Abstract
BackgroundPrevious studies in mice and humans have implicated the lipoprotein receptor SCARB1 in association with atherosclerosis and lipid levels. In the current study, we sought to examine association of SCARB1 missense single nucleotide polymorphism (SNP) rs4238001 with incident coronary heart disease (CHD).Methods and ResultsGenotypes for rs4238001 were imputed for 2,319 White, 1,570 African American, and 1,292 Hispanic-American MESA participants using the 1,000 Genomes reference set. Cox proportional hazards models were used to determine association of rs4238001 with incident CHD, with adjustments for age, sex, study site, principal components of ancestry, body mass index, diabetes status, serum creatinine, lipid levels, hypertension status, education and smoking exposure. Meta-analysis across race/ethnic groups within MESA showed statistically significant association of the T allele with higher risk of CHD under a consistent and formally adjudicated definition of CHD events in this contemporary cohort study (hazard ratio [HR]=1.49, 95% CI [1.04, 2.14], P = 0.028). Analyses combining MESA with additional population-based cohorts expanded our samples in Whites (total n = 11,957 with 871 CHD events) and African Americans (total n = 5,962 with 355 CHD events) and confirmed an increased risk of CHD overall (HR of 1.19 with 95% CI [1.04, 1.37], P = 0.013), in African Americans (HR of 1.49 with 95% CI [1.07, 2.06], P = 0.019), in males (HR of 1.29 with 95% CI [1.08, 1.54], P = 4.91x10-3) and in White males (HR of 1.24 with 95% CI [1.03, 1.51], P = 0.026).Conclusion SCARB1 missense rs4238001 is statistically significantly associated with incident CHD across a large population of multiple race/ethnic groups.
Highlights
Deficiency of the scavenger receptor class B type I (SR-BI) in mice is significantly associated with abnormal lipoprotein composition and accelerated atherosclerosis in the background of ApoE-/- or ldlr-/, among other phenotypic changes [1,2,3,4,5]
Analyses combining Multi-Ethnic Study of Atherosclerosis (MESA) with additional population-based cohorts expanded our samples in Whites and African Americans and confirmed an increased risk of coronary heart disease (CHD) overall (HR of 1.19 with 95% CI [1.04, 1.37], P = 0.013), in African
We focus the current investigation on the single single nucleotide polymorphisms (SNPs) rs4238001, as it was the only common SCARB1 missense variant reported in the Exome Variant Server with minor allele frequency (MAF) > 5%
Summary
Deficiency of the scavenger receptor class B type I (SR-BI) in mice is significantly associated with abnormal lipoprotein composition (especially LDL-cholesterol [LDL-C] and HDL-cholesterol [HDL-C]) and accelerated atherosclerosis in the background of ApoE-/- or ldlr-/-, among other phenotypic changes [1,2,3,4,5]. Braun et al [7] subsequently reported the association of SR-BI deficiency in mice with early onset atherosclerotic disease. Many of these phenotypic changes have been identified in humans who are carriers of certain SCARB1 single nucleotide polymorphisms (SNPs). In one of the earlier observations, Acton et al [8] reported that the missense rs4238001 variant, which is a nonsynonymous coding SNP in exon 1 that encodes an amino acid change at the second position from glycine to serine (p.Gly2Ser), was significantly associated with higher levels of HDL-C and lower levels of LDL-C in males, with no association observed in females. West et al [9] showed that SR-BI protein expression was an independent predictor of HDL-C levels in subjects with hyperalphalipoproteinemia. We sought to examine association of SCARB1 missense single nucleotide polymorphism (SNP) rs4238001 with incident coronary heart disease (CHD)
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