| BackgroundAsthma is a chronic inflammatory disorder of the airways in which many cells and cellular elements play a role, and it is characterized by airway hyperresponsiveness, obstruction, and airway wall remodeling. Based on data from World Health Survey, the global prevalence of doctor-diagnosed asthma in adults was estimated at4.3%. The prevalence reported in several studies indicated that asthma may still be increasing in western countries and developing countries. Asthma is a complex disease and has a strong genetic component in its pathogenesis. With the advance of genomics and genetics, considerable efforts have made to evaluate the association between genetic variants and asthma risk, and numerous genes have been identified as asthma susceptible genes.The β2-adrenoceptor (ADRB2) mediates the physiological responses in the normal airway, which include bronchodilation, bronchoprotection, enhanced mucociliary clearance. The ADRB2gene is located on chromosome5q31-q32, a region that is genetically linked to asthma and related phenotypes. Genes in this region encode proinflammatory cytokines such as IL-3,-4,-5,etc. Many studies have investigated these polymorphisms to assess their potential contribution to the risk of asthma. It was observed in some studies that ADRB2gene may play a significant role in the pathogenesis of asthma. However, other studies shown no associations between asthma and ADRB2gene polymorphisms. Human uteroglobulin-related protein1(UGRP1) gene is also located on chromosome5q31-32, encoding uteroglobulin-related protein1. UGRP1mRNA is predominantly expressed in the lung, and was found with high level of expression in the epithelial cells of lung airway. Because its similarity in amino acid sequence with Clara cell protein(CC16), which has several immunomodulatory and anti-inflammatory effects, it is possible that UGRP1may possess similar functions. Taken together, these facts suggested that UGRP1gene may play an important role in pathogenesis of asthma. Several studies reported the association between the-112G/A polymorphisms of UGRP1gene and asthma risk, while some reported significantly association, others found no such association.In summary, to date, the role of ADRB2and UGRP1gene polymorphisms in the pathogenesis of asthma are not so clear. A single study may lack the robust power to provide reliable conclusion due to its small sample size, in the present study, we thus performed a comprehensive search of literature and meta-analysis to explore whether the ADRB2and UGRP1gene polymorphisms contribute to asthma susceptibility.ObjectivesBy comprehensive searching published articles, extracting relevant data, we evaluate the associations between the ADRB2and UGRP1gene polymorphisms using meta-analysis in a qualitative and quantitative way.Materials and methodsWe followed criteria of the Preferred Reporting Items for Systematic Reviews and Meta-analysis (PRISMA) to perform this meta-analysis. After preliminary searching several time, we develop a systematic and comprehensive search strategies, in which medical subject terms and free words were adopted in combination. We carried out a systematic search of the PubMed, EMBASE, BIOSIS Previews and EBSCO databases for original articles and conference proceedings published until March,2013(UGRP1) and January,2014(ARDB2), to identify articles related to the exploring of the role of ADRB2and UGRP1gene polymorphisms in asthma pathogenesis. We sifted out eligible articles with rigorously predesigned inclusion/exclusioncriteria and then data were extracted by two investigator independently. The pooled estimate was combined by a random-effect model (DerSimonian-Laird method) or a fixed effect Model (Mantel-Haenszel method) according to whether the heterogeneity existed or not. Subgroup analysis based on ethnicity, atopy, and age were further conducted respectively to explore the potential sources of heterogeneity. Sensitivity analysis was elucidate the stability of our meta-analysis results. All analyses were conducted using RevMa5.2and Stata11.0software.Results1.Meta-analysis of the associations between ADRB2Arg/Glyl6and Gln/Glu27polymorphisms and asthma risk.Thirty-seven studies involving6648asthma patients and15943controls were included in the meta-analysis. The distributions of the ADRB2polymorphism in normal controls were consistent with HWE in every study.1). Among37studies included in the meta-analysis,29investigated the contribution of ADRB2Arg/Gly16polymorphisms to asthma risk. Overall, slightly significant associations were found in allelic genetic model (OR=1.06,95%CI=1.01～1.12), recessive genetic model (OR=1.11,95%CI=1.02～1.21) for Arg/Gly16. Stratified by ethnicity, significant associations were also found in Asian population in allelic genetic model (OR=1.14,95%CI=1.05-1.23), recessive genetic model (OR=1.26,95%CI=1.12～1.43) and addictive model (OR=1.23,95%CI=1.06～1.44), but not in Caucasian population. No association was found in adults and children subgroup in term of age. 2). There were22studies investigating the association between Gln/Glu27polymorphisms and asthma risk. One study maybe the main contributor to heterogeneity and has significantly influenced pooled results. Therefore, it was not included in data synthesis process. Overall, no significant association was found in all genetic models when combined all other21studies. Age stratification shown significant association in adults in allelic genetic model (OR=1.10,95%CI=1.01～1.19, p=0.03) and recessive genetic model (OR=1.20,95%CI=1.07～1.34, p=0.002), but no association were found in ethnicity stratification.2.Meta-analysis of the associations between UGRP1-112G/A polymorphisms and asthma risk.Six studies involving6648asthma patients and15943controls were included in the meta-analysis. The distributions of the ADRB2polymorphism in normal controls were consistent with HWE in every study. The combined results of all studies showed that there were significant associations between the UGRP1-112G/A polymorphism and asthma risk in the genetic model of AA vs GG (OR1.76,95%CI [1.12,2.78], p=0.01), and in the genetic model of AA vs GA/GG (0R1.70,95%CI [1.09,2.67], p=0.02). In subgroup analysis by ethnicity, significant association was found among Asians in the genetic model of A vs G (OR1.42,95%CI [1.06,1.90], p=0.02), AA vs GG(OR2.08,95%CI [1.16,3.72], p=0.01), and AA vs GA/GG(OR1.90,95%CI [1.07,3.38]), but not in Caucasian.Subgroup analysis was also performed by age, but no associations found.Conclusion1).This meta-analysis implied that the β2-adrenoceptor Arg/Gly16polymorphisms was likely to contribute to asthma risk in Asian population. Gln/Glu27polymorphisms might be a contributor to asthma susceptibility for adults.2). This meta-analysis implied that the-112G/A polymorphism of UGRP1gene was likely to contribute to asthma risk, particularly in Asian population.3). However, due to some limitations, such as heterogeneity among various studies and lack of considering the gene-gene and gene-environment interaction in published studies, GWAS or more case-control studies with explicit diagnosis criteria and rigorous quality control are needed to support finding in our study in various ethnic groups. |
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