Genetic architecture of tissue-type plasminogen activator and plasminogen activator inhibitor-1.
Important biochemical constituents of the fibrinolytic system include tissue-type plasminogen activator (t-PA) and plasminogen activator inhibitor-1 (PAI-1). In the current review, we aim to describe the genetic architecture of t-PA and PAI-1. Several genetic polymorphisms in the T-PA and PAI-1 gene have been found to be associated with t-PA and PAI-1 levels in different patient cohorts. However, these genetic variations explain only a minor part of the heritability of t-PA and PAI-1, suggesting that genes in other pathways may influence t-PA and PAI-1 levels, and that epistasis and gene-environment interactions may play an important role in determining plasma levels of t-PA and PAI-1. Several studies reported that interindividual variation in plasma levels of t-PA and PAI-1 are significantly influenced by common polymorphisms in genes from the renin-angiotensin and bradykinin systems. In addition, we and others documented several gene-environment interactions and epistatic effects of genetic polymorphisms in the renin-angiotensin, bradykinin, and fibrinolytic systems on plasma t-PA and PAI-1 levels. In future studies, we need to consider high-order interactions and additional polymorphisms in genes from other (unknown) pathways detected by genome-wide association studies to fully understand the complex genetic architecture of these important intermediate quantitative traits and thereby thrombosis.
Asselbergs
Folkert W
FW
Department of Cardiology, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands. fwasselbergs@hotmail.com
Pattin
Kristine
K
Snieder
Harold
H
Hillege
Hans L
HL
van Gilst
Wiek H
WH
Moore
Jason H
JH
D001920:Bradykinin / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D017395:Plasminogen Activator Inhibitor 1 / Q000097:blood / Q000235:genetics* / Q000378:metabolism; D011110:Polymorphism, Genetic; D012084:Renin-Angiotensin System / Q000235:genetics*; D013927:Thrombosis / Q000235:genetics* / Q000378:metabolism; D010959:Tissue Plasminogen Activator / Q000097:blood / Q000235:genetics* / Q000378:metabolism
D017395:Plasminogen Activator Inhibitor 1; D010959:Tissue Plasminogen Activator; D001920:Bradykinin