Promoter (4G/5G) Plasminogen Activator Inhibitor-1 Genotype and Plasminogen Activator Inhibitor-1 Levels in Blacks, Hispanics, and Non-Hispanic Whites

Abstract

Background-The 4G/5G polymorphism of the plasminogen activator inhibitor-1 (PAI-1) gene has been related to cardiovascular disease. Methods and Results-Insulin resistance was measured with a frequently sampled intravenous glucose tolerance test in the Insulin Resistance Atherosclerosis Study (IRAS), and PAI-1 4G/5G promoter genotype was established by allelespecific polymerase chain reaction amplification of genomic DNA. There were 287 subjects with the 4G/4G genotype (18.4%), 691 heterozygote subjects (44.2%), and 586 carriers of the 5G/5G genotype (37.5%). The genotype distribution was different across the 3 ethnic groups (Pϭ0.001). PAI-1 levels were lower in blacks than in non-Hispanic whites and Hispanics and lower in non-Hispanic whites than in Hispanics (all Pϭ0.0001). Subjects homozygous for the 4G allele had the highest plasma PAI-1, heterozygote subjects were intermediate, and 5G homozygotes had the lowest levels of PAI-1. These patterns remained unaffected by adjustments for age, gender, clinical center, glucose tolerance status, body mass index, waist, triglycerides, and insulin resistance. Multiple linear regression analyses showed that the 4G/5G genotype explained very little of the variation in PAI-1 levels (0.63% in non-Hispanic whites, 0.99% in Hispanics, and 2.37% in blacks), and interaction analyses revealed no significant differences in the relation of circulating PAI-1 levels to the 4G/5G genotype by ethnicity (Pϭ0.4). Conclusions-We have shown ethnic differences in the PAI-1 4G/5G polymorphism along with corresponding differences in circulating PAI-1 levels. The association of the genotype with PAI-1 levels was seen consistently among all 3 ethnic groups and was unaffected by metabolic covariates, including insulin resistance. (Circulation. 2003;107:2422-2427.)

Plasminogen activator inhibitor-1 promoter activity in adipocytes is not influenced by the 4 G/5 G promoter polymorphism and is regulated by a USF-1/2 binding site immediately preceding the polymorphic region

“…Our results are comparable with those of others who found no significant association between the 4 G/5 G polymorphism and plasma levels of PAI-1 in diabetic or non-diabetic patients (Mansfield et al 1995b, Matsubara et al 1999, Festa et al 2003. In addition, Van Harmelen et al (2000) reported that PAI-1 secretion from abdominal subcutaneous adipose tissue is not influenced by the polymorphism.…”

The determinants of plasma plasminogen activator inhibitor-1 levels differ for American and Japanese men aged 40–49

“…Third, it may be explained by the differences in genetic factors between these ethnic groups. Subjects homozygous for the 4G allele at position -675 in the promoter have higher PAI-1 levels 33 and ethnic differences in the distribution of 4G/5G polymorphism have been reported 6 . Although our study did not conduct genotyping, one mechanism for lower PAI-1 levels in Americans may be explained by lower prevalence of 4G/4G genotype in Americans compared to the Japanese 34 .…”

“…Festa et al reported that blacks had lower PAI-1 levels and Hispanics had higher PAI-1 levels compared to non-Hispanic whites even after adjustment of waist, insulin sensitivity and other associated factors 6 . Iso et al reported a decade ago that Americans had higher PAI-1 levels as well as higher cholesterol levels compared to Japanese 7 .…”

Perspective on Selected Issues in Cardiovascular Disease Research With a Focus on Black Americans

“…36 Additional data also show that PAI-1 levels were lower among blacks than among whites and Hispanics and that there was an association between the PAI-1 4G/5G polymorphism and serum levels of PAI-1, as well as with ethnicity. 37 These data further emphasize the need for large-scale prospective data that investigate the interrelations between novel markers of thrombosis and inflammation and cardiovascular disease across ethnic groups.…”