Resequencing genomic DNA of patients with severe hypertriglyceridemia (MIM 144650)

Arterioscler Thromb Vasc Biol. 2007 Nov;27(11):2450-5. doi: 10.1161/ATVBAHA.107.150680. Epub 2007 Aug 23.

Abstract

Objective: The genetic determinants of severe hypertriglyceridemia (HTG; MIM 144650) in adults are poorly defined. We therefore resequenced 3 candidate genes, namely LPL, APOC2, and APOA5, to search for accumulation of missense mutations in patients with severe HTG compared with normolipidemic subjects.

Methods and results: We resequenced >2 million base pairs of genomic DNA from 110 nondiabetic patients with severe HTG and determined the prevalence of coding sequence variants compared with 472 age- and sex-matched normolipidemic controls. We found: (1) heterozygous mutations (LPL p.Q-12E >11X, p.D25H, p.W86R, p.G188E, p.I194T and p.P207L; APOC2 p.K19T and IVS2-30G>A) in 10.0% of severe HTG patients compared with 0.2% of controls (carrier odds ratio [OR] 52, 95% confidence interval [CI] 8.6 to 319); and (2) an association of the APOA5 p.S19W missense variant with severe HTG (carrier OR 5.5 95% CI 3.3 to 9.1). Furthermore, either rare mutations or the APOA5 p.S19W variant were found in 41.8% of HTG subjects compared with 8.9% of controls (carrier OR 7.4, 95% CI 4.5 to 12.0). Also, heterozygotes for rare mutations had a significantly reduced plasma triglyceride response to fibrate monotherapy.

Conclusions: Both common and rare DNA variants in candidate genes were found in a substantial proportion of severe HTG patients. The findings underscore the value of candidate gene resequencing to understand the genetic contribution in complex lipoprotein and metabolic disorders.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Apolipoprotein A-V
  • Apolipoprotein C-II / genetics*
  • Apolipoproteins A / genetics*
  • Case-Control Studies
  • Clofibric Acid / pharmacology
  • Female
  • Gene Frequency
  • Humans
  • Hyperlipoproteinemia Type IV / drug therapy
  • Hyperlipoproteinemia Type IV / genetics*
  • Hypolipidemic Agents / pharmacology
  • Lipoprotein Lipase / genetics*
  • Male
  • Middle Aged
  • Mutation, Missense
  • Polymorphism, Single Nucleotide / genetics
  • White People

Substances

  • APOA5 protein, human
  • Apolipoprotein A-V
  • Apolipoprotein C-II
  • Apolipoproteins A
  • Hypolipidemic Agents
  • Clofibric Acid
  • Lipoprotein Lipase