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 De Craen, Panos Deloukas, Naveed Sattar, Ian Ford, Chris Packard, Abdullah Al Shafi Majumder, Dewan S. Alam, Emanuele Di AngelantonioGoncalo Abecasis, Rajiv Chowdhury, Jeanette Erdmann, Børge G. Nordestgaard, Sune F. Nielsen, Anne Tybjærg-Hansen, Frikke Schmidt Ruth Frikke Schmidt, Kari Kuulasmaa, Dajiang J. Liu, Markus Perola, Stefan Blankenberg, Veikko Salomaa, Satu Männistö, Philippe Amouyel, Dominique Arveiler, Jean Ferrieres, Martina Möller-Nurasyid, Marco Ferrario, Frank Kee, Cristen J. Willer, Nilesh Samani, Heribert Schunkert, Adam S. Butterworth, Joanna M.M. Howson, Gina M. Peloso, Nathan O. Stitziel, John Danesh, Sekar Kathiresan, Daniel J. Rader*

*Corresponding author for this work
114 Citations (Scopus)


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 lossof-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
Issue number6278
Pages (from-to)1166-1171
Number of pages6
Publication statusPublished - 11.03.2016


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