Limits...
Genetic contribution of SCARB1 variants to lipid traits in African Blacks: a candidate gene association study.

Niemsiri V, Wang X, Pirim D, Radwan ZH, Bunker CH, Barmada MM, Kamboh MI, Demirci FY - BMC Med. Genet. (2015)

Bottom Line: Then, we genotyped 147 selected variants (78 sequence variants, 69 HapMap tagSNPs, and 2 previously reported relevant variants) in the entire sample of 788 African Blacks using either the iPLEX Gold or TaqMan methods.A total of 137 successfully genotyped variants were further evaluated for association with major lipid traits.To our knowledge, this is the first report of a comprehensive association study of SCARB1 variations with lipid traits in an African Black population.

View Article: PubMed Central - PubMed

Affiliation: Department of Human Genetics, Graduate School of Public Health, University of Pittsburgh, 130 DeSoto Street, Pittsburgh, PA, 15261, USA. vin4@pitt.edu.

ABSTRACT

Background: High-density lipoprotein cholesterol (HDL-C) exerts many anti-atherogenic properties including its role in reverse cholesterol transport (RCT). Scavenger receptor class B member 1 (SCARB1) plays a key role in RCT by selective uptake of HDL cholesteryl esters. We aimed to explore the genetic contribution of SCARB1 to affecting lipid levels in African Blacks from Nigeria.

Methods: We resequenced 13 exons and exon-intron boundaries of SCARB1 in 95 individuals with extreme HDL-C levels using Sanger method. Then, we genotyped 147 selected variants (78 sequence variants, 69 HapMap tagSNPs, and 2 previously reported relevant variants) in the entire sample of 788 African Blacks using either the iPLEX Gold or TaqMan methods. A total of 137 successfully genotyped variants were further evaluated for association with major lipid traits.

Results: The initial gene-based analysis demonstrated evidence of association with HDL-C and apolipoprotein A-I (ApoA-I). The follow-up single-site analysis revealed nominal evidence of novel associations of nine common variants with HDL-C and/or ApoA-I (P < 0.05). The strongest association was between rs11057851 and HDL-C (P = 0.0043), which remained significant after controlling for multiple testing using false discovery rate. Rare variant association testing revealed a group of 23 rare variants (frequencies ≤1 %) associated with HDL-C (P = 0.0478). Haplotype analysis identified four SCARB1 regions associated with HDL-C (global P < 0.05).

Conclusions: To our knowledge, this is the first report of a comprehensive association study of SCARB1 variations with lipid traits in an African Black population. Our results showed the consistent association of SCARB1 variants with HDL-C across various association analyses, supporting the role of SCARB1 in lipoprotein-lipid regulatory mechanism.

No MeSH data available.


Related in: MedlinePlus

Summary of the study design and flow. Chart presents an overview of the study design and flow, including sequencing and genotyping stages and analysis approaches. ApoA-I, apolipoprotein A-I; ApoB, apolipoprotein B; HDL-C, high-density lipoprotein cholesterol; LD, linkage disequilibrium; LDL-C, low-density lipoprotein cholesterol; LoF, low-frequency; MAF, minor allele frequency; SD, standard deviation; SKAT-O, an optimal sequence kernel association test; SNP, single nucleotide polymorphism; TG, triglycerides; YRI, Yoruba people of Ibadan from Nigeria
© Copyright Policy - OpenAccess
Related In: Results  -  Collection

License 1 - License 2
getmorefigures.php?uid=PMC4643515&req=5

Fig1: Summary of the study design and flow. Chart presents an overview of the study design and flow, including sequencing and genotyping stages and analysis approaches. ApoA-I, apolipoprotein A-I; ApoB, apolipoprotein B; HDL-C, high-density lipoprotein cholesterol; LD, linkage disequilibrium; LDL-C, low-density lipoprotein cholesterol; LoF, low-frequency; MAF, minor allele frequency; SD, standard deviation; SKAT-O, an optimal sequence kernel association test; SNP, single nucleotide polymorphism; TG, triglycerides; YRI, Yoruba people of Ibadan from Nigeria

Mentions: The values of each lipid phenotype outside the mean ± 3.5 standard deviation (SD) were excluded from downstream gene-based, single-site, and haplotype analyses. However, the extreme phenotypic values associated with rare variants (MAF ≤1 %) were maintained during rare variant analysis, as was the case for the p70201/chr12:125279319 variant (see study workflow in Fig. 1). Values of the five lipid and apolipoprotein traits—HDL-C, LDL-C, TG, ApoA-I, and ApoB—were transformed using the Box-Cox transformation. For each trait, we used stepwise regression method to select the most parsimonious set of covariates from the following list: sex, age, body mass index, waist, current smoking (yes/no), minutes of walking or biking to work each day (jobmin), and occupational status (staff: junior [non-professional staff]/senior [professional and administrative staff]). Genetic association analyses, including gene-based, single-site, LoF/rare variant, and haplotype association tests, were performed using linear regression models that included significant covariates for each variable (Additional file 13: Table S8).Fig. 1


Genetic contribution of SCARB1 variants to lipid traits in African Blacks: a candidate gene association study.

Niemsiri V, Wang X, Pirim D, Radwan ZH, Bunker CH, Barmada MM, Kamboh MI, Demirci FY - BMC Med. Genet. (2015)

Summary of the study design and flow. Chart presents an overview of the study design and flow, including sequencing and genotyping stages and analysis approaches. ApoA-I, apolipoprotein A-I; ApoB, apolipoprotein B; HDL-C, high-density lipoprotein cholesterol; LD, linkage disequilibrium; LDL-C, low-density lipoprotein cholesterol; LoF, low-frequency; MAF, minor allele frequency; SD, standard deviation; SKAT-O, an optimal sequence kernel association test; SNP, single nucleotide polymorphism; TG, triglycerides; YRI, Yoruba people of Ibadan from Nigeria
© Copyright Policy - OpenAccess
Related In: Results  -  Collection

License 1 - License 2
Show All Figures
getmorefigures.php?uid=PMC4643515&req=5

Fig1: Summary of the study design and flow. Chart presents an overview of the study design and flow, including sequencing and genotyping stages and analysis approaches. ApoA-I, apolipoprotein A-I; ApoB, apolipoprotein B; HDL-C, high-density lipoprotein cholesterol; LD, linkage disequilibrium; LDL-C, low-density lipoprotein cholesterol; LoF, low-frequency; MAF, minor allele frequency; SD, standard deviation; SKAT-O, an optimal sequence kernel association test; SNP, single nucleotide polymorphism; TG, triglycerides; YRI, Yoruba people of Ibadan from Nigeria
Mentions: The values of each lipid phenotype outside the mean ± 3.5 standard deviation (SD) were excluded from downstream gene-based, single-site, and haplotype analyses. However, the extreme phenotypic values associated with rare variants (MAF ≤1 %) were maintained during rare variant analysis, as was the case for the p70201/chr12:125279319 variant (see study workflow in Fig. 1). Values of the five lipid and apolipoprotein traits—HDL-C, LDL-C, TG, ApoA-I, and ApoB—were transformed using the Box-Cox transformation. For each trait, we used stepwise regression method to select the most parsimonious set of covariates from the following list: sex, age, body mass index, waist, current smoking (yes/no), minutes of walking or biking to work each day (jobmin), and occupational status (staff: junior [non-professional staff]/senior [professional and administrative staff]). Genetic association analyses, including gene-based, single-site, LoF/rare variant, and haplotype association tests, were performed using linear regression models that included significant covariates for each variable (Additional file 13: Table S8).Fig. 1

Bottom Line: Then, we genotyped 147 selected variants (78 sequence variants, 69 HapMap tagSNPs, and 2 previously reported relevant variants) in the entire sample of 788 African Blacks using either the iPLEX Gold or TaqMan methods.A total of 137 successfully genotyped variants were further evaluated for association with major lipid traits.To our knowledge, this is the first report of a comprehensive association study of SCARB1 variations with lipid traits in an African Black population.

View Article: PubMed Central - PubMed

Affiliation: Department of Human Genetics, Graduate School of Public Health, University of Pittsburgh, 130 DeSoto Street, Pittsburgh, PA, 15261, USA. vin4@pitt.edu.

ABSTRACT

Background: High-density lipoprotein cholesterol (HDL-C) exerts many anti-atherogenic properties including its role in reverse cholesterol transport (RCT). Scavenger receptor class B member 1 (SCARB1) plays a key role in RCT by selective uptake of HDL cholesteryl esters. We aimed to explore the genetic contribution of SCARB1 to affecting lipid levels in African Blacks from Nigeria.

Methods: We resequenced 13 exons and exon-intron boundaries of SCARB1 in 95 individuals with extreme HDL-C levels using Sanger method. Then, we genotyped 147 selected variants (78 sequence variants, 69 HapMap tagSNPs, and 2 previously reported relevant variants) in the entire sample of 788 African Blacks using either the iPLEX Gold or TaqMan methods. A total of 137 successfully genotyped variants were further evaluated for association with major lipid traits.

Results: The initial gene-based analysis demonstrated evidence of association with HDL-C and apolipoprotein A-I (ApoA-I). The follow-up single-site analysis revealed nominal evidence of novel associations of nine common variants with HDL-C and/or ApoA-I (P < 0.05). The strongest association was between rs11057851 and HDL-C (P = 0.0043), which remained significant after controlling for multiple testing using false discovery rate. Rare variant association testing revealed a group of 23 rare variants (frequencies ≤1 %) associated with HDL-C (P = 0.0478). Haplotype analysis identified four SCARB1 regions associated with HDL-C (global P < 0.05).

Conclusions: To our knowledge, this is the first report of a comprehensive association study of SCARB1 variations with lipid traits in an African Black population. Our results showed the consistent association of SCARB1 variants with HDL-C across various association analyses, supporting the role of SCARB1 in lipoprotein-lipid regulatory mechanism.

No MeSH data available.


Related in: MedlinePlus