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

PLoS One. 2014 Jun 30;9(6):e101082. doi: 10.1371/journal.pone.0101082. eCollection 2014.

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).

Conclusion: 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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aged
  • Alleles
  • Apolipoprotein A-I / blood
  • Apolipoprotein A-I / genetics
  • Apolipoprotein A-V
  • Apolipoprotein C-III / blood
  • Apolipoprotein C-III / genetics
  • Apolipoproteins A / blood
  • Apolipoproteins A / genetics
  • Body Mass Index
  • Cholesterol, HDL / blood
  • Cholesterol, LDL / blood
  • Female
  • Gene Expression
  • Gene Frequency
  • Humans
  • Hypertriglyceridemia / blood
  • Hypertriglyceridemia / genetics*
  • Hypertriglyceridemia / pathology
  • Male
  • Metabolic Syndrome / blood
  • Metabolic Syndrome / genetics*
  • Metabolic Syndrome / pathology
  • Middle Aged
  • Multigene Family
  • Obesity / blood
  • Obesity / genetics*
  • Obesity / pathology
  • Polymorphism, Single Nucleotide*
  • Prospective Studies
  • Triglycerides / blood*
  • Vascular Diseases / blood
  • Vascular Diseases / genetics*
  • Vascular Diseases / pathology

Substances

  • APOA5 protein, human
  • Apolipoprotein A-I
  • Apolipoprotein A-V
  • Apolipoprotein C-III
  • Apolipoproteins A
  • Cholesterol, HDL
  • Cholesterol, LDL
  • Triglycerides
  • apolipoprotein A-IV

Grants and funding

This study was made possible, in part, by a Complementation Grant to P.I.W.d.B. from the Biobanking and Biomolecular Resources Research Infrastructure in the Netherlands (BBMRI-NL) (http://www.bbmri.nl/). F.W.A. is supported by a clinical fellowship from the Netherlands Organisation for Health Research and Development (ZonMw grant 90700342)(www.zonmw.nl). The Secondary Manifestations of Arterial Disease Study was financially supported by a grant of the University Medical Center Utrecht, The Netherlands (www.umcutrecht.nl). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.