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Scavenger Receptor Class B Type I Protein as an Independent Predictor of High-Density Lipoprotein Cholesterol Levels in Subjects with Hyperalphalipoproteinemia

Department of Medicine (M.W., E.G., A.K., A.R.), Division of Endocrinology and Metabolism, The Johns Hopkins University School of Medicine, Baltimore, Maryland 21224; Department of Medicine (T.I.P.), Division of Endocrinology, Metabolism and Nutrition, University of Maryland, Baltimore, Maryland 21215-5271; Human Nutrition Research Center on Aging at Tufts University (B.A.), Boston, Massachusetts 02111; and University of Kentucky (A.J.), Lexington, Kentucky 40507

Address all correspondence and requests for reprints to: Dr. Annabelle Rodriguez, The Johns Hopkins University School of Medicine, Bayview Medical Center, 5200 Eastern Avenue, Baltimore, Maryland 21224. E-mail: arodrig5{at}jhmi.edu.

Context: In mice, scavenger receptor class B, type I (SR-BI) receptor protein deficiency is associated with elevated high-density lipoprotein (HDL)-cholesterol (HDL-C) levels.

Objective: Our objective was to determine the relationship between SR-BI protein and HDL-C levels in humans.

Design: This was a prospective study of adults with hyperalphalipoproteinemia. Fasting blood was obtained for lipid and lipoprotein measurement, genomic DNA, and monocyte-derived macrophages. SR-BI protein levels were measured by Western blots, and SR-BI activity was measured by cholesteryl ester (CE) uptake of each donor’s radiolabeled HDL with their monocyte-derived macrophages, or by degradation and specific cell association of dual-labeled HDL in vitro.

Setting: The study was performed in a tertiary university teaching hospital.

Results: The mean age was 57.2 ± 10.9 yr (n = 65). SR-BI protein levels were inversely associated with HDL-C levels (P < 0.002), HDL particle size (P < 0.05), and positively associated with CE uptake (P < 0.004); there was no association with plasma apolipoprotein levels. SR-BI protein levels (P = 0.01) were independent predictors of HDL-C levels. Subjects who were carriers of the A allele for the rs4238001 (glycine to serine at position 2) polymorphism [single nucleotide polymorphism (SNP)] had lower SR-BI protein levels (P = 0.01), whereas carriers of the C allele for the rs2278986 SNP also had lower SR-BI protein levels (P = 0.02). Body mass index (P = 0.05), rs4238001 (P = 0.01), and rs2278986 (P = 0.01) SNPs were independent predictors of SR-BI protein levels. In vitro studies of murine macrophages stably expressing the glycine to serine at position 2 SNP showed less degradation (P < 0.0004) and specific cell association (P < 0.0004) of [¹²⁵I, ³H]-CE-labeled HDL.

Conclusions: SR-BI protein has an independent effect on HDL-C levels in women with hyperalphalipoproteinemia. Two SNPs were significantly associated with lower SR-BI protein levels.