title: 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).
authors.affiliation: Departments of Genetics and Medicine, Division of Translational Medicine and Human Genetics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
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authors.affiliation: Departments of Genetics and Medicine, Division of Translational Medicine and Human Genetics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
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authors.initials: SA
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authors.affiliation: Departments of Genetics and Medicine, Division of Translational Medicine and Human Genetics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
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authors.affiliation: Departments of Genetics and Medicine, Division of Translational Medicine and Human Genetics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA. INSERM UMR 1166 ICAN, Université Pierre et Marie Curie Paris 6, Hôpital de la Pitié, Paris, France.
authors.forename: William F
authors.initials: WF
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authors.affiliation: Departments of Genetics and Medicine, Division of Translational Medicine and Human Genetics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
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authors.affiliation: Departments of Genetics and Medicine, Division of Translational Medicine and Human Genetics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
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authors.affiliation: Departments of Genetics and Medicine, Division of Translational Medicine and Human Genetics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
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authors.lastname: DerOhannessian
authors.affiliation: INSERM UMR 1166 ICAN, Université Pierre et Marie Curie Paris 6, Hôpital de la Pitié, Paris, France.
authors.forename: Anatol
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authors.affiliation: Cardiovascular Epidemiology Unit, Department of Public Health and Primary Care, University of Cambridge, Cambridge, UK.
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authors.affiliation: Cardiovascular Epidemiology Unit, Department of Public Health and Primary Care, University of Cambridge, Cambridge, UK. Department of Biostatistics and Epidemiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA. Centre for Non-Communicable Diseases, Karachi, Pakistan.
authors.forename: Danish
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authors.affiliation: Department of Gerontology and Geriatrics, Leiden University Medical Center, Leiden, Netherlands.
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authors.affiliation: Wellcome Trust Sanger Institute, Genome Campus, Hinxton, UK.
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authors.affiliation: Department of Clinical Biochemistry, Herlev Hospital, Copenhagen University Hospital, Herlev, Denmark.
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authors.affiliation: Department of Clinical Biochemistry, Herlev Hospital, Copenhagen University Hospital, Herlev, Denmark.
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authors.affiliation: Departments of Genetics and Medicine, Division of Translational Medicine and Human Genetics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA. rader@mail.med.upenn.edu.
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mesh_terms: D000368:Aged; D019943:Amino Acid Substitution; D000818:Animals; D008076:Cholesterol, HDL / Q000097:blood*; D003327:Coronary Disease / Q000097:blood* / Q000235:genetics*; D004252:DNA Mutational Analysis; D005260:Female; D014644:Genetic Variation; D006579:Heterozygote; D006720:Homozygote; D006801:Humans; D007930:Leucine / Q000235:genetics; D008297:Male; D051379:Mice; D008875:Middle Aged; D011392:Proline / Q000235:genetics; D011499:Protein Processing, Post-Translational; D012306:Risk; D051122:Scavenger Receptors, Class B / Q000235:genetics* / Q000378:metabolism
chemical_list: D008076:Cholesterol, HDL; C495124:SCARB1 protein, human; D051122:Scavenger Receptors, Class B; D011392:Proline; D007930:Leucine