Elsevier

Annales de Génétique

Volume 47, Issue 2, April–June 2004, Pages 155-162
Annales de Génétique

Genotype and allele frequency of PAI-1 promoter polymorphism in healthy subjects from the west of Mexico. Association with biochemical and hematological parameters

https://doi.org/10.1016/j.anngen.2003.12.001Get rights and content

Abstract

We investigated the genotype and allelic frequency of the –675 bp insertion/deletion polymorphism at the PAI-1 gene promoter, in healthy Mexican subjects. It was compared to the lipid profile and hematological parameters, and to other healthy worldwide populations. A Mexican population sample of 110 individuals was studied. Demographic data and clinical characteristics of the subjects were registered. Fasting lipid profile, serum glucose, fibrinogen, hematological parameters and leukocyte genomic DNA isolation from peripheral blood were performed in all the participants. Screening of the PAI-1 genotype was done by PCR and restriction analysis. Genotype 4G/4G, 4G/5G, 5G/5G frequency in Mexican healthy subjects was: 14.55%, 39.09%, 46.36%, respectively, whereas the allelic frequency for 5G allele was 65.9%. A significant lesser frequency for 4G allele and related genotypes (4G/4G and 4G/5G) was established in healthy subjects from Mexico, respect to all the compared populations. A particular genotype and allelic frequency of this PAI-1 polymorphism was established in Mexico. The clinical parameters were not associated according to each genotype of PAI-1.

Introduction

The plasminogen activator inhibitor type 1 (PAI-1) is a linear glycoprotein composed by 379 amino acids with a molecular weight of 48,000 Da. The main function of PAI-1 is to decrease fibrinolysis, which leads to fibrin accumulation [1], [2] and elevations in plasma PAI-1 appear to compromise normal fibrin clearance mechanisms and promote thrombosis [3]. Plasmin, the enzyme responsible of fibrin degradation, is formed when plasminogen is partly cleaved by t-PA or u-PA on the surface of fibrin. Both plasminogen and t-PA bind to fibrin under circumstances in which t-PA is protected from inhibition by PAI-1. This process facilitates both the activation of plasminogen and the fibrin degradation [4], [5]. The human PAI-1 gene is located on the long arm of chromosome 7 and contains nine exons and eight introns. Several polymorphisms have been described within the gene, among them, there is a single base pair polymorphism (four/five guanine bases: 4G/5G) in the promoter region of the gene, 675 bp upstream of the transcriptional start site [1], [2]. It has been reported that homozygous subjects for the 4G allele (4G/4G genotype) have plasma PAI-1 concentration that are approximately 25% higher than those of subjects who are homozygous for the 5G allele (5G/5G genotype) [6]. In vitro studies have identified differential binding of transcription-regulating proteins at this site. Increased gene transcription is associated with four guanine bases (4G allele), and it results in the binding of a transcriptional activator alone. The five guanine bases (5G allele), binds to a repressor protein that decreases the binding of the activator [6], [7]. The –675 bp polymorphism at PAI-1 has been related with some diseases and dyslipidemias, including: arterial thrombosis in antiphospholipid syndrome, insulin resistance syndrome, type 2 diabetic nephropathy, atherosclerosis, myocardial infarction, coronary artery disease, venous thrombosis in factor V Leiden carriers and rheumatoid arthritis [6], [8], [9], [10], [11], [12], [13], [14], [15]. We investigated the genetic variability of the –675 bp polymorphism at the PAI-1 promoter in healthy subjects from a Mexican population; it was correlated with clinical parameters and frequencies were compared to reports from healthy worldwide populations.

Section snippets

Healthy subjects

We recruited 110 healthy subjects residents from Guadalajara Jalisco, Mexico; consecutively from December 2001 to December 2002. All participants were Mexican Mestizo population between 25 and 69 years old, 84 females and 26 males. According to the National Institute of Anthropology, the definition of a Mexican Mestizo states that the person must have been born in the country, having a Spanish derived last name, with family history of Mexican ancestors, at least back to the third generation [16]

Healthy subjects

Demographic and clinical characteristics of the healthy subjects are shown in the Table 1.

Electrophoretic PAI-1 genotype restriction patterns

Digestion fragments of 77 and 22 bp represent wild genotype (5G/5G); fragments of 98, 77, 22 bp represent heterozygote genotype (4G/5G); and fragment 98 bp represent homozygote genotype (4G/4G). Size of 22 bp was not observed on the gel (Fig. 1 ).

PAI-1 genotype and allelic frequency

Counts and percentage of PAI-1 alleles and genotypes are presented in Table 2. The genotype distribution in Mexican population was in equilibrium with the

Discussion

This is the first study in Mexico that investigates the genetic variability of the insertion/deletion (4G/5G) polymorphism in the promoter region of the PAI-1 gene. The comparison of lipid profile and hematological parameters between PAI-1 genotypes in Mexican healthy population did not show any significant difference.

There is evidence from some in vitro cell stimulation experiments that implicates insulin, VLDL-c and high glucose levels in the production of elevate PAI-1 levels. Supporting

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