Rare Variant in Scavenger Receptor BI Raises HDL Cholesterol and Increases Risk of Coronary Heart Disease

Science. 2016 Mar 11;351(6278):1166-71. doi: 10.1126/science.aad3517.

Abstract

Scavenger receptor BI (SR-BI) is the major receptor for high-density lipoprotein (HDL) cholesterol (HDL-C). In humans, high amounts of HDL-C in plasma are associated with a lower risk of coronary heart disease (CHD). Mice that have depleted Scarb1 (SR-BI knockout mice) have markedly elevated HDL-C levels but, paradoxically, increased atherosclerosis. The impact of SR-BI on HDL metabolism and CHD risk in humans remains unclear. Through targeted sequencing of coding regions of lipid-modifying genes in 328 individuals with extremely high plasma HDL-C levels, we identified a homozygote for a loss-of-function variant, in which leucine replaces proline 376 (P376L), in SCARB1, the gene encoding SR-BI. The P376L variant impairs posttranslational processing of SR-BI and abrogates selective HDL cholesterol uptake in transfected cells, in hepatocyte-like cells derived from induced pluripotent stem cells from the homozygous subject, and in mice. Large population-based studies revealed that subjects who are heterozygous carriers of the P376L variant have significantly increased levels of plasma HDL-C. P376L carriers have a profound HDL-related phenotype and an increased risk of CHD (odds ratio = 1.79, which is statistically significant).

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aged
  • Amino Acid Substitution
  • Animals
  • Cholesterol, HDL / blood*
  • Coronary Disease / blood*
  • Coronary Disease / genetics*
  • DNA Mutational Analysis
  • Female
  • Genetic Variation
  • Heterozygote
  • Homozygote
  • Humans
  • Leucine / genetics
  • Male
  • Mice
  • Middle Aged
  • Proline / genetics
  • Protein Processing, Post-Translational
  • Risk
  • Scavenger Receptors, Class B / genetics*
  • Scavenger Receptors, Class B / metabolism

Substances

  • Cholesterol, HDL
  • SCARB1 protein, human
  • Scavenger Receptors, Class B
  • Proline
  • Leucine

Associated data

  • GEO/GSE76065
  • SRA/SRX1458096