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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

Lipid-associated SCARB1 common variants and haplotype regions identified in US Non-Hispanic Whites (previous study; Ref [49]) and African Blacks (this study). Lipid-associated variants with MAF ≥5 % with P-values <0.05 and haplotype regions with global P-values < 0.05 that were previously identified in US Non-Hispanic Whites (US NHWs; n = 623) are shown in top panel and those identified in African Blacks (n = 788) are shown in bottom panel (see details in Table 9 and Table 10). SCARB1 variants and haplotype regions are shown on SCARB1 gene (5′ → 3′; RefSeq: hg19, NM_005505). All SNP IDs are based on dbSNP build 139. Regions I and II that are defined based on consecutive haplotype windows with evidence of lipid-association in US NHWs (global P < 0.05; see details in Ref [49]) also show some significant associations in African Blacks (global P < 0.05; see details in Table 7 and Table 8). ApoA-I, apolipoprotein A-I; ApoB, apolipoprotein B; HDL-C, high-density lipoprotein cholesterol; MAF, minor allele frequency; NHW, Non-Hispanic White; SNP, single nucleotide polymorphism; UTR, untranslated region
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Fig4: Lipid-associated SCARB1 common variants and haplotype regions identified in US Non-Hispanic Whites (previous study; Ref [49]) and African Blacks (this study). Lipid-associated variants with MAF ≥5 % with P-values <0.05 and haplotype regions with global P-values < 0.05 that were previously identified in US Non-Hispanic Whites (US NHWs; n = 623) are shown in top panel and those identified in African Blacks (n = 788) are shown in bottom panel (see details in Table 9 and Table 10). SCARB1 variants and haplotype regions are shown on SCARB1 gene (5′ → 3′; RefSeq: hg19, NM_005505). All SNP IDs are based on dbSNP build 139. Regions I and II that are defined based on consecutive haplotype windows with evidence of lipid-association in US NHWs (global P < 0.05; see details in Ref [49]) also show some significant associations in African Blacks (global P < 0.05; see details in Table 7 and Table 8). ApoA-I, apolipoprotein A-I; ApoB, apolipoprotein B; HDL-C, high-density lipoprotein cholesterol; MAF, minor allele frequency; NHW, Non-Hispanic White; SNP, single nucleotide polymorphism; UTR, untranslated region

Mentions: We compared SCARB1 single-site and haplotype association results in African Blacks reported in this study to those in US Non-Hispanic Whites (NHWs) reported in our previously published study [49]. In the sequencing stage, the number of variants identified in African Blacks (n = 83) was greater than that in US NHWs (n = 44). Notably, most (~90 %) of the 22 sequence variants that were shared between the two populations differed in minor alleles and/or MAFs. Although our major findings included the associations with HDL-C and ApoA-I in African Blacks, we also sought to replicate four associations observed with ApoB levels in US NHWs [49] (Table 9); the association between rs11057820 and ApoB (P < 0.05) that we previously reported in US NHWs [49] was also observed in African Blacks (US NHWs [G allele]: β = 0.8700, P = 0.0436; African Blacks [A allele]: β = 1.8661, P = 0.0292). In addition, we observed two variants (rs4765615 and rs701106) exhibiting nominal associations (P < 0.05) in both populations, albeit with different lipid traits (US NHWs/ rs4765615 [G allele]: β = 1.2493, P = 0.0059 for ApoB; rs701106 [T allele]: β = 0.0394, P = 0.0066 for HDL-C; African Blacks/ rs4765615 [A allele]: β = −0.4646, P = 0.013 for HDL-C and β = −0.9139, P = 0.048 for ApoA-I; rs701106 [T allele]: β = 1.2967, P = 0.0156 for ApoA-I). Moreover, we noticed that two regions associated with HDL-C or ApoA-I (global P < 0.05; Table 10) in African Blacks spanning intron 2 and intron 3 overlapped with the ApoB-associated region (Region I in Fig. 4) previously reported in US NHWs [49]. Three haplotype regions associated with HDL-C (global P < 0.05) spanning intron 11 and exon 13-3′ UTR in African Blacks also overlapped with a large HDL-C-associated region (Region II in Fig. 4) previously reported in US NHWs [49].Table 9


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)

Lipid-associated SCARB1 common variants and haplotype regions identified in US Non-Hispanic Whites (previous study; Ref [49]) and African Blacks (this study). Lipid-associated variants with MAF ≥5 % with P-values <0.05 and haplotype regions with global P-values < 0.05 that were previously identified in US Non-Hispanic Whites (US NHWs; n = 623) are shown in top panel and those identified in African Blacks (n = 788) are shown in bottom panel (see details in Table 9 and Table 10). SCARB1 variants and haplotype regions are shown on SCARB1 gene (5′ → 3′; RefSeq: hg19, NM_005505). All SNP IDs are based on dbSNP build 139. Regions I and II that are defined based on consecutive haplotype windows with evidence of lipid-association in US NHWs (global P < 0.05; see details in Ref [49]) also show some significant associations in African Blacks (global P < 0.05; see details in Table 7 and Table 8). ApoA-I, apolipoprotein A-I; ApoB, apolipoprotein B; HDL-C, high-density lipoprotein cholesterol; MAF, minor allele frequency; NHW, Non-Hispanic White; SNP, single nucleotide polymorphism; UTR, untranslated region
© Copyright Policy - OpenAccess
Related In: Results  -  Collection

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

Fig4: Lipid-associated SCARB1 common variants and haplotype regions identified in US Non-Hispanic Whites (previous study; Ref [49]) and African Blacks (this study). Lipid-associated variants with MAF ≥5 % with P-values <0.05 and haplotype regions with global P-values < 0.05 that were previously identified in US Non-Hispanic Whites (US NHWs; n = 623) are shown in top panel and those identified in African Blacks (n = 788) are shown in bottom panel (see details in Table 9 and Table 10). SCARB1 variants and haplotype regions are shown on SCARB1 gene (5′ → 3′; RefSeq: hg19, NM_005505). All SNP IDs are based on dbSNP build 139. Regions I and II that are defined based on consecutive haplotype windows with evidence of lipid-association in US NHWs (global P < 0.05; see details in Ref [49]) also show some significant associations in African Blacks (global P < 0.05; see details in Table 7 and Table 8). ApoA-I, apolipoprotein A-I; ApoB, apolipoprotein B; HDL-C, high-density lipoprotein cholesterol; MAF, minor allele frequency; NHW, Non-Hispanic White; SNP, single nucleotide polymorphism; UTR, untranslated region
Mentions: We compared SCARB1 single-site and haplotype association results in African Blacks reported in this study to those in US Non-Hispanic Whites (NHWs) reported in our previously published study [49]. In the sequencing stage, the number of variants identified in African Blacks (n = 83) was greater than that in US NHWs (n = 44). Notably, most (~90 %) of the 22 sequence variants that were shared between the two populations differed in minor alleles and/or MAFs. Although our major findings included the associations with HDL-C and ApoA-I in African Blacks, we also sought to replicate four associations observed with ApoB levels in US NHWs [49] (Table 9); the association between rs11057820 and ApoB (P < 0.05) that we previously reported in US NHWs [49] was also observed in African Blacks (US NHWs [G allele]: β = 0.8700, P = 0.0436; African Blacks [A allele]: β = 1.8661, P = 0.0292). In addition, we observed two variants (rs4765615 and rs701106) exhibiting nominal associations (P < 0.05) in both populations, albeit with different lipid traits (US NHWs/ rs4765615 [G allele]: β = 1.2493, P = 0.0059 for ApoB; rs701106 [T allele]: β = 0.0394, P = 0.0066 for HDL-C; African Blacks/ rs4765615 [A allele]: β = −0.4646, P = 0.013 for HDL-C and β = −0.9139, P = 0.048 for ApoA-I; rs701106 [T allele]: β = 1.2967, P = 0.0156 for ApoA-I). Moreover, we noticed that two regions associated with HDL-C or ApoA-I (global P < 0.05; Table 10) in African Blacks spanning intron 2 and intron 3 overlapped with the ApoB-associated region (Region I in Fig. 4) previously reported in US NHWs [49]. Three haplotype regions associated with HDL-C (global P < 0.05) spanning intron 11 and exon 13-3′ UTR in African Blacks also overlapped with a large HDL-C-associated region (Region II in Fig. 4) previously reported in US NHWs [49].Table 9

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