Rare variant in scavenger receptor BI raises HDL cholesterol and increases risk of coronary heart disease
Publikation: Bidrag til tidsskrift › Tidsskriftartikel › Forskning › fagfællebedømt
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 Jm de Craen, Panos Deloukas, Naveed Sattar, Ian Ford, Chris Packard, Abdullah al Shafi Majumder, Dewan S Alam, Emanuele Di Angelantonio & 32 andre
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).
|Tidsskrift||Science (New York, N.Y.)|
|Status||Udgivet - 11 mar. 2016|