title: 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.
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).
  
  
  OBJECTIVE
  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.
authors.affiliation: 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.
authors.forename: Guanglin
authors.initials: G
authors.lastname: Cui
authors.affiliation: 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.
authors.forename: Zongzhe
authors.initials: Z
authors.lastname: Li
authors.affiliation: 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.
authors.forename: Rui
authors.initials: R
authors.lastname: Li
authors.affiliation: 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.
authors.forename: Jin
authors.initials: J
authors.lastname: Huang
authors.affiliation: 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.
authors.forename: Haoran
authors.initials: H
authors.lastname: Wang
authors.affiliation: 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.
authors.forename: Lina
authors.initials: L
authors.lastname: Zhang
authors.affiliation: 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.
authors.forename: Hu
authors.initials: H
authors.lastname: Ding
authors.affiliation: 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.
authors.forename: Dao Wen
authors.initials: DW
authors.lastname: Wang
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D016632:Apolipoprotein A-I / Q000235:genetics; D000072040:Apolipoprotein A-V; D053305:Apolipoprotein C-III / Q000235:genetics; D001054:Apolipoproteins A / Q000235:genetics*; D044466:Asian People / Q000235:genetics; D015331:Cohort Studies; D003324:Coronary Artery Disease / Q000097:blood / Q000175:diagnosis / Q000235:genetics*; D005260:Female; D014644:Genetic Variation / Q000235:genetics*; D006801:Humans; D008297:Male; D035683:MicroRNAs / Q000235:genetics* / Q000378:metabolism; D008875:Middle Aged; D005810:Multigene Family / Q000235:genetics*; D011485:Protein Binding / Q000502:physiology; D012720:Severity of Illness Index; D014280:Triglycerides / Q000097:blood; D055815:Young Adult
chemical_list: C505693:APOA1 protein, human; C437704:APOA5 protein, human; D016632:Apolipoprotein A-I; D000072040:Apolipoprotein A-V; D053305:Apolipoprotein C-III; D001054:Apolipoproteins A; C000591648:MIRN3201 microRNA, human; D035683:MicroRNAs; D014280:Triglycerides; C022205:apolipoprotein A-IV
keywords: APOA5/A4/C3/A1 gene cluster; coronary artery disease; genetics; lipids