Identification of a BamHI Polymorphism for the Urokinase Gene Associated with Symptomatic Coronary Artery Disease

Urokinase-type plasminogen activator (u-PA) and plasmin have been implicated in a number of processes, including activation of a variety of metalloproteinases, matrix remodeling, and cell migration, which may underlie the early initiation and progression of atherosclerosis and coronary artery disease (CAD). These studies were carried out to determine whether variations in the u-PA gene, using a BamHI restriction fragment length polymorphism (RFLP) as a new marker for genetic variation, may be associated with CAD. Southern blot analysis of individual digested genomic DNA (BamHI), hybridized with a 2-kb human u-PA cDNA probe, identified a two-allele RFLP with allelic bands at 6 and 1.5 kb. A constant band at 9 kb was detected. Three genotypes were identified and designated as 1/1 (6.0-kb band only), 1/2 (6.0 and 1.5-kb bands), and 2/2(1.5-kb band only). For these studies, 43, individual human umbilical cord samples, representing a "control" population, were analyzed and compared in terms of their u-PA genotypes with 34 saphenous vein samples from patients requiring coronary artery bypass grafting (CABG). Controls, presumed to reflect the normal population distribution, showed a u-PA genotype distribution of 1/1(n = 8, 18.6%), 1/2 (n = 33, 76.7%) and 2/2 (n = 2, 4.7%), whereas CAD patients showed a distribution of 1/1 (n = 16, 47.1%), 1/2 (n = 13, 38.2%), and 2/2 (n = 5, 14.7%). Comparison of the "control" genotype distribution with data derived from CABG patients demonstrated a significant difference in the distribution of u-PA genotypes (P = 0.002), with an increased prevalence of the homozygous 1/1 and 2/2 genotypes in CAD patients. These early studies demonstrate a significant association between u-PA gene polymorphism and the presence or absence of CAD.