A hypothesis-driven study to comprehensively investigate the association between genetic polymorphisms in EPHX2 gene and cardiovascular diseases: Findings from the UK Biobank

• Published in: Gene 2022-05, Vol.822, p.146340-146340, Article 146340
• Main Authors: Zhu, Xiaoming, Li, Yuxin, Yu, Tingting, Li, Sen, Chen, Mulei
• Format: Article
• Language: English
• Subjects: Adult; Aged; Biological Specimen Banks; Cardiovascular diseases; Cardiovascular Diseases - epidemiology; Cardiovascular Diseases - genetics; Electronic Health Records; EPHX2; Epoxide Hydrolases - genetics; Female; Genetic Association Studies; Genetic polymorphisms; Genetic Predisposition to Disease; Humans; Incidence; Male; Middle Aged; Phenomics - methods; PheWAS; Polymorphism, Single Nucleotide; Soluble epoxide hydrolase; United Kingdom - epidemiology
• ISSN: 0378-1119; 1879-0038
• DOI: 10.1016/j.gene.2022.146340

•The associations between 210 variants in EPHX2 gene and 118 CVDs were investigated.•The variant rs116932590 was associated with “aneurysm and dissection of heart”.•The variant rs751141 was associated with several metabolic traits.•Our results highlight the important role of EPHX2 genetic variation in CVDs. Epoxyeicosatrienoic acids (EETs) are protective factors against cardiovascular diseases (CVDs) because of their vasodilatory, cholesterol-lowering, and anti-inflammatory effects. Soluble epoxide hydrolase (sEH), encoded by the EPHX2 gene, degrades EETs into less biologically active metabolites. EPHX2 is highly polymorphic, and genetic polymorphisms in EPHX2 have been linked to various types of CVDs, such as coronary heart disease, essential hypertension, and atrial fibrillation recurrence. Methods: Based on a priori hypothesis that EPHX2 genetic polymorphisms play an important role in the pathogenesis of CVDs, we comprehensively investigated the associations between 210 genetic polymorphisms in the EPHX2 gene and an array of 118 diseases in the circulatory system using a large sample from the UK Biobank (N = 307,516). The diseases in electronic health records were mapped to the phecode system, which was more representative of independent phenotypes. Survival analyses were employed to examine the effects of EPHX2 variants on CVD incidence, and a phenome-wide association study was conducted to study the impact of EPHX2 polymorphisms on 62 traits, including blood pressure, blood lipid levels, and inflammatory indicators. Results: A novel association between the intronic variant rs116932590 and the phenotype “aneurysm and dissection of heart” was identified. In addition, the rs149467044 and rs200286838 variants showed nominal evidence of association with arterial aneurysm and cerebrovascular disease, respectively. Furthermore, the variant rs751141, which was linked with a lower hydrolase activity of sEH, was significantly associated with metabolic traits, including blood levels of triglycerides, creatinine, and urate. Conclusions: Multiple novel associations observed in the present study highlight the important role of EPHX2 genetic variation in the pathogenesis of CVDs.