In Black South Africans from Rural and Urban Communities, the 4G/5G PAI-1 Polymorphism Influences PAI-1 Activity, but Not Plasma Clot Lysis Time

Zelda de Lange,Marlien Pieters,Karin R. Conradie,Tiny Hoekstra,Johann C. Jerling,Dingeman C. Rijken,Hugo ten Cate

doi:10.1371/journal.pone.0083151

Zelda de Lange, Marlien Pieters + Show 5 more

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https://doi.org/10.1371/journal.pone.0083151

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Abstract

Data on genetic and environmental factors influencing PAI-1 levels and their consequent effect on clot lysis in black African populations are limited. We identified polymorphisms in the promoter area of the PAI-1 gene and determined their influence on PAI-1act levels and plasma clot lysis time (CLT). We also describe gene-environment interactions and the effect of urbanisation. Data from 2010 apparently healthy urban and rural black participants from the South African arm of the PURE study were cross-sectionally analysed. The 5G allele frequency of the 4G/5G polymorphism was 0.85. PAI-1act increased across genotypes in the urban subgroup (p = 0.009) but not significantly in the rural subgroup, while CLT did not differ across genotypes. Significant interaction terms were found between the 4G/5G polymorphism and BMI, waist circumference and triglycerides in determining PAI-1act, and between the 4G/5G polymorphism and fibrinogen and fibrinogen gamma prime in determining CLT. The C428T and G429A polymorphisms did not show direct relationships with PAI-1act or CLT but they did influence the association of other environmental factors with PAI-1act and CLT. Several of these interactions differed significantly between rural and urban subgroups, particularly in individuals harbouring the mutant alleles. In conclusion, although the 4G/5G polymorphism significantly affected PAI-1act, it contributed less than 1% to the PAI-1act variance. (Central) obesity was the biggest contributor to PAI-1act variance (12.5%). Urbanisation significantly influenced the effect of the 4G/5G polymorphism on PAI-1act as well as gene-environment interactions for the C428T and G429A genotypes in determining PAI-1act and CLT.

Highlights

The prevalence of cardiovascular disease (CVD) has increased significantly in developing countries, and will continue to do so in the future [1]
Owing to large differences in environmental factors between the rural and urban setting, we aimed to investigate the effect of geneenvironment interactions (e.g. BMI, blood lipids) on PAI-1act and clot lysis time (CLT) and whether these interactions were influenced by urbanisation which can be viewed as a specific combination/grouping of environmental factors
This study provides the first population-based data for genotype frequencies of the 4G/5G polymorphism in a large black African population

Summary

Introduction

The prevalence of cardiovascular disease (CVD) has increased significantly in developing countries, and will continue to do so in the future [1]. One of the factors that have repeatedly been shown to be associated with an increased risk of CVD is increased levels of plasminogen activator inhibitor type-1 (PAI-1) [4,5]. PAI-1 can contribute to the development of CVD through several mechanisms, including influencing plaque formation as well as being a major inhibitor of blood clot lysis [6,7]. The speed with which the body can lyse clots, often reported as lysis time, has been linked to CVD [8]. This reflects an individual’s fibrinolytic potential and can be measured with the use of global fibrinolytic assays. PAI-1 antigen (PAI-1ag) levels have been found to explain a large portion (24%) of the variance in clot lysis time (CLT) in a white population [9], while PAI-1 activity (PAI-1act) explained 27% of CLT variance in the black African PURE population [10]

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