Guanglin Cui1, Zongzhe Li1, Rui Li1, Jin Huang1, Haoran Wang1, Lina Zhang1, Hu Ding2, Dao Wen Wang3. 1. Institute of Hypertension and Department of Internal Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, People's Republic of China. 2. Institute of Hypertension and Department of Internal Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, People's Republic of China. Electronic address: huding@tjh.tjmu.edu.cn. 3. Institute of Hypertension and Department of Internal Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, People's Republic of China. Electronic address: dwwang@tjh.tjmu.edu.cn.
Abstract
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 × 10(-19)), modified Gensini scores (p = 1.67 × 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 × 10(-4)). Functional study demonstrated that the rs2266788 C allele destroyed microRNA 3201 binding to the 3' 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.
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 × 10(-19)), modified Gensini scores (p = 1.67 × 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 × 10(-4)). Functional study demonstrated that the rs2266788 C allele destroyed microRNA 3201 binding to the 3' 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.
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