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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

Haplotype association results for HDL (a), TG (b), LDL-C (b), ApoA1 (d) and ApoB (e) levels. The log of the global P-value is presented on the y axis and SNPs are presented across the x axis in chromosomal order. Horizontal lines are 4-SNP haplotype windows. The red horizontal line shows the significance threshold. A full color version of this figure is available at the European Journal of Human Genetics journal online.
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fig3: Haplotype association results for HDL (a), TG (b), LDL-C (b), ApoA1 (d) and ApoB (e) levels. The log of the global P-value is presented on the y axis and SNPs are presented across the x axis in chromosomal order. Horizontal lines are 4-SNP haplotype windows. The red horizontal line shows the significance threshold. A full color version of this figure is available at the European Journal of Human Genetics journal online.

Mentions: A total of 123 overlapping windows, each containing four SNPs, were constructed using the sliding window approach (sliding one SNP at a time) for haplotype analysis of 126 variants with lipid traits (Figure 3). P-values were calculated based on the comparison of each haplotype with the most common reference haplotype. The strongest haplotype effects were observed on HDL-C, followed by ApoB, comprising 19 and 18 nominally significant (P<0.05) global P-values, respectively (Supplementary Table 11). The most significant window (‘window 81' containing rs313:A>G, rs314:A>G, rs77434393:G>A and rs316:C>A) was associated with both HDL-C (global P=2.32E-04) and ApoA1 (global P=0.021). The only SNP in this window that showed association in single-site analysis was rs316:C>A (P=0.003 with HDL-C; P=0.022 with ApoA1) and thus the observed haplotype association seemed to be primarily driven by this SNP. Although the haplotypes in intron 6–intron 8 region were associated with HDL-C and ApoA1, those in intron 8–intron 9 were associated with ApoB. Although no common LPL SNPs were associated with TG in single-site analysis, seven haplotype windows showed nominal associations with TG. Overall, haplotype analysis was more informative for TG and LDL-C than single-site analysis.


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)

Haplotype association results for HDL (a), TG (b), LDL-C (b), ApoA1 (d) and ApoB (e) levels. The log of the global P-value is presented on the y axis and SNPs are presented across the x axis in chromosomal order. Horizontal lines are 4-SNP haplotype windows. The red horizontal line shows the significance threshold. A full color version of this figure is available at the European Journal of Human Genetics journal online.
© Copyright Policy
Related In: Results  -  Collection

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

fig3: Haplotype association results for HDL (a), TG (b), LDL-C (b), ApoA1 (d) and ApoB (e) levels. The log of the global P-value is presented on the y axis and SNPs are presented across the x axis in chromosomal order. Horizontal lines are 4-SNP haplotype windows. The red horizontal line shows the significance threshold. A full color version of this figure is available at the European Journal of Human Genetics journal online.
Mentions: A total of 123 overlapping windows, each containing four SNPs, were constructed using the sliding window approach (sliding one SNP at a time) for haplotype analysis of 126 variants with lipid traits (Figure 3). P-values were calculated based on the comparison of each haplotype with the most common reference haplotype. The strongest haplotype effects were observed on HDL-C, followed by ApoB, comprising 19 and 18 nominally significant (P<0.05) global P-values, respectively (Supplementary Table 11). The most significant window (‘window 81' containing rs313:A>G, rs314:A>G, rs77434393:G>A and rs316:C>A) was associated with both HDL-C (global P=2.32E-04) and ApoA1 (global P=0.021). The only SNP in this window that showed association in single-site analysis was rs316:C>A (P=0.003 with HDL-C; P=0.022 with ApoA1) and thus the observed haplotype association seemed to be primarily driven by this SNP. Although the haplotypes in intron 6–intron 8 region were associated with HDL-C and ApoA1, those in intron 8–intron 9 were associated with ApoB. Although no common LPL SNPs were associated with TG in single-site analysis, seven haplotype windows showed nominal associations with TG. Overall, haplotype analysis was more informative for TG and LDL-C than single-site analysis.

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