Association Analysis of the Plasminogen Activator Inhibitor-1 4G/5G Polymorphism in Hispanics and African Americans: The IRAS Family Study

Abstract

Objective: Plasminogen activator inhibitor type-1 (PAI-1) plays a central role in fibrolysis and has recently been hypothesized to influence components of the insulin resistance syndrome. We consider whether the 4G/5G polymorphism influences components of insulin resistance and obesity solely through PAI-1 protein levels or also though a secondary pathway. In addition, we explore whether transforming growth factor (TGF-β1), a key regulator of PAI-1 expression, modifies the influence of the PAI-1 4G/5G polymorphism on these traits. Methods and Results: The Insulin Resistance and Atherosclerosis (IRAS) Family Study genotyped 287 African American (18 pedigrees) and 811 Hispanic American (45 pedigrees) individuals for the 4G/5G PAI-1 and two TGF-β1 polymorphisms (R25P, C-509T). Individuals were recruited from three clinical centers located in San Antonio (urban Hispanic), San Luis Valley (rural Hispanic) and Los Angeles (African American). The presence of the 4G PAI-1 allele was positively associated with PAI-1 protein level (combined sample p < 0.0001). Hispanic Americans average 65% higher PAI-1 protein levels than African Americans (p < 0.0001). Consistently across ethnic groups, increased PAI-1 protein levels were associated with increased insulin resistance and overall and central obesity (p value < 0.0001, combined sample). Adjusting for PAI-1 protein levels, there was evidence of an association of PAI-1 genotype (4G) with insulin sensitivity (p < 0.002) and subcutaneous fat (p < 0.01). These associations were not influenced by TGF-β1 genotypes. Conclusions: PAI-1 protein is a strong correlate of insulin resistance (IR) and obesity in Hispanics and African Americans. However, PAI-1 4G/5G polymorphism appears to influence insulin resistance and obesity beyond its direct influence on serum PAI-1 protein levels.

4G/5G Plasminogen Activator Inhibitor-1 Polymorphisms and Haplotypes Are Associated with Pneumonia

“…The cohort was randomly chosen from two urban areas in the United States, and the incidence of CAP in our cohort is similar to other population-based studies (41,43). The genotype and haplotype frequencies are consistent with previous studies in blacks and whites, including recently published highdensity SNP map analysis of the PAI-1 gene (28,29,44,45).…”

Polymorphisms in the Genes Related to Angiogenesis Are Associated With Uterine Cervical Cancer

“…29 Not only that the report is not a LD between SNPs studied, but also they bet that other genetic variants may be interacting because it is known that TGF-A1 is the main determinant of the level of PAI-1 protein. 30 In our report, the LD has been observed; this is to say that these polymorphisms individually represent different associations with UCC, but when they are combined, the interactions is clear; as a consequence, an epistatic effect could be generated among these 2 SNPs.…”

Nutrition and hemostasis: A focus on urbanization in South Africa

“…In general, the highest PAI-1 levels are observed for the 4G-allele [64,65], although the influence of this polymorphism on plasma PAI-1 levels is considered to be only moderate. In African Americans, the 4G-allele is less common than in Caucasians; African Americans have a higher prevalence of the 5G-allele [57,66,67]. The only evidence form Africans is from a small case-control study performed in South African Zulu women in which the prevalence of the 5G-allele was even higher than generally observed in African Americans [68].…”