with varicose veins and the need for vein ablation therapy. These results have demonstrated that PTVs in the PIEZO1 gene are rare but represent strong genetic risk factors for varicose veins and the need for vein ablation therapy. These results have also identified a potential biologic mechanism and target for the development of novel therapies.