title: SCARB1 Gene Variants Are Associated With the Phenotype of Combined High High-Density Lipoprotein Cholesterol and High Lipoprotein (a).
abstract: BACKGROUND
  SR-B1 (scavenger receptor class B type 1), encoded by the gene SCARB1, is a lipoprotein receptor that binds both high-density lipoprotein (HDL) and low-density lipoprotein. We reported that SR-B1 is also a receptor for lipoprotein (a) (Lp(a)), mediating cellular uptake of Lp(a) in vitro and promoting clearance of Lp(a) in vivo. Although genetic variants in SCARB1 are associated with variations in HDL level, no SCARB1 variants affecting Lp(a) have been reported.
  
  
  RESULTS
  In an index subject with high levels of HDL cholesterol and Lp(a), SCARB1 was sequenced and demonstrated a missense mutation resulting in an S129L substitution in exon 3. To follow up, 2 cohorts (GeneSTAR, the family-based Genetic Study of Atherosclerosis Risk [n=543], and CCHS, the population-based Copenhagen City Heart Study [n=5835]) were screened for combined HDL cholesterol and Lp(a) elevations. Subjects with the extreme phenotype (HDL >80 mg/dL and Lp(a) >100 nmol/L in GeneSTAR, n=8, and >100 mg/dL in CCHS, n=9) underwent sequencing of SCARB1 exons; 15 of 18 from the combined population demonstrated genetic variants, including rare or uncommon missense or splice site mutations in 9 and homozygous synonymous variants in 6. Functional studies with 4 of the SCARB1 variants (c.386C>T, c.631-14T>G, c.4G>A, and c.631-53mC>T & c.726+55mCG>CA) showed decreased receptor function in vitro.
  
  
  CONCLUSIONS
  Human SCARB1 gene variants are associated with a new lipid phenotype, characterized by high levels of both HDL cholesterol and Lp(a). SCARB1 exonic variants often result in diminished function of translated SR-B1 via reduced binding/intracellular transport of Lp(a).
authors.affiliation: From the Department of Medicine, Johns Hopkins Medical Institutions, Baltimore, MD (X.Y., L.R.Y., D.M.B., R.A.M., L.C.B.); Lipoprotein Metabolism Section, Pulmonary and Vascular Medicine Branch, NHLBI, National Institutes of Health, Bethesda, MD (A.S., C.K., A.T.R.); and Copenhagen University Hospital, Faculty of Health Sciences, University of Copenhagen, Denmark (B.G.N., A.T.-H.).
authors.forename: Xiaoping
authors.initials: X
authors.lastname: Yang
authors.affiliation: From the Department of Medicine, Johns Hopkins Medical Institutions, Baltimore, MD (X.Y., L.R.Y., D.M.B., R.A.M., L.C.B.); Lipoprotein Metabolism Section, Pulmonary and Vascular Medicine Branch, NHLBI, National Institutes of Health, Bethesda, MD (A.S., C.K., A.T.R.); and Copenhagen University Hospital, Faculty of Health Sciences, University of Copenhagen, Denmark (B.G.N., A.T.-H.).
authors.forename: Amar
authors.initials: A
authors.lastname: Sethi
authors.affiliation: From the Department of Medicine, Johns Hopkins Medical Institutions, Baltimore, MD (X.Y., L.R.Y., D.M.B., R.A.M., L.C.B.); Lipoprotein Metabolism Section, Pulmonary and Vascular Medicine Branch, NHLBI, National Institutes of Health, Bethesda, MD (A.S., C.K., A.T.R.); and Copenhagen University Hospital, Faculty of Health Sciences, University of Copenhagen, Denmark (B.G.N., A.T.-H.).
authors.forename: Lisa R
authors.initials: LR
authors.lastname: Yanek
authors.affiliation: From the Department of Medicine, Johns Hopkins Medical Institutions, Baltimore, MD (X.Y., L.R.Y., D.M.B., R.A.M., L.C.B.); Lipoprotein Metabolism Section, Pulmonary and Vascular Medicine Branch, NHLBI, National Institutes of Health, Bethesda, MD (A.S., C.K., A.T.R.); and Copenhagen University Hospital, Faculty of Health Sciences, University of Copenhagen, Denmark (B.G.N., A.T.-H.).
authors.forename: Cathy
authors.initials: C
authors.lastname: Knapper
authors.affiliation: From the Department of Medicine, Johns Hopkins Medical Institutions, Baltimore, MD (X.Y., L.R.Y., D.M.B., R.A.M., L.C.B.); Lipoprotein Metabolism Section, Pulmonary and Vascular Medicine Branch, NHLBI, National Institutes of Health, Bethesda, MD (A.S., C.K., A.T.R.); and Copenhagen University Hospital, Faculty of Health Sciences, University of Copenhagen, Denmark (B.G.N., A.T.-H.).
authors.forename: Børge G
authors.initials: BG
authors.lastname: Nordestgaard
authors.affiliation: From the Department of Medicine, Johns Hopkins Medical Institutions, Baltimore, MD (X.Y., L.R.Y., D.M.B., R.A.M., L.C.B.); Lipoprotein Metabolism Section, Pulmonary and Vascular Medicine Branch, NHLBI, National Institutes of Health, Bethesda, MD (A.S., C.K., A.T.R.); and Copenhagen University Hospital, Faculty of Health Sciences, University of Copenhagen, Denmark (B.G.N., A.T.-H.).
authors.forename: Anne
authors.initials: A
authors.lastname: Tybjærg-Hansen
authors.affiliation: From the Department of Medicine, Johns Hopkins Medical Institutions, Baltimore, MD (X.Y., L.R.Y., D.M.B., R.A.M., L.C.B.); Lipoprotein Metabolism Section, Pulmonary and Vascular Medicine Branch, NHLBI, National Institutes of Health, Bethesda, MD (A.S., C.K., A.T.R.); and Copenhagen University Hospital, Faculty of Health Sciences, University of Copenhagen, Denmark (B.G.N., A.T.-H.).
authors.forename: Diane M
authors.initials: DM
authors.lastname: Becker
authors.affiliation: From the Department of Medicine, Johns Hopkins Medical Institutions, Baltimore, MD (X.Y., L.R.Y., D.M.B., R.A.M., L.C.B.); Lipoprotein Metabolism Section, Pulmonary and Vascular Medicine Branch, NHLBI, National Institutes of Health, Bethesda, MD (A.S., C.K., A.T.R.); and Copenhagen University Hospital, Faculty of Health Sciences, University of Copenhagen, Denmark (B.G.N., A.T.-H.).
authors.forename: Rasika A
authors.initials: RA
authors.lastname: Mathias
authors.affiliation: From the Department of Medicine, Johns Hopkins Medical Institutions, Baltimore, MD (X.Y., L.R.Y., D.M.B., R.A.M., L.C.B.); Lipoprotein Metabolism Section, Pulmonary and Vascular Medicine Branch, NHLBI, National Institutes of Health, Bethesda, MD (A.S., C.K., A.T.R.); and Copenhagen University Hospital, Faculty of Health Sciences, University of Copenhagen, Denmark (B.G.N., A.T.-H.).
authors.forename: Alan T
authors.initials: AT
authors.lastname: Remaley
authors.affiliation: From the Department of Medicine, Johns Hopkins Medical Institutions, Baltimore, MD (X.Y., L.R.Y., D.M.B., R.A.M., L.C.B.); Lipoprotein Metabolism Section, Pulmonary and Vascular Medicine Branch, NHLBI, National Institutes of Health, Bethesda, MD (A.S., C.K., A.T.R.); and Copenhagen University Hospital, Faculty of Health Sciences, University of Copenhagen, Denmark (B.G.N., A.T.-H.). lbecker@jhmi.edu.
authors.forename: Lewis C
authors.initials: LC
authors.lastname: Becker
mesh_terms: D054058:Acute Coronary Syndrome / Q000097:blood* / Q000175:diagnosis / Q000453:epidemiology / Q000235:genetics*; D000328:Adult; D000368:Aged; D019943:Amino Acid Substitution; D050197:Atherosclerosis / Q000097:blood* / Q000175:diagnosis / Q000453:epidemiology / Q000235:genetics*; D015415:Biomarkers / Q000097:blood; D016022:Case-Control Studies; D008076:Cholesterol, HDL / Q000097:blood*; D003718:Denmark / Q000453:epidemiology; D050171:Dyslipidemias / Q000097:blood* / Q000175:diagnosis / Q000453:epidemiology / Q000235:genetics*; D005091:Exons; D005260:Female; D056726:Genetic Association Studies; D020022:Genetic Predisposition to Disease; D057809:HEK293 Cells; D006720:Homozygote; D006801:Humans; D017270:Lipoprotein(a) / Q000097:blood*; D008297:Male; D008875:Middle Aged; D020125:Mutation, Missense; D010641:Phenotype; D015995:Prevalence; D011446:Prospective Studies; D012307:Risk Factors; D051122:Scavenger Receptors, Class B / Q000235:genetics* / Q000378:metabolism; D014162:Transfection; D014481:United States / Q000453:epidemiology; D015854:Up-Regulation
chemical_list: D015415:Biomarkers; D008076:Cholesterol, HDL; D017270:Lipoprotein(a); C495124:SCARB1 protein, human; D051122:Scavenger Receptors, Class B
keywords: Copenhagen City Heart Study; GeneSTAR; SCARB1 gene variants; SR-B1 receptor; high-density lipoprotein cholesterol; lipids and lipoproteins; lipoprotein (a)