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].…”

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.…”

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.…”