Penrod, NM;
Poku, KA;
Vaughan, DE;
Asselbergs, FW;
Brown, NJ;
Moore, JH;
Williams, SM;
(2011)
Epistatic interactions in genetic regulation of t-PA and PAI-1 levels in a Ghanaian population.
PLoS One
, 6
(1)
, Article e16639. 10.1371/journal.pone.0016639.
![[thumbnail of journal.pone.0016639.pdf]](https://discovery.ucl.ac.uk/style/images/fileicons/application_pdf.png) Preview |
PDF
journal.pone.0016639.pdf Download (322kB) |
Abstract
The proteins, tissue plasminogen activator (t-PA) and plasminogen activator inhibitor 1 (PAI-1), act in concert to balance thrombus formation and degradation, thereby modulating the development of arterial thrombosis and excessive bleeding. PAI-1 is upregulated by the renin-angiotensin system (RAS), specifically by angiotensin II, the product of angiotensin converting enzyme (ACE) cleavage of angiotensin I, which is produced by the cleavage of angiotensinogen (AGT) by renin (REN). ACE indirectly stimulates the release of t-PA which, in turn, activates the corresponding fibrinolytic system. Single polymorphisms in these pathways have been shown to significantly impact plasma levels of t-PA and PAI-1 differently in Ghanaian males and females. Here we explore the involvement of epistatic interactions between the same polymorphisms in central genes of the RAS and fibrinolytic systems on plasma t-PA and PAI-1 levels within the same population (n = 992). Statistical modeling of pairwise interactions was done using two-way ANOVA between polymorphisms in the ETNK2, RENIN, ACE, PAI-1, t-PA, and AGT genes. The most significant interactions that associated with t-PA levels were between the ETNK2 A6135G and the REN T9435C polymorphisms in females (p = 0.006) and the REN T9435C and the TPA I/D polymorphisms (p = 0.005) in males. The most significant interactions for PAI-1 levels were with REN T9435C and the TPA I/D polymorphisms (p = 0.001) in females, and the association of REN G6567T with the TPA I/D polymorphisms (p = 0.032) in males. Our results provide evidence for multiple genetic effects that may not be detected using single SNP analysis. Because t-PA and PAI-1 have been implicated in cardiovascular disease these results support the idea that the genetic architecture of cardiovascular disease is complex. Therefore, it is necessary to consider the relationship between interacting polymorphisms of pathway specific genes that predict t-PA and PAI-1 levels.
| Type: | Article |
|---|---|
| Title: | Epistatic interactions in genetic regulation of t-PA and PAI-1 levels in a Ghanaian population |
| Location: | United States |
| Open access status: | An open access version is available from UCL Discovery |
| DOI: | 10.1371/journal.pone.0016639 |
| Publisher version: | http://dx.doi.org/10.1371/journal.pone.0016639 |
| Language: | English |
| Additional information: | © 2011 Penrod et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. PMCID: PMC3031598 |
| Keywords: | Analysis of Variance, Epistasis, Genetic, Female, Gene Expression Regulation, Ghana, Humans, Male, Plasminogen Activator Inhibitor 1, Polymorphism, Genetic, Sex Factors, Tissue Plasminogen Activator |
| UCL classification: | UCL UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Population Health Sciences > Institute of Health Informatics |
| URI: | https://discovery.ucl.ac.uk/id/eprint/1414415 |
Archive Staff Only
 |
View Item |
