Details

Autor(en) / Beteiligte

• 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.

Titel

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

Ist Teil von

• Science (American Association for the Advancement of Science), 2016-03, Vol.351 (6278), p.1166-1171

Ort / Verlag

United States: American Association for the Advancement of Science

Erscheinungsjahr

2016

Quelle

Science Online_科学在线

Beschreibungen/Notizen

• 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).