Identification of four novel genes contributing to familial elevated plasma HDL cholesterol in humans

Roshni R. Singaraja, Ian Tietjen, G. Kees Hovingh, Patrick L. Franchini, Chris Radomski, Kenny Wong, Margaret VanHeek, Ioannis M. Stylianou, Linus Lin, Liangsu Wang, Lyndon Mitnaul, Brian Hubbard, Michael Winther, Maryanne Mattice, Annick Legendre, Robin Sherrington, John J. Kastelein, Karen Akinsanya, Andrew Plump, Michael R. Hayden

Research output: Contribution to journalArticlepeer-review

25 Scopus citations

Abstract

While genetic determinants strongly influence HDL cholesterol (HDLc) levels, most genetic causes underlying variation in HDLc remain unknown. We aimed to identify novel rare mutations with large effects in candidate genes contributing to extreme HDLc in humans, utilizing family-based Mendelian genetics. We performed next-generation sequencing of 456 candidate HDLc-regulating genes in 200 unrelated probands with extremely low (≤10th percentile) or high (≥90th percentile) HDLc. Probands were excluded if known mutations existed in the established HDLc-regulating genes ABCA1, APOA1, LCAT, cholesteryl ester transfer protein (CETP), endothelial lipase (LIPG), and UDP-N-acetyl-α-D-galactosamine:polypeptide N- acetylgalactosaminyltransferase 2 (GALNT2). We identified 93 novel coding or splice-site variants in 72 candidate genes. Each variant was genotyped in the proband's family. Family-based association analyses were performed for variants with sufficient power to detect significance at P < 0.05 with a total of 627 family members being assessed. Mutations in the genes glucokinase regulatory protein (GCKR), RNase L (RNASEL), leukocyte immunoglobulin-like receptor 3 (LILRA3), and dynein axonemal heavy chain 10 (DNAH10) segregated with elevated HDLc levels in families, while no mutations associated with low HDLc. Taken together, we have identified mutations in four novel genes that may play a role in regulating HDLc levels in humans.

Original languageEnglish
Pages (from-to)1693-1701
Number of pages9
JournalJournal of Lipid Research
Volume55
Issue number8
DOIs
StatePublished - Aug 2014

Keywords

  • Genetics
  • High density lipoprotein
  • High density lipoprotein metabolism
  • Lipids
  • Lipoproteins
  • Mendelian genetics

Fingerprint

Dive into the research topics of 'Identification of four novel genes contributing to familial elevated plasma HDL cholesterol in humans'. Together they form a unique fingerprint.

Cite this