A Functional Variant in APOA5/A4/C3/A1 Gene Cluster Contributes to Elevated Triglycerides and Severity of CAD by Interfering With MicroRNA 3201 Binding Efficiency

作者：Cui, Guanglin; Li, Zongzhe; Li, Rui; Huang, Jin; Wang, Haoran; Zhang, Lina; Ding, Hu; Wang, Dao Wen^*

来源：Journal of the American College of Cardiology, 2014, 64(3): 267-277.

DOI：10.1016/j.jacc.2014.03.050

• APOA5/A4/C3/A1 gene cluster
• coronary artery disease
• genetics
• lipids

BACKGROUND Recent genome-wide association studies identified the APOA5/A4/C3/A1 gene cluster polymorphisms influencing triglyceride level and risk of coronary artery disease (CAD). @@@ OBJECTIVES The purposes of this study were to fine-map triglyceride association signals in the APOA5/A4/C3/A1 gene cluster and then explore the clinical relevance in CAD and potential underlying mechanisms. @@@ METHODS We resequenced the APOA5/A4/C3/A1 gene cluster in 200 patients with extremely high triglyceride levels (>= 10 mm/l) and 200 healthy control subjects who were ethnically matched and genotyped 20 genetic markers among 4,991 participants with Chinese Han ethnicity. Subsequently, 8 risk markers were investigated in 917 early-onset and 1,149 late-onset CAD patients, respectively. The molecular mechanism was explored. @@@ RESULTS By resequencing, a number of newly and potentially functional variants were identified, and both the common and rare variants have remarkable cumulative effects on hypertriglyceridemia risk. Of note, gene dosage of rs2266788 demonstrated a robust association with triglyceride level (p = 1.39 x 10(-19)), modified Gensini scores (p = 1.67 x 10(-3)), and numbers of vascular lesions in CAD patients (odds ratio: 1.96, 95% confidence interval: 1.31 to 2.14, p = 8.96 x 10(-4)). Functional study demonstrated that the rs2266788 C allele destroyed microRNA 3201 binding to the 30 UTR of APOA5, resulting in prolonging the half-life of APOA5 messenger RNA and increasing its expression levels. @@@ CONCLUSIONS Genetic variants in APOA5/A4/C3/A1 gene cluster play an important role in the regulation of plasma triglyceride levels by an increased APOA5 concentration and contribute to the severity of CAD.

• 出版日期2014-7-22
• 单位华中科技大学