Rare variant in scavenger receptor BI raises HDL cholesterol and increases risk of coronary heart disease.
Zanoni P., Khetarpal SA., Larach DB., Hancock-Cerutti WF., Millar JS., Cuchel M., DerOhannessian S., Kontush A., Surendran P., Saleheen D., Trompet S., Jukema JW., De Craen A., Deloukas P., Sattar N., Ford I., Packard C., Majumder AAS., Alam DS., Di Angelantonio E., Abecasis G., Chowdhury R., Erdmann J., Nordestgaard BG., Nielsen SF., Tybjærg-Hansen A., Schmidt RF., Kuulasmaa K., Liu DJ., Perola M., Blankenberg S., Salomaa V., Männistö S., Amouyel P., Arveiler D., Ferrieres J., Müller-Nurasyid M., Ferrario M., Kee F., Willer CJ., Samani N., Schunkert H., Butterworth AS., Howson JMM., Peloso GM., Stitziel NO., Danesh J., Kathiresan S., Rader DJ., CHD Exome+ Consortium None., CARDIoGRAM Exome Consortium None., Global Lipids Genetics Consortium None.
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).