Abstract 16954: SCARB1 Gene Variants are Associated With the New Lipid Phenotype of Combined High HDL-C and Lp(a)

Abstract

Introduction: Although lipoprotein(a) (Lp(a)) is atherogenic, little is known about how it is transported from the plasma. Scavenger receptor class B type 1 (SR-B1), encoded by the gene SCARB1, binds high density lipoproteins (HDL). Recently we found that SR-B1 is also a receptor for Lp(a), mediates cellular uptake of Lp(a) in vitro, and promotes clearance of Lp(a) in vivo in mice. Genetic variants in SCARB1 have been associated with HDL level in humans, but no SCARB1 variants affecting Lp(a) have been reported. We hypothesized that loss of function mutations in SCARB1 would be associated with a phenotype of combined high HDL-C and Lp(a). Methods and Results: An index subject was identified in the NIH Lipid Clinic with high levels of both HDL-C and Lp(a). SCARB1 was sequenced and demonstrated a missense mutation at c.386 resulting in an S129L substitution in exon 3. To follow up on this finding, two cohorts of subjects (n=543 in the Genetic Study of Atherosclerosis Risk (GeneSTAR) and n=5907 in the Copenhagen City Heart Study) were screened for combined elevations of HDL-C and Lp(a). Subjects having 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 all SCARB1 exons and splice junctions; 15 from the combined population of 18 were found to have variants predicted or demonstrated to have reduced function of the translated protein. Functional studies showed that 4 of the SCARB1 variants (c.386C>T; c.631-14T>G, c.4G>A and c.631-53mC>T & c.726+55mCG>CA, all heterozygous) had decreased receptor function in vitro, and the latter two were novel and not previously reported. Six of the subjects were homozygous for a common synonymous SCARB1 polymorphism (c.1050C>T) which has been reported to be associated with reduced protein expression. Conclusion: Human SCARB1 gene variants are associated with a new lipid phenotype, characterized by increases in both HDL-C and Lp(a). We demonstrate that SCARB1 exonic variants often result in diminished function of the translated SR-B1 lipid receptor with reduced binding/intracellular transport of Lp(a).