Association between the Promoter -675 4G/5G Polymorphism of the Plasminogen Activator Inhibitor-1 Gene and Asthma: An Update of Meta-Analysis

Research Article

Austin Immunol. 2016; 1(2): 1011.

Association between the Promoter -675 4G/5G Polymorphism of the Plasminogen Activator Inhibitor-1 Gene and Asthma: An Update of Meta-Analysis

Huang X, Yang M, Wang Y, Zhang X and Yang H*

Department of Preventive Medicine, Hubei University of Chinese Medicine, P. R. China

*Corresponding author: Haijun Yang, Department of Preventive Medicine, College of Basic Medical Sciences, Hubei University of Chinese Medicine, Wuhan 430065, Hubei, P. R. China

Received: October 12, 2016; Accepted: November 09, 2016; Published: November 10, 2016

Abstract

Background and Objectives: Several studies have explored the association between the promoter -675 4G/5G polymorphism of the Plasminogen Activator Inhibitor-1 (PAI-1) gene and asthma risk; however the results are inconsistent. The purpose of this study was to evaluate the genetic risk of this polymorphism for asthma using the method of meta-analysis.

Methods: Systemic electronic literature search was conducted on PAI-1 polymorphism and asthma risk in several databases. The data were pooled employing the meta-analysis method.

Results: Eight case-control studies involving 1551 asthmatics and 2339 healthy controls were included in this meta-analysis. In the overall population, our results showed that the PAI-1 -675 4G/5G polymorphism was significantly associated with elevated asthma risk in a dominant genetic model [odds ratio (OR)=1.716, 95% confidence interval (CI)=1.190-2.474]. Stratified analyses were conducted based on ethnicity, age and atopic status of asthmatic patients. We observed that the PAI-1 -675 4G allele carriers have increased risk of asthma in both Caucasian and Asian populations (OR=1.749, 95% CI=1.084- 2.823 and OR=1.456, 95% CI=1.019-2.081, respectively). Increased risk of asthma was also seen in adult and children populations of the PAI-1 -675 4G allele carriers (OR=1.558, 95% CI=1.028-2.360 and OR=2.380, 95% CI=1.486- 3.811, respectively). In the case of atopic asthma and non-atopic asthma, the PAI-1 4G/5G polymorphism was significantly associated with atopic asthma susceptibility (OR=2.436, 95% CI=1.783-3.328 for 4G4G+4G5G vs. 5G5G).

Conclusion: Data indicated that the PAI-1 -675 4G/5G polymorphism was associated with increased asthma risk. Recommendations for further studies include pooling of individual data to facilitate assessment of gene-gene and gene-environment interactions in asthma susceptibility.

Keywords: Asthma; Meta-analysis; Plasminogen activator inhibitor-1; Polymorphism

Abbreviations

BHR: Bronchial Hyperresponsiveness; PAI: Plasminogen Activator Inhibitor; OR: Odds Ratio; CI: Confidence Interval; CNKI: Chinese National Knowledge Infrastructure; HWE: Hardy-Weinberg Equilibrium

Introduction

Asthma is a common chronic inflammatory respiratory disease, which is characterized by chronic airway inflammation, Bronchial Hyperresponsiveness (BHR) and airway remodeling. The prevalence of asthma is high in developed countries and there is a concern that its prevalence is still rising in both developed and developing countries [1]. It is widely accepted that asthma is a complex polygenic disease whose pathogenesis involves complex interactions of environmental and genetic factors [2,3]. In the past decades, much effort has been made to explore the susceptible genes of asthma.

The Plasminogen Activator Inhibitor (PAI)-1, a 50 kD glycoprotein, belongs to the SERPIN family, which is abbreviated from the serine protease inhibitor. PAI-1 is the key inhibitor of the fibrinolytic system by hindering the activation of plasminogen and is known to play an essential role in tissue remodeling [4]. PAI-1 might play an important role in the pathogenesis of asthma [4]. For instance, Kowal, et al. and Xiao, et al. have reported that there are elevated PAI- 1 levels in the induced sputum or plasma of patients with asthma in comparison with that of healthy controls [5,6], and the plasma PAI-1 levels of asthmatics were pronouncedly up-regulated during allergen challenge [6]. A large number of mast cells, a predominant effector cell of asthma, expressing high level of PAI-1 were found in the lung tissue of severe asthmatics [7].

A polymorphism at position -675 in the 5’ terminal promoter region of the PAI-1 gene, consisting of two alleles 4G and 5G (PAI-1 -675 4G/5G, rs1799889), has been described to regulate transcription of the PAI-1 gene. For example, Dawson, et al. and Kowal, et al. have reported that the plasma levels of PAI-1 are higher in individuals with the 4G4G genotype than in those with the 5G5G genotype, whereas the 4G5G genotype has intermediate values [6,8]. Since Cho, et al. demonstrated that the PAI-1 4G allele is preferentially transmitted to asthmatic children based on the transmission disequilibrium test in nuclear families from the UK [9], several case-control studies have investigated the association between the PAI-1 4G/5G polymorphism and asthma risk [10-18]. However, the results of these studies were inconsistent and inconclusive. Because a single study may have low power to detect the effect of polymorphism, it is necessary to carry out a meta-analysis to summarize the effect size of PAI-1 4G/5G polymorphism on asthma risk. To date, one meta-analysis of association of this polymorphism with asthma risk has been reported [19], however, the results needed further evaluation for the following reasons: firstly, the included studies were not strictly checked in accordance with their inclusion criteria and some overlapped studies were included into the meta-analysis more than once; secondly, the previous meta-analysis was performed using a classical meta-analysis method. Considering a meta-analysis of genetic polymorphism association studies involving multiple comparisons with a classical method, this might increase the risk of type I error. Thirdly, one new case-control study concerning this polymorphism and asthma risk has been reported since the meta-analysis was published.

Based on above analysis, an updated meta-analysis was performed to summarize reported case-control studies concerning the PAI-1 -675 4G/5G polymorphism and asthma risk in all ethnic populations according to the framework for conducting a meta-analysis of molecular association studies [20]. To overcome the limitation of the classical meta-analysis involving multiple comparisons in genetic association studies, a logistic-regression based meta-analysis of genetic association case-control studies was applied to calculate the Odds Ratio (OR) and 95% Confidence Interval (CI) for PAI-1 -675 4G4G versus (vs.) 5G5G (OR4G4G vs. 5G5G) and 4G5G vs. 5G5G (OR4G5G vs. 5G5G) and to decipher the most plausible genetic action model [21].

Methods

Search strategy and inclusion criteria

A systematic literature search was carried out in Medline, Embase, Wanfang, Weipu and Chinese National Knowledge Infrastructure (CNKI) to indentify studies concerning the association between the PAI-1 polymorphism and asthma susceptibility. The following search terms were used: “asthma or asthmatic” in combination with “plasminogen activator inhitor-1 or PAI-1 or SERPIN-1”. We reviewed all related studies published before October 1, 2016.

The studies which meet the following criteria were incorporated into this meta-analysis: (1) the paper should include asthma risk and PAI-1 4G/5G polymorphism; (2) the article should be published in English or Chinese; (3) only case-control or cohort studies were considered, however, the study design should not be a family-based association or sibling pairs; (4) the study should clearly report the frequencies of each genotype; (5) when there were multiple publications from the same group, only the most recent or the publication with more complete information was included in the analysis.

Data extraction

The following information was extracted from each study: the name of the first author, publication year, country of origin, ethnicity and age of subjects, sample size and asthma definition and frequencies of each genotype.

Statistical analysis

The effect size of the PAI-1 -675 4G/5G polymorphism on asthma risk was evaluated using OR with corresponding 95% CI. Firstly, the 4G and 5G alleles of PAI-1 4G/5G promoter polymorphism were compared. Then the risks of a dominant model (4G4G+4G5G vs. 5G5G) and a recessive model (4G4G vs. 4G5G+5G5G) were estimated. Data were pooled using a fixed-effect model when there was no significant heterogeneity, otherwise a random-effect model (DerSimonian and Laird method) was used [22]. The statistical significance of summary ORs was analyzed by the Z test. A chisquare- based Cochran’s Q statistic and index of inconsistency (I2) were employed to assess heterogeneity among studies [23].

To calculate ORs for 4G4G vs. 5G5G genotypes and 4G5G vs. 5G5G genotypes, which involve multiple comparisons if using the classical meta-analysis method, a novel logistic-regression based meta-analysis of case-control genetic association studies was adopted [21]. It was reported that this methodology could avoid multiple comparisons and give the most plausible genetic model based on statistical results rather than empirical observations. The estimation algorisms are as follows: OR4G4G vs. 5G5G (OR1) and OR4G5G vs. 5G5G (OR2) are calculated using the logic-regression-based method and then compared, if OR1=OR2=1, no statistically significant association was indicated; if OR1>1 and OR2=1 (the difference between OR1 and OR2 are statistically significant), then a recessive genetic model is proposed; if OR1>OR2>1 (statistically significantly), then a codominant model is suggested; if OR1=OR2>1, then a dominant model is indicated.

Deviations from Hardy-Weinberg Equilibrium (HWE) of the genotype distribution of each control group were assessed by Pearson’s chi-squared test. Publication bias was examined using Egger’s regression test and Begg’s rank correlation method [24,25]. All statistical analyses were performed using STATA of version 10.1 (STATA Corporation, College Station, Texas, USA). All tests were two-sided, and a P value of less than 0.05 was considered to be statistically significant, with the exception of heterogeneity tests where a P value less than 0.10 and I2 value of more than 50.0% were used.

Results

Characteristics of studies included in the meta-analysis

A total of 57 articles were identified after the initial search, including 46 papers written in English and 11 in Chinese. Based on the abstract of each article, 11 studies were enrolled for full-text review. After reading the full texts, three studies were excluded from the meta-analysis for the following reasons: one for repeated publication [12], one for a family-based association study design [9] and one for being unrelated to asthma risk and PAI-1 4G/5G polymorphism [26]. Accordingly, eight case-control studies were summarized in this meta-analysis, including 1551 asthmatics and 2339 controls [10,11,13-18]. Among all studies, 6 were conducted in Caucasians [10,13-15,17,18] and 2 were performed in Asians [11,16]. Six studies were conducted in adults [10,11,13,14,16,17] and 2 were performed in children [15,18]. Four studies involved atopic asthmatics [10,13,14,18] and 2 studies clearly reported non-atopic asthmatics [14,18]. The characteristics of the included studies are listed in (Table 1) and the detailed allele and genotype frequencies of the 4G/5G polymorphism of PAI-1 in each study are shown in (Table 2). The genotype frequency distributions of control groups were all in consistent with HWE (Table 2).