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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).

Original publication

DOI

10.1126/science.aad3517

Type

Journal article

Journal

Science (New York, N.Y.)

Publication Date

03/2016

Volume

351

Pages

1166 - 1171

Addresses

Departments of Genetics and Medicine, Division of Translational Medicine and Human Genetics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.

Keywords

CHD Exome+ Consortium, CARDIoGRAM Exome Consortium, Global Lipids Genetics Consortium, Animals, Humans, Mice, Coronary Disease, Leucine, Proline, Risk, Amino Acid Substitution, DNA Mutational Analysis, Protein Processing, Post-Translational, Heterozygote, Homozygote, Aged, Middle Aged, Female, Male, Scavenger Receptors, Class B, Cholesterol, HDL, Genetic Variation