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Genetics of Plasminogen Activator Inhibitor-1 (PAI-1) in a Ghanaian Population.

White MJ, Kodaman NM, Harder RH, Asselbergs FW, Vaughan DE, Brown NJ, Moore JH, Williams SM - PLoS ONE (2015)

Bottom Line: We also analyzed the upper quartile of PAI-1, the most clinically relevant part of the distribution, and found 19 SNPs significantly associated in this quartile.Of note an association was found in period circadian clock 3 (PER3).They also provide evidence of the generalizability of the circadian pathway's effect on PAI-1, as a recent meta-analysis performed in Caucasian populations identified another circadian clock gene (ARNTL).

View Article: PubMed Central - PubMed

Affiliation: Center for Human Genetics Research, Vanderbilt University, Nashville, Tennessee, United States of America; Department of Genetics and Institute of Quantitative Biomedical Sciences, Dartmouth College, Hanover, New Hampshire, United States of America.

ABSTRACT
Plasminogen activator inhibitor 1 (PAI-1), a major modulator of the fibrinolytic system, is an important factor in cardiovascular disease (CVD) susceptibility and severity. PAI-1 is highly heritable, but the few genes associated with it explain only a small portion of its variation. Studies of PAI-1 typically employ linear regression to estimate the effects of genetic variants on PAI-1 levels, but PAI-1 is not normally distributed, even after transformation. Therefore, alternative statistical methods may provide greater power to identify important genetic variants. Additionally, most genetic studies of PAI-1 have been performed on populations of European descent, limiting the generalizability of their results. We analyzed >30,000 variants for association with PAI-1 in a Ghanaian population, using median regression, a non-parametric alternative to linear regression. Three variants associated with median PAI-1, the most significant of which was in the gene arylsulfatase B (ARSB) (p = 1.09 x 10(-7)). We also analyzed the upper quartile of PAI-1, the most clinically relevant part of the distribution, and found 19 SNPs significantly associated in this quartile. Of note an association was found in period circadian clock 3 (PER3). Our results reveal novel associations with median and elevated PAI-1 in an understudied population. The lack of overlap between the two analyses indicates that the genetic effects on PAI-1 are not uniform across its distribution. They also provide evidence of the generalizability of the circadian pathway's effect on PAI-1, as a recent meta-analysis performed in Caucasian populations identified another circadian clock gene (ARNTL).

No MeSH data available.


Related in: MedlinePlus

Manhattan Plot of Common Variant Association Analysis with Upper Quartile of PAI-1 distribution.Only markers on chromosomes 1–22 are presented above; regions from the X chromosome, Y chromosome, pseudo-autosomal region of the X chromosome, and mitochondrial markers have been excluded. Top three significant markers are labeled in bold. Red Line represents FDR significance threshold (2.57 x 10−6). Loci with more than one significant variant are signified by a box. Noteworthy significant associations are labeled in bold.
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pone.0136379.g002: Manhattan Plot of Common Variant Association Analysis with Upper Quartile of PAI-1 distribution.Only markers on chromosomes 1–22 are presented above; regions from the X chromosome, Y chromosome, pseudo-autosomal region of the X chromosome, and mitochondrial markers have been excluded. Top three significant markers are labeled in bold. Red Line represents FDR significance threshold (2.57 x 10−6). Loci with more than one significant variant are signified by a box. Noteworthy significant associations are labeled in bold.

Mentions: Quantile regression analyses were performed on the upper quartile of the PAI-1 distribution. Nineteen variants were significant after correction for multiple testing with FDR (Table 3, Fig 2). The most significant effect in the upper quartile of the PAI-1 distribution was observed for rs4755779, located on chromosome 11 (p = 1.44 x 10−10), while the largest negative and positive effects were observed for rs10462021 (β = -0.434), located on chromosome 1, and rs116307792 (β = 0.249), located on chromosome 3 (Table 3). Of note, a 72.6kb region on chromosome 11 containing both the pleckstrin homology-like domain, family B, member 1 (PHLDB1) and trehalase (TREH) genes (PHLDB1/TREH gene region) harbored three SNPS that were significantly associated in the upper quartile, two of which (rs7389 and rs519982) remained significant after Bonferroni correction.


Genetics of Plasminogen Activator Inhibitor-1 (PAI-1) in a Ghanaian Population.

White MJ, Kodaman NM, Harder RH, Asselbergs FW, Vaughan DE, Brown NJ, Moore JH, Williams SM - PLoS ONE (2015)

Manhattan Plot of Common Variant Association Analysis with Upper Quartile of PAI-1 distribution.Only markers on chromosomes 1–22 are presented above; regions from the X chromosome, Y chromosome, pseudo-autosomal region of the X chromosome, and mitochondrial markers have been excluded. Top three significant markers are labeled in bold. Red Line represents FDR significance threshold (2.57 x 10−6). Loci with more than one significant variant are signified by a box. Noteworthy significant associations are labeled in bold.
© Copyright Policy
Related In: Results  -  Collection

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Show All Figures
getmorefigures.php?uid=PMC4556460&req=5

pone.0136379.g002: Manhattan Plot of Common Variant Association Analysis with Upper Quartile of PAI-1 distribution.Only markers on chromosomes 1–22 are presented above; regions from the X chromosome, Y chromosome, pseudo-autosomal region of the X chromosome, and mitochondrial markers have been excluded. Top three significant markers are labeled in bold. Red Line represents FDR significance threshold (2.57 x 10−6). Loci with more than one significant variant are signified by a box. Noteworthy significant associations are labeled in bold.
Mentions: Quantile regression analyses were performed on the upper quartile of the PAI-1 distribution. Nineteen variants were significant after correction for multiple testing with FDR (Table 3, Fig 2). The most significant effect in the upper quartile of the PAI-1 distribution was observed for rs4755779, located on chromosome 11 (p = 1.44 x 10−10), while the largest negative and positive effects were observed for rs10462021 (β = -0.434), located on chromosome 1, and rs116307792 (β = 0.249), located on chromosome 3 (Table 3). Of note, a 72.6kb region on chromosome 11 containing both the pleckstrin homology-like domain, family B, member 1 (PHLDB1) and trehalase (TREH) genes (PHLDB1/TREH gene region) harbored three SNPS that were significantly associated in the upper quartile, two of which (rs7389 and rs519982) remained significant after Bonferroni correction.

Bottom Line: We also analyzed the upper quartile of PAI-1, the most clinically relevant part of the distribution, and found 19 SNPs significantly associated in this quartile.Of note an association was found in period circadian clock 3 (PER3).They also provide evidence of the generalizability of the circadian pathway's effect on PAI-1, as a recent meta-analysis performed in Caucasian populations identified another circadian clock gene (ARNTL).

View Article: PubMed Central - PubMed

Affiliation: Center for Human Genetics Research, Vanderbilt University, Nashville, Tennessee, United States of America; Department of Genetics and Institute of Quantitative Biomedical Sciences, Dartmouth College, Hanover, New Hampshire, United States of America.

ABSTRACT
Plasminogen activator inhibitor 1 (PAI-1), a major modulator of the fibrinolytic system, is an important factor in cardiovascular disease (CVD) susceptibility and severity. PAI-1 is highly heritable, but the few genes associated with it explain only a small portion of its variation. Studies of PAI-1 typically employ linear regression to estimate the effects of genetic variants on PAI-1 levels, but PAI-1 is not normally distributed, even after transformation. Therefore, alternative statistical methods may provide greater power to identify important genetic variants. Additionally, most genetic studies of PAI-1 have been performed on populations of European descent, limiting the generalizability of their results. We analyzed >30,000 variants for association with PAI-1 in a Ghanaian population, using median regression, a non-parametric alternative to linear regression. Three variants associated with median PAI-1, the most significant of which was in the gene arylsulfatase B (ARSB) (p = 1.09 x 10(-7)). We also analyzed the upper quartile of PAI-1, the most clinically relevant part of the distribution, and found 19 SNPs significantly associated in this quartile. Of note an association was found in period circadian clock 3 (PER3). Our results reveal novel associations with median and elevated PAI-1 in an understudied population. The lack of overlap between the two analyses indicates that the genetic effects on PAI-1 are not uniform across its distribution. They also provide evidence of the generalizability of the circadian pathway's effect on PAI-1, as a recent meta-analysis performed in Caucasian populations identified another circadian clock gene (ARNTL).

No MeSH data available.


Related in: MedlinePlus