Segregation of LIPG, CETP, and GALNT2 mutations in Caucasian families with extremely high HDL cholesterol

PLoS One. 2012;7(8):e37437. doi: 10.1371/journal.pone.0037437. Epub 2012 Aug 27.

Abstract

To date, few mutations are described to underlie highly-elevated HDLc levels in families. Here we sequenced the coding regions and adjacent sequence of the LIPG, CETP, and GALNT2 genes in 171 unrelated Dutch Caucasian probands with HDLc≥90th percentile and analyzed segregation of mutations with lipid phenotypes in family members. In these probands, mutations were most frequent in LIPG (12.9%) followed by GALNT2 (2.3%) and CETP (0.6%). A total of 6 of 10 mutations in these three genes were novel (60.0%), and mutations segregated with elevated HDLc in families. Interestingly, the LIPG mutations N396S and R476W, which usually result in elevated HDLc, were unexpectedly found in 6 probands with low HDLc (i.e., ≤10th percentile). However, 5 of these probands also carried mutations in ABCA1, LCAT, or LPL. Finally, no CETP and GALNT2 mutations were found in 136 unrelated probands with low HDLc. Taken together, we show that rare coding and splicing mutations in LIPG, CETP, and GALNT2 are enriched in persons with hyperalphalipoproteinemia and segregate with elevated HDLc in families. Moreover, LIPG mutations do not overcome low HDLc in individuals with ABCA1 and possibly LCAT and LPL mutations, indicating that LIPG affects HDLc levels downstream of these proteins.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • ATP Binding Cassette Transporter 1
  • ATP-Binding Cassette Transporters / genetics
  • Aged
  • Alternative Splicing
  • Cholesterol Ester Transfer Proteins / genetics*
  • Cholesterol, HDL / genetics*
  • Cohort Studies
  • Coronary Artery Disease / genetics
  • Family Health
  • Female
  • Humans
  • Hypercholesterolemia / genetics*
  • Lipase / genetics*
  • Male
  • Middle Aged
  • Mutation*
  • N-Acetylgalactosaminyltransferases / genetics*
  • Phenotype
  • Sequence Analysis, DNA
  • Whites

Substances

  • ABCA1 protein, human
  • ATP Binding Cassette Transporter 1
  • ATP-Binding Cassette Transporters
  • CETP protein, human
  • Cholesterol Ester Transfer Proteins
  • Cholesterol, HDL
  • N-Acetylgalactosaminyltransferases
  • polypeptide N-acetylgalactosaminyltransferase
  • LIPG protein, human
  • Lipase

Grant support

The funders, Xenon Pharmaceuticals Inc., did have a role in study design, data collection and analysis, decision to publish, and preparation of the manuscript, since some of the authors are employees of this company.