Rare variant in scavenger receptor BI raises HDL cholesterol and increases risk of coronary heart disease

Paolo Zanoni, Sumeet A. Khetarpal, Daniel B Larach, William F Hancock-Cerutti, John S. Millar, Marina Cuchel, Stephanie DerOhannessian, Anatol Kontush, Praveen Surendran, Danish Saleheen, Stella Trompet, J. Wouter Jukema, Anton J Mde Craen, Panos Deloukas, Naveed Sattar, Ian Ford, Chris J. Packard, Abdullah al Shafi Majumder, Dewan S Alam, Emanuele Di AngelantonioGoncalo R. Abecasis, Rajiv Chowdhury, Jeanette Erdmann, Børge G. Nordestgaard, Sune F. Nielsen, Anne Tybjærg-Hansen, Ruth Frikke Schmidt, Kari Kuulasmaa, Dajiang J Liu, Markus Perola, Stefan Blankenberg, Veikko Salomaa, Satu Männistö, Philippe Amouyel, Dominique Arveiler, Jean Ferrieres, Martina Müller-Nurasyid, Marco Ferrario, Frank Kee, Cristen J. Willer, Nilesh J. Samani, Heribert Schunkert, Adam S. Butterworth, Joanna M M Howson, Gina M Peloso, Nathan O. Stitziel, John Danesh, Sekar Kathiresan, Daniel J. Rader, CHD Exome+ Consortium, Elena Tremoli

Research output: Contribution to journalArticlepeer-review


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).

Original languageEnglish
Pages (from-to)1166-71
Number of pages6
Issue number6278
Publication statusPublished - Mar 11 2016


  • Aged
  • Amino Acid Substitution
  • Animals
  • Cholesterol, HDL
  • Coronary Disease
  • DNA Mutational Analysis
  • Female
  • Genetic Variation
  • Heterozygote
  • Homozygote
  • Humans
  • Leucine
  • Male
  • Mice
  • Middle Aged
  • Proline
  • Protein Processing, Post-Translational
  • Risk
  • Scavenger Receptors, Class B
  • Journal Article
  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't


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