title: Rs964184 (APOA5-A4-C3-A1) is related to elevated plasma triglyceride levels, but not to an increased risk for vascular events in patients with clinically manifest vascular disease.
abstract: BACKGROUND
  Single nucleotide polymorphisms in the APOA5-A4-C3-A1 gene complex are associated with elevated plasma triglycerides and elevated vascular risk in healthy populations. In patients with clinically manifest vascular disease, hypertriglyceridemia and metabolic syndrome are frequently present, but the contribution of these single nucleotide polymorphisms to plasma triglycerides, effect modification by obesity and risk of recurrent vascular events is unknown in these patients.
  
  
  METHODS
  Prospective cohort study of 5547 patients with vascular disease. Rs964184 (APOA5-A4-C3-A1 gene complex) was genotyped, and we evaluated the relation with plasma lipid levels, presence of metabolic syndrome and the risk for new vascular events.
  
  
  RESULTS
  The minor allele of rs964184 was strongly associated with log plasma triglycerides (β 0.12; 95%CI 0.10-0.15, p = 1.1*10(-19)), and was also associated with 0.03 mmol/L lower high-density lipoprotein-cholesterol (95%CI 0.01-0.04), and 0.14 mmol/L higher non-high-density lipoprotein-cholesterol (95%CI 0.09-0.20). The minor allele frequency increased from 10.9% in patients with plasma triglycerides <1 mmol/L to 24.6% in patients with plasma triglycerides between 4 and 10 mmol/L. The relation between rs964184 and plasma triglycerides was modified by body mass index in patients with one minor allele (β 0.02; (95%CI -0.04-0.09) if body mass index <24 kg/m2, β 0.17 (95%CI 0.12-0.22) if body mass index >27 kg/m2, p for interaction = 0.02). The prevalence of the metabolic syndrome increased from 52% for patients with two copies of the major allele to 62% for patients with two copies of the minor allele (p = 0.01). Rs964184 was not related with recurrent vascular events (HR 0.99; 95%CI 0.86-1.13).
  
  
  CONCLUSIONS
  The single nucleotide polymorphism rs964184 (APOA5-A4-C3-A1) is associated with elevated plasma triglycerides concentrations in patients with clinically manifest vascular disease. In carriers of one minor allele, the effect on plasma triglycerides was modified by body mass index. There is no relation between rs964184 and recurrent vascular events in these patients.
authors: Department of Vascular Medicine, University Medical Center Utrecht, Utrecht, The Netherlands.
authors: Anton P
authors: AP
authors: van de Woestijne
authors: Julius Center for Health Sciences and Primary Care, University Medical Center Utrecht, Utrecht, The Netherlands.
authors: Yolanda
authors: Y
authors: van der Graaf
authors: Julius Center for Health Sciences and Primary Care, University Medical Center Utrecht, Utrecht, The Netherlands; Department of Medical Genetics, University Medical Center Utrecht, Utrecht, The Netherlands; Broad Institute of Harvard and MIT, Cambridge, Massachusetts, United States of America; Division of Genetics, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, United States of America.
authors: Paul I W
authors: PI
authors: de Bakker
authors: Julius Center for Health Sciences and Primary Care, University Medical Center Utrecht, Utrecht, The Netherlands; Department of Cardiology, Division Heart and Lungs, University Medical Center Utrecht, Utrecht, The Netherlands; Durrer Center for Cardiogenetic Research, ICIN-Netherlands Heart Institute, Utrecht, The Netherlands.
authors: Folkert W
authors: FW
authors: Asselbergs
authors: Department of Vascular Medicine, University Medical Center Utrecht, Utrecht, The Netherlands.
authors: Wilko
authors: W
authors: Spiering
authors: Department of Vascular Medicine, University Medical Center Utrecht, Utrecht, The Netherlands.
authors: Frank L J
authors: FL
authors: Visseren
mesh_terms: D000368:Aged; D000483:Alleles; D016632:Apolipoprotein A-I / Q000097:blood / Q000235:genetics; D000072040:Apolipoprotein A-V; D053305:Apolipoprotein C-III / Q000097:blood / Q000235:genetics; D001054:Apolipoproteins A / Q000097:blood / Q000235:genetics; D015992:Body Mass Index; D008076:Cholesterol, HDL / Q000097:blood; D008078:Cholesterol, LDL / Q000097:blood; D005260:Female; D015870:Gene Expression; D005787:Gene Frequency; D006801:Humans; D015228:Hypertriglyceridemia / Q000097:blood / Q000235:genetics* / Q000473:pathology; D008297:Male; D024821:Metabolic Syndrome / Q000097:blood / Q000235:genetics* / Q000473:pathology; D008875:Middle Aged; D005810:Multigene Family; D009765:Obesity / Q000097:blood / Q000235:genetics* / Q000473:pathology; D020641:Polymorphism, Single Nucleotide; D011446:Prospective Studies; D014280:Triglycerides / Q000097:blood*; D014652:Vascular Diseases / Q000097:blood / Q000235:genetics* / Q000473:pathology
chemical_list: C437704:APOA5 protein, human; D016632:Apolipoprotein A-I; D000072040:Apolipoprotein A-V; D053305:Apolipoprotein C-III; D001054:Apolipoproteins A; D008076:Cholesterol, HDL; D008078:Cholesterol, LDL; D014280:Triglycerides; C022205:apolipoprotein A-IV