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Rare variant in scavenger receptor BI raises HDL cholesterol and increases risk of coronary heart disease.
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2016 (English)In: Science, ISSN 0036-8075, E-ISSN 1095-9203, Vol. 351, no 6278Article in journal (Refereed) Published
Abstract [en]

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).

Place, publisher, year, edition, pages
2016. Vol. 351, no 6278
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URN: urn:nbn:se:umu:diva-122129DOI: 10.1126/science.aad3517PubMedID: 26965621OAI: oai:DiVA.org:umu-122129DiVA: diva2:937424
Available from: 2016-06-15 Created: 2016-06-15 Last updated: 2016-06-15

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Hallmans, Göran
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Nutritional ResearchDepartment of Biobank Research
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