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

Abstract

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).

Bioinformatic analysis of endogenous and exogenous small RNAs on lipoproteins

“…Loss-of-function variants in human SCARB1 (SR-BI) were associated with increased in circulating HDL-C levels [37]. Likewise, Scarb1 mutations in mice also resulted in increased HDL-C levels [38].…”

Causal Effect of Plasminogen Activator Inhibitor Type 1 on Coronary Heart Disease

“…While observational studies consistently report a protective association of high blood HDL‐C levels with lower CHD risk, previous MR studies show that HDL‐C is not a causal risk factor for CHD 48, 57. Furthermore, a recent study has reported that a loss‐of‐function variant in scavenger receptor BI ( SRB1 ) raises HDL‐C and increases CHD risk 58. Further studies are warranted to understand potential biological mechanisms of a PAI‐1 effect on HDL‐C and whether HDL‐C is an intermediary between the PAI‐1 and CHD associations.…”

Regulation of lipid metabolism by obeticholic acid in hyperlipidemic hamsters

“…Furthermore, additional studies in mice have established an inverse relationship between SR-BI expression and atherosclerosis, primarily via the mechanism of promoting reverse cholesterol transport (12,13). The impacts of SR-BI on human HDL metabolism were demonstrated by the identification of a loss-of-function SR-BI variant that is associated with an extremely high plasma HDL-C level (9) and identification of human SR-BI variants (14,15).…”

“…SR-BI is a physiologically relevant HDL receptor and plays distinct roles in plasma HDL metabolism and transhepatic cholesterol efflux in preclinical animal models and in humans (5)(6)(7)(8)(9). SR-BI mediates selective uptake of cholesterol ester from HDL particles into cells.…”