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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

LD structure of 17 LPL SNPs associated with one or more lipid/lipoprotein traits (HDL-C, LDL-C, ApoA1 or ApoB levels). The values in the cells are the pairwise degree of LD indicated by r2 × 100. Shades of white indicate r2=0, shades of gray indicate 0<r2<1 and shades of black indicate r2=1.
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fig2: LD structure of 17 LPL SNPs associated with one or more lipid/lipoprotein traits (HDL-C, LDL-C, ApoA1 or ApoB levels). The values in the cells are the pairwise degree of LD indicated by r2 × 100. Shades of white indicate r2=0, shades of gray indicate 0<r2<1 and shades of black indicate r2=1.

Mentions: The most significant SNP, rs252:delA (intronic variant), was associated with LDL-C (β=−1.037; P=0.002; FDR=0.134) and ApoB (β=−2.364; P=0.012; FDR=0.328) levels. This is a novel association given that the rs252:delA SNP was not in high LD (r2≤0.20) with other nominally associated SNPs (Figure 2), including two functional LPL variants rs1801177:G>A (p.(Asp36Asn)) and rs13702:C>T (resides in 3′-UTR and disrupts a microRNA-410 recognition element seed site).30 One additional SNP, rs74304285:G>A, which again was not highly correlated (r2≤0.11) with other relevant SNPs, was also associated with both LDL-C (β=0.995; P=0.019; FDR= 0.627) and ApoB (β=3.014; P=0.010; FDR=0.328). In addition, four other weakly correlated (r2≤0.20) SNPs (rs1801177:G>A, rs8176337:G>C, rs329:A>G and rs12679834:T>C) were nominally associated with ApoB levels, of which rs12679834:T>C was also associated with ApoA1 levels. Two of these SNPs (rs1801177:G>A and rs8176337:G>C) were previously reported to be associated with TG,31, 32 but showed only 0.05<P<0.20 for TG levels in our study.


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)

LD structure of 17 LPL SNPs associated with one or more lipid/lipoprotein traits (HDL-C, LDL-C, ApoA1 or ApoB levels). The values in the cells are the pairwise degree of LD indicated by r2 × 100. Shades of white indicate r2=0, shades of gray indicate 0<r2<1 and shades of black indicate r2=1.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC4538195&req=5

fig2: LD structure of 17 LPL SNPs associated with one or more lipid/lipoprotein traits (HDL-C, LDL-C, ApoA1 or ApoB levels). The values in the cells are the pairwise degree of LD indicated by r2 × 100. Shades of white indicate r2=0, shades of gray indicate 0<r2<1 and shades of black indicate r2=1.
Mentions: The most significant SNP, rs252:delA (intronic variant), was associated with LDL-C (β=−1.037; P=0.002; FDR=0.134) and ApoB (β=−2.364; P=0.012; FDR=0.328) levels. This is a novel association given that the rs252:delA SNP was not in high LD (r2≤0.20) with other nominally associated SNPs (Figure 2), including two functional LPL variants rs1801177:G>A (p.(Asp36Asn)) and rs13702:C>T (resides in 3′-UTR and disrupts a microRNA-410 recognition element seed site).30 One additional SNP, rs74304285:G>A, which again was not highly correlated (r2≤0.11) with other relevant SNPs, was also associated with both LDL-C (β=0.995; P=0.019; FDR= 0.627) and ApoB (β=3.014; P=0.010; FDR=0.328). In addition, four other weakly correlated (r2≤0.20) SNPs (rs1801177:G>A, rs8176337:G>C, rs329:A>G and rs12679834:T>C) were nominally associated with ApoB levels, of which rs12679834:T>C was also associated with ApoA1 levels. Two of these SNPs (rs1801177:G>A and rs8176337:G>C) were previously reported to be associated with TG,31, 32 but showed only 0.05<P<0.20 for TG levels in our study.

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