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 impl icated in a number of processes, including activation of a variety of metalloproteinases, matrix remodeling, and cell migration, which may u nderlie the early initiation and progression of atherosclerosis and co ronary artery disease (CAD). These studies were carried out to determi ne whether variations in the u-PA gene, using a BamHI restriction frag ment length polymorphism (RFLP) as a new marker for genetic variation, may be associated with CAD. Southern blot analysis of individual dige sted 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 c onstant 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 umbil ical cord samples, representing a ''control'' population, were analyze d 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, s howed 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 distribut ion 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 deriv ed from CABG patients demonstrated a significant difference in the dis tribution 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 s tudies demonstrate a significant association between u-PA gene polymor phism and the presence or absence of CAD.