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

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).

Genetic Susceptibility Determines β-Cell Function and Fasting Glycemia Trajectories Throughout Childhood: A 12-Year Cohort Study (EarlyBird 76)

“…50th percentile) was considered as an analog to the mean of each trait. However, in genetic studies of metabolic traits, genetic variants may display quantile-specific effects (15)(16)(17). Quantile regression was thus performed on the 75 th percentile for each trait to identify common genetic variants associated with high values of glycemic and insulin traits.…”

Leveraging cell type specific regulatory regions to detect SNPs associated with tissue factor pathway inhibitor plasma levels

“…We also tested top SNPs for association with TFPI plasma levels in the F5L family study under quantile regression models, with quantiles set at 0.50 and 0.25. Quantile regression differentially weights associations at different values of the outcome distribution, and may be more powerful than mean regression when the outcome is skewed (White et al., ). We used the R package lqmm (Geraci, ), which accounted for clustering by family, but did not explicitly model family structures as in our primary (mean regression) analysis.…”

Polymorphism of the trehalase gene (TREH) in native populations of Siberia

“…Единственное отличие гаплотипа SQ2 от SQ1 -замена в локусе rs7389, который расположен в нетранслируемой области между генами PHLDB1 и TREH. Предполагается, что эта мутация повреждает сайт связывания с микроРНК, ингибируя тем самым трансляцию белковых продуктов расположенных рядом генов (White et al, 2015). Можно предположить, что уже на данном этапе начинается про-цесс снижения активности трегалазы.…”

“…Можно предположить, что уже на данном этапе начинается про-цесс снижения активности трегалазы. Кроме того, ранее была обнаружена ассоциация между полиморфизмом в локусе rs7389 и ингибированием активации плазминогена типа 1, что может повышать риск сосудистых осложнений и различных тромбоэмболий (White et al, 2015). Следу-ющая мутация появляется в гаплотипе SQ3.…”