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Resequencing of LPL in African Blacks and associations with lipoprotein-lipid levels.

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

Bottom Line: It has been hypothesized that the remaining heritability may partly be explained by rare variants with strong effect sizes.The most significant SNP, rs252:delA, represented a novel association observed with LDL-C (P=0.002) and ApoB (P=0.012).Our study indicates that both common and uncommon/rare LPL variants/haplotypes may affect plasma lipoprotein-lipid levels in general African population.

View Article: PubMed Central - PubMed

Affiliation: Department of Human Genetics, Graduate School of Public Health, University of Pittsburgh, Pittsburgh, PA, USA.

ABSTRACT
Genome-wide association studies have identified several loci associated with plasma lipid levels but those common variants together account only for a small proportion of the genetic variance of lipid traits. It has been hypothesized that the remaining heritability may partly be explained by rare variants with strong effect sizes. Here, we have comprehensively investigated the associations of both common and uncommon/rare variants in the lipoprotein lipase (LPL) gene in relation to plasma lipoprotein-lipid levels in African Blacks (ABs). For variant discovery purposes, the entire LPL gene and flanking regions were resequenced in 95 ABs with extreme high-density lipoprotein cholesterol (HDL-C) levels. A total of 308 variants were identified, of which 64 were novel. Selected common tagSNPs and uncommon/rare variants were genotyped in the entire sample (n=788), and 126 QC-passed variants were evaluated for their associations with lipoprotein-lipid levels by using single-site, haplotype and rare variant (SKAT-O) association analyses. We found eight not highly correlated (r(2)<0.40) signals (rs1801177:G>A, rs8176337:G>C, rs74304285:G>A, rs252:delA, rs316:C>A, rs329:A>G, rs12679834:T>C, and rs4921684:C>T) nominally (P<0.05) associated with lipid traits (HDL-C, LDL-C, ApoA1 or ApoB levels) in our sample. The most significant SNP, rs252:delA, represented a novel association observed with LDL-C (P=0.002) and ApoB (P=0.012). For TG and LDL-C, the haplotype analysis was more informative than the single-site analysis. The SKAT-O analysis revealed that the bin (group) containing 22 rare variants with MAF≤0.01 exhibited nominal association with TG (P=0.039) and LDL-C (P=0.027). Our study indicates that both common and uncommon/rare LPL variants/haplotypes may affect plasma lipoprotein-lipid levels in general African population.

No MeSH data available.


Related in: MedlinePlus

(a) Minor allele frequency distribution of LPL variants identified in African Blacks (n=95). (b) Distribution of LPL variants by location in the gene and comparison with size distribution of those locations. (c) Number and locations of LPL variants identified in African Blacks (n=95).
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fig1: (a) Minor allele frequency distribution of LPL variants identified in African Blacks (n=95). (b) Distribution of LPL variants by location in the gene and comparison with size distribution of those locations. (c) Number and locations of LPL variants identified in African Blacks (n=95).

Mentions: A total of 308 variants were identified, of which 130 were common (MAF≥0.05), 118 were uncommon (0.01≤MAF<0.05) and 60 were rare (MAF<0.01; Figure 1a); 19 were indels and 2 triallelic SNPs (Supplementary Table 1); 246 were identified in introns, 30 in 3′-UTR, 14 in flanking regions, 12 in coding regions and 6 in 5′-UTR (Figures 1b and c). All identified coding variants were known SNPs; seven nonsynonymous and five synonymous. We successfully identified all but three common variants (rs1470187:G>T, rs59184895:T>C and rs328:C>G) reported in African-descent populations (dbSNP build 138); these variants were located at the beginning or end of resequencing amplicons where the sequence read quality is usually low in Sanger sequencing, which probably hampered their identification in our sequencing sample, however, they were successfully genotyped in our entire sample. Of 308 variants, 64 (2 common and 62 uncommon/rare) have not been previously reported in dbSNP and thus have been submitted to dbSNP database (http://www.ncbi.nlm.nih.gov/SNP/snp_viewTable.cgi?handle=KAMBOH). Four of 64 novel variants were located in flanking regions, 3 in 5′-UTR, 6 in 3′-UTR and 51 in introns; majority (69%) had MAF<0.01. We identified nine novel indels (all located in introns) ranging in size from 1 to 15 bases. In addition to ‘novel variants', we identified ‘novel uncommon/rare alleles' at two nucleotide positions where common diallelic variations were previously reported (rs7002728:G>T and rs28599962:T>C), thus we detected triallelic variations at these positions where the least frequently observed allele was unique to our sample. Of 308 variants, 24 were found only in high HDL-C group vs 54 only in low HDL-C group.


Resequencing of LPL in African Blacks and associations with lipoprotein-lipid levels.

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

(a) Minor allele frequency distribution of LPL variants identified in African Blacks (n=95). (b) Distribution of LPL variants by location in the gene and comparison with size distribution of those locations. (c) Number and locations of LPL variants identified in African Blacks (n=95).
© Copyright Policy
Related In: Results  -  Collection

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getmorefigures.php?uid=PMC4538195&req=5

fig1: (a) Minor allele frequency distribution of LPL variants identified in African Blacks (n=95). (b) Distribution of LPL variants by location in the gene and comparison with size distribution of those locations. (c) Number and locations of LPL variants identified in African Blacks (n=95).
Mentions: A total of 308 variants were identified, of which 130 were common (MAF≥0.05), 118 were uncommon (0.01≤MAF<0.05) and 60 were rare (MAF<0.01; Figure 1a); 19 were indels and 2 triallelic SNPs (Supplementary Table 1); 246 were identified in introns, 30 in 3′-UTR, 14 in flanking regions, 12 in coding regions and 6 in 5′-UTR (Figures 1b and c). All identified coding variants were known SNPs; seven nonsynonymous and five synonymous. We successfully identified all but three common variants (rs1470187:G>T, rs59184895:T>C and rs328:C>G) reported in African-descent populations (dbSNP build 138); these variants were located at the beginning or end of resequencing amplicons where the sequence read quality is usually low in Sanger sequencing, which probably hampered their identification in our sequencing sample, however, they were successfully genotyped in our entire sample. Of 308 variants, 64 (2 common and 62 uncommon/rare) have not been previously reported in dbSNP and thus have been submitted to dbSNP database (http://www.ncbi.nlm.nih.gov/SNP/snp_viewTable.cgi?handle=KAMBOH). Four of 64 novel variants were located in flanking regions, 3 in 5′-UTR, 6 in 3′-UTR and 51 in introns; majority (69%) had MAF<0.01. We identified nine novel indels (all located in introns) ranging in size from 1 to 15 bases. In addition to ‘novel variants', we identified ‘novel uncommon/rare alleles' at two nucleotide positions where common diallelic variations were previously reported (rs7002728:G>T and rs28599962:T>C), thus we detected triallelic variations at these positions where the least frequently observed allele was unique to our sample. Of 308 variants, 24 were found only in high HDL-C group vs 54 only in low HDL-C group.

Bottom Line: It has been hypothesized that the remaining heritability may partly be explained by rare variants with strong effect sizes.The most significant SNP, rs252:delA, represented a novel association observed with LDL-C (P=0.002) and ApoB (P=0.012).Our study indicates that both common and uncommon/rare LPL variants/haplotypes may affect plasma lipoprotein-lipid levels in general African population.

View Article: PubMed Central - PubMed

Affiliation: Department of Human Genetics, Graduate School of Public Health, University of Pittsburgh, Pittsburgh, PA, USA.

ABSTRACT
Genome-wide association studies have identified several loci associated with plasma lipid levels but those common variants together account only for a small proportion of the genetic variance of lipid traits. It has been hypothesized that the remaining heritability may partly be explained by rare variants with strong effect sizes. Here, we have comprehensively investigated the associations of both common and uncommon/rare variants in the lipoprotein lipase (LPL) gene in relation to plasma lipoprotein-lipid levels in African Blacks (ABs). For variant discovery purposes, the entire LPL gene and flanking regions were resequenced in 95 ABs with extreme high-density lipoprotein cholesterol (HDL-C) levels. A total of 308 variants were identified, of which 64 were novel. Selected common tagSNPs and uncommon/rare variants were genotyped in the entire sample (n=788), and 126 QC-passed variants were evaluated for their associations with lipoprotein-lipid levels by using single-site, haplotype and rare variant (SKAT-O) association analyses. We found eight not highly correlated (r(2)<0.40) signals (rs1801177:G>A, rs8176337:G>C, rs74304285:G>A, rs252:delA, rs316:C>A, rs329:A>G, rs12679834:T>C, and rs4921684:C>T) nominally (P<0.05) associated with lipid traits (HDL-C, LDL-C, ApoA1 or ApoB levels) in our sample. The most significant SNP, rs252:delA, represented a novel association observed with LDL-C (P=0.002) and ApoB (P=0.012). For TG and LDL-C, the haplotype analysis was more informative than the single-site analysis. The SKAT-O analysis revealed that the bin (group) containing 22 rare variants with MAF≤0.01 exhibited nominal association with TG (P=0.039) and LDL-C (P=0.027). Our study indicates that both common and uncommon/rare LPL variants/haplotypes may affect plasma lipoprotein-lipid levels in general African population.

No MeSH data available.


Related in: MedlinePlus