Xiaoping Yang1, Amar Sethi1, Lisa R Yanek1, Cathy Knapper1, Børge G Nordestgaard1, Anne Tybjærg-Hansen1, Diane M Becker1, Rasika A Mathias1, Alan T Remaley1, Lewis C Becker2. 1. 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.). 2. 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.
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. METHODS AND 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).
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. METHODS AND 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:HumanSCARB1 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: Sotirios Tsimikas; Sergio Fazio; Keith C Ferdinand; Henry N Ginsberg; Marlys L Koschinsky; Santica M Marcovina; Patrick M Moriarty; Daniel J Rader; Alan T Remaley; Gissette Reyes-Soffer; Raul D Santos; George Thanassoulis; Joseph L Witztum; Simhan Danthi; Michelle Olive; Lijuan Liu Journal: J Am Coll Cardiol Date: 2018-01-16 Impact factor: 24.094
Authors: Huan Tao; Patricia G Yancey; John L Blakemore; Youmin Zhang; Lei Ding; W Gray Jerome; Jonathan D Brown; Kasey C Vickers; MacRae F Linton Journal: J Clin Invest Date: 2021-04-01 Impact factor: 14.808