Dataset Information

Impact of genetic variants in human scavenger receptor class B type I (SCARB1) on plasma lipid traits.

ABSTRACT: BACKGROUND:Scavenger receptor class B type 1 (SCARB1) plays an important role in high-density lipoprotein cholesterol (HDL-C) metabolism in selective cholesteryl ester uptake and in free cholesterol cellular efflux. METHODS AND RESULTS:This study aims to identify common (minor allele frequency ?5%) and low-frequency/rare (minor allele frequency <5%) variants, using resequencing all 13 exons and exon-intron boundaries of SCARB1 in 95 individuals with extreme HDL-C levels selected from a population-based sample of 623 US non-Hispanic whites. The sequencing step identified 44 variants, of which 11 were novel with minor allele frequency <1%. Seventy-six variants (40 sequence variants, 32 common HapMap tag single nucleotide polymorphisms, and 4 relevant variants) were selected for genotyping in the total sample of 623 subjects followed by association analyses with lipid traits. Seven variants were nominally associated with apolipoprotein B (apoB; n=4) or HDL-C (n=3; P<0.05). Three variants associated with apoB remained significant after controlling false discovery rate. The most significant association was observed between rs4765615 and apoB (P=0.0059), while rs11057844 showed the strongest association with HDL-C (P=0.0035). A set of 17 rare variants (minor allele frequency ?1%) showed significant association with apoB (P=0.0284). Haplotype analysis revealed 4 regions significantly associated with either apoB or HDL-C. CONCLUSIONS:Our findings provide new information about the genetic role of SCARB1 in affecting plasma apoB levels in addition to its established role in HDL-C metabolism.

SUBMITTER: Niemsiri V

PROVIDER: S-EPMC4270916 | biostudies-literature | 2014 Dec

REPOSITORIES: biostudies-literature

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Impact of genetic variants in human scavenger receptor class B type I (SCARB1) on plasma lipid traits.

Niemsiri Vipavee V Wang Xingbin X Pirim Dilek D Radwan Zaheda H ZH Hokanson John E JE Hamman Richard F RF Barmada M Michael MM Demirci F Yesim FY Kamboh M Ilyas MI

Circulation. Cardiovascular genetics 20140922 6

<h4>Background</h4>Scavenger receptor class B type 1 (SCARB1) plays an important role in high-density lipoprotein cholesterol (HDL-C) metabolism in selective cholesteryl ester uptake and in free cholesterol cellular efflux.<h4>Methods and results</h4>This study aims to identify common (minor allele frequency ≥5%) and low-frequency/rare (minor allele frequency <5%) variants, using resequencing all 13 exons and exon-intron boundaries of SCARB1 in 95 individuals with extreme HDL-C levels selected f ...[more]

PMID: 25245032

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Project description:BackgroundWe previously reported association of SCARB1 SNP rs10846744 with common carotid IMT (cIMT) and cardiovascular disease (CVD) events. Since rs10846744 has been reported in association with Lp-PLA2 mass and activity, we hypothesized that inflammatory pathways might mediate the association of rs10846744 with atherosclerosis.MethodsWe first examined association of rs10846744 in CVD in multiple large-scale consortium-based genome-wide association studies. We further examined 27 parameters of interest, including Lp-PLA2 mass and activity, inflammatory markers, and plasma phospholipid fatty acids, and fatty acid ratios in participants from the Multi-Ethnic Study of Atherosclerosis (MESA), as potential mediators in the pathway linking rs10846744 with cIMT and incident CVD. Finally, we examined the association of rs10846744 with Lp-PLA2 activity, cardiovascular outcomes, and interaction with the Lp-PLA2 inhibitor, darapladib, in the Stabilization of Atherosclerotic Plaque by Initiation of Darapladib Therapy (STABILITY) and Stabilization of Plaque using Darapladib-Thrombolysis in Myocardial Infarction 52 (SOLID-TIMI 52) studies.ResultsSCARB1 rs10846744 was associated with coronary artery disease events in CARDIoGRAMplusC4D (odds ratio 1.05; 95% CI [1.02, 1.07]; P = 1.4x10-4). In combined analysis across race/ethnic groups in MESA, rs10846744 was associated with Lp-PLA2 mass (P = 0.04) and activity (P = 0.001), homocysteine (P = 0.03), LDL particle number (P = 0.01), docosahexaenoic acid [DHA] (P = 0.01), docosapentaenoic acid [DPA] (P = 0.04), DPA/ eicosapentaenoic acid [EPA] ratio (P = 0.002), and DHA/EPA ratio (P = 0.008). Lp-PLA2 activity was identified as a mediator of rs10846744 with cIMT in a basic model (P = 8x10-5), but not after adjustment for CVD risk factors. There was no interaction or modifier effect of the Lp-PLA2 inhibitor darapladib assignment on the relationship between rs10846744 and major CVD events in either STABILITY or SOLID-TIMI 52.SummarySCARB1 rs10846744 is significantly associated with Lp-PLA2 activity, atherosclerosis, and CVD events, but Lp-PLA2 activity is not a mediator in the association of rs10846744 with cIMT in MESA.

Project description:ObjectiveTo investigate association of scavenger receptor class B, member 1 (SCARB1) genetic variants with serum carotenoid levels of lutein (L) and zeaxanthin (Z) and macular pigment optical density (MPOD).DesignA cross-sectional study of healthy adults aged 20 to 70.ParticipantsWe recruited 302 participants after local advertisement.MethodsWe measured MPOD by customized heterochromatic flicker photometry. Fasting blood samples were taken for serum L and Z measurement by high-performance liquid chromatography and lipoprotein analysis by spectrophotometric assay. Forty-seven single nucleotide polymorphisms (SNPs) across SCARB1 were genotyped using Sequenom technology. Association analyses were performed using PLINK to compare allele and haplotype means, with adjustment for potential confounding and correction for multiple comparisons by permutation testing. Replication analysis was performed in the TwinsUK and Carotenoids in Age-Related Eye Disease Study (CAREDS) cohorts.Main outcome measuresOdds ratios for MPOD area, serum L and Z concentrations associated with genetic variations in SCARB1 and interactions between SCARB1 and gender.ResultsAfter multiple regression analysis with adjustment for age, body mass index, gender, high-density lipoprotein cholesterol, low-density lipoprotein cholesterol, triglycerides, smoking, and dietary L and Z levels, 5 SNPs were significantly associated with serum L concentration and 1 SNP with MPOD (P<0.01). Only the association between rs11057841 and serum L withstood correction for multiple comparisons by permutation testing (P<0.01) and replicated in the TwinsUK cohort (P = 0.014). Independent replication was also observed in the CAREDS cohort with rs10846744 (P = 2×10(-4)), an SNP in high linkage disequilibrium with rs11057841 (r(2) = 0.93). No interactions by gender were found. Haplotype analysis revealed no stronger association than obtained with single SNP analyses.ConclusionsOur study has identified association between rs11057841 and serum L concentration (24% increase per T allele) in healthy subjects, independent of potential confounding factors. Our data supports further evaluation of the role for SCARB1 in the transport of macular pigment and the possible modulation of age-related macular degeneration risk through combating the effects of oxidative stress within the retina.Financial disclosure(s)Proprietary or commercial disclosures may be found after the references.

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Dataset Information

Impact of genetic variants in human scavenger receptor class B type I (SCARB1) on plasma lipid traits.

Publications

Impact of genetic variants in human scavenger receptor class B type I (SCARB1) on plasma lipid traits.

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