The relationship between plasma t‐PA and PAI‐1 levels is dependent on epistatic effects of theACE I/DandPAI‐1 4G/5Gpolymorphisms

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Abstract
Thrombus formation and degradation is partly due to a complex interplay between tissue‐type plasminogen activator (t‐PA) and plasminogen activator inhibitor 1 (PAI‐1). There is accumulating evidence that plasma levels of t‐PA and PAI‐1 may be influenced by an interaction between the fibrinolytic and renin‐angiotensin systems. The goal of this study was to conduct an exploratory data analysis to determine whether there is evidence that the relationship (i.e. correlation) between plasma t‐PA and PAI‐1 is influenced by interactive effects of theangiotensin converting enzyme (ACE) insertion/deletion (I/D)andplasminogen activator inhibitor 1 (PAI‐1) 4G/5Gpolymorphisms in a sample of 50 unrelated African Americans and 117 unrelated Caucasians. In a single‐locus analysis, no evidence for heterogeneity of plasma t‐PA and PAI‐1 correlations among eitherACE I/DorPAI‐1 4G/5Ggenotypes was detected. However, using the combinatorial partitioning method for exploratory data analysis, we identified evidence that is suggestive of heterogeneity of plasma t‐PA and PAI‐1 correlations among multilocusACE I/DandPAI‐1 4G/5Ggenotypes in African American females, Caucasian females, Caucasian males, but not African American males. From these results, we propose as a working hypothesis that the correlation between plasma t‐PA and PAI‐1 may be dependent on epistatic effects of theACE I/DandPAI‐1 4G/5Gpolymorphisms. This study supports the idea that interactions between the fibrinolytic and renin‐angiotensin systems play an important role in the genetic architecture of plasma t‐PA and PAI‐1.