Dawson et al. (1993) and Eriksson et al. (1995) demonstrated that raised PAI1 plasma levels are related to a 1-bp guanine deletion/insertion (4G/5G) polymorphism in the promoter of the PAI1 gene. The 4G allele is associated with higher plasma PAI1 transcription and activity. Although both alleles bind a transcriptional activator, the 5G allele also binds a repressor protein to an overlapping binding site. In the absence of bound repressor, the 4G allele is associated with an increased basal level of PAI1 transcription. Eriksson et al. (1995) found that the prevalence of the 4G allele was significantly higher in patients with myocardial infarction before the age of 45 (allele frequency of 0.63) than in population-based controls (allele frequency of 0.53).
Margaglione et al. (1998) investigated the relationship between the PAI1 4G/5G polymorphism in 1,179 healthy employees and the occurrence of coronary artery disease in their first-degree relatives. The group with a first-degree relative who had suffered from a coronary ischemic episode had a higher number of homozygotes for the 4G allele compared with subjects without such a family history (odds ratio = 1.62). The frequency of the 4G allele was abnormally high in individuals with a family history who also had a higher body mass index and total cholesterol levels.
In a study of the PAI1 genotype in 175 children with meningococcal disease, Hermans et al. (1999) found that the median PAI1 concentration in children who died was substantially higher than that in survivors. Patients with the 4G/4G genotype had significantly higher PAI1 concentrations than those with the 4G/5G or 5G/5G genotype and had an increased risk of death. The findings suggested that impaired fibrinolysis is an important factor in the pathophysiology of meningococcal sepsis.
Some patients infected with Neisseria meningitidis develop septic shock accompanied by fibrin deposition and microthrombus formation in various organs, whereas others develop bacteremia or meningitis without septic shock. Westendorp et al. (1999) investigated whether genetic differences in the fibrinolytic system influence the development of meningococcal septic shock. They studied 50 patients who survived meningococcal infection, and 131 controls from the same geographic region. Because they had no information on genotypes of patients who died, they also genotyped 183 first-degree relatives of a consecutive series of patients with meningococcal infection for the 4G/5G deletion/insertion polymorphism in the promoter region of the PAI1 gene. The 4G allele was associated with increased gene transcription in cell lines in vitro and with increased PAI1 concentrations in carriers in vivo. The allele frequencies of 4G and 5G were similar between patients and controls. However, the 4G/4G genotype was present in only 9% of relatives of patients with meningitis compared with 36% of relatives of patients with septic shock. Patients whose relatives were carriers of the 4G/4G genotype had a 6-fold higher risk of developing septic shock than meningitis compared with all other genotypes. Westendorp et al. (1999) concluded that variation in the PAI1 gene does not affect the probability of contracting meningococcal infection, but does influence the development of septic shock.
Preeclampsia is associated with thrombosis of the intervillous or spiral artery of the placenta. Yamada et al. (2000) assessed the association between preeclampsia and the 4G/5G polymorphism of the PAI1 gene in 115 preeclampsia patients, 210 pregnant controls, and 298 healthy volunteer controls. The frequency of homozygotes for the 4G allele was significantly higher in the patients than in the control pregnant women or healthy volunteers. The 4G allele frequency was also significantly higher in the patients than in the 2 control groups.
Yoon et al. (1999) found no association between the 4G/5G polymorphism in the PAI1 gene and abdominal aortic aneurysm in a study of 47 Finnish patients and 74 controls.
The 5G variant of PAI1 is associated with less inhibition of the plasminogen activators and, consequently, increased conversion of plasminogen to plasmin and increased activation of matrix metalloproteinases. Thus, patients with this variant may be more at risk of the development of abdominal aortic aneurysm (AAA; 100070). Rossaak et al. (2000) studied the ratios of the 4G:5G genotypes in 190 patients with AAA, including 39 patients with strong family histories, and 163 controls. The frequency of the 4G:5G alleles in the AAA population and in the control population was 0.6:0.4. However, 26% of patients with familial AAA were homozygous 5G compared with 13% of the control population. The 4G allele frequency was 0.47 in the familial AAAs, compared with 0.62 in the nonfamilial patients (P = 0.02) and 0.61 in the control population (P = 0.03). The association of the 5G homozygous genotype with familial AAA questioned the idea that atherosclerosis causes AAAs. Whereas the 4G variant of PAI1 shows a protective role in AAA, it is undesirable in the context of coronary artery disease and atherosclerosis (Harris, 2001).
