Genetic uptake in Loeys-dietz syndrome genes is highest in spontaneous coronary artery dissection patients with extra-coronary arterial involvement

Abstract

Background: Recent GWAS studies have reported significant associations between loci including genes involved in thrombosis and peripheral artery disease (PAD). However, the respective contribution of monogenic vs polygenic thrombophilia to PAD remains unclear. Study design: To address this question, we analyzed clinical and genetic data from 469,814 individuals (45-69 years old) from the UK Biobank. Exome sequencing and imputed genotyping array data were used to identify individuals with monogenic (F5 [rs6025] and F2 variants [rs1799963]) or polygenic thrombophilia (venous thromboembolism polygenic risk score [PRS-VTE] using 248 variants excluding SNPs defining F5 and F2 mutation). Results: Monogenic F5 and F2 genetic variants were found with a higher cumulative frequency in 699 PAD cases (7.4%, N cases = 9,504) compared to 38,348 in the control group (6.6%, N controls = 460,310) (P chi-square = 0.003). Carriers of these variants were significantly more likely to experience a PAD event (OR: 1.13 [95% CI: 1.04-1.22]) compared to non-carriers. In contrast, these variants were not associated with coronary artery disease (CAD) (P = 0.72) nor cerebrovascular disease (CVD) (P = 0.58). The PRS-VTE was also associated with PAD (OR: 1.05 [95% CI: 1.03-1.04], per 1SD increase in PRS). Conclusions: Both monogenic and polygenic thrombophilia are associated with an increased risk of PAD. This study points to a particular benefit of anti-coagulants in preventing or treating PAD in a subset of patients genetically predisposed to thrombophilia.