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

• Published in: Science (American Association for the Advancement of Science) Vol. 351; no. 6278; pp. 1166 - 1171
• Main Authors: Zanoni, Paolo, Khetarpal, Sumeet A., Larach, Daniel B., Hancock-Cerutti, William F., Millar, John S., Cuchel, Marina, DerOhannessian, Stephanie, Kontush, Anatol, Surendran, Praveen, Saleheen, Danish, Trompet, Stella, Jukema, J. Wouter, De Craen, Anton, Deloukas, Panos, Sattar, Naveed, Ford, Ian, Packard, Chris, Majumder, Abdullah al Shafi, Alam, Dewan S., Di Angelantonio, Emanuele, Abecasis, Goncalo, Chowdhury, Rajiv, Erdmann, Jeanette, Nordestgaard, Børge G., Nielsen, Sune F., Tybjærg-Hansen, Anne, Schmidt, Ruth Frikke, Kuulasmaa, Kari, Liu, Dajiang J., Perola, Markus, Blankenberg, Stefan, Salomaa, Veikko, Männistö, Satu, Amouyel, Philippe, Arveiler, Dominique, Ferrieres, Jean, Müller-Nurasyid, Martina, Ferrario, Marco, Kee, Frank, Willer, Cristen J., Samani, Nilesh, Schunkert, Heribert, Butterworth, Adam S., Howson, Joanna M. M., Peloso, Gina M., Stitziel, Nathan O., Danesh, John, Kathiresan, Sekar, Rader, Daniel J.
• Format: Journal Article
• Language: English
• Published: United States American Association for the Advancement of Science 11.03.2016; The American Association for the Advancement of Science; American Association for the Advancement of Science (AAAS)
• Subjects: Aged; Amino Acid Substitution; Animals; Cardiovascular disease; Cardiovascular diseases; Cholesterol; Cholesterol, HDL - blood; Coding; Coronary Disease - blood; Coronary Disease - genetics; DNA Mutational Analysis; Female; Genetic Variation; Genotype & phenotype; Heart Disorders; Heterozygote; Homozygote; Humans; Leucine - genetics; Life Sciences; Lipoproteins; Male; Mice; Middle Aged; Population studies; Proline - genetics; Protein Processing, Post-Translational; Risk; Risk factors; Scavenger Receptors, Class B - genetics; Scavenger Receptors, Class B - metabolism; Stem cells
• ISSN: 0036-8075; 1095-9203
• DOI: 10.1126/science.aad3517

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).