Journal
SCIENCE
Volume 351, Issue 6278, Pages 1166-1171Publisher
AMER ASSOC ADVANCEMENT SCIENCE
DOI: 10.1126/science.aad3517
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Funding
- National Center for Research Resources [TL1RR024133]
- National Center for Advancing Translational Sciences of the NIH [TL1R000138]
- Doris Duke Charitable Foundation
- MRC [MR/L003120/1, MR/K013351/1, G0801566, MR/N003284/1, G0800270] Funding Source: UKRI
- British Heart Foundation [RG/13/13/30194, RG/08/014/24067, RG/14/5/30893, PG/08/094/26019] Funding Source: researchfish
- Medical Research Council [G0800270, MR/K013351/1, G0801566, G0401527, MR/L003120/1, MR/N003284/1] Funding Source: researchfish
- National Institute for Health Research [NF-SI-0514-10027, NF-SI-0611-10170, NF-SI-0512-10165, NF-SI-0512-10114, NF-SI-0507-10228] Funding Source: researchfish
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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).
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