An Updated Meta-Analysis of the Association between Tumor Necrosis Factor-α -308G/A Polymorphism and Obstructive Sleep Apnea-Hypopnea Syndrome

Shi M (2014) An Updated Meta-Analysis of the Association between Tumor Necrosis Factor-a -308G/A Polymorphism and Obstructive Sleep Apnea-Hypopnea Syndrome. PLoS ONE 9(9): e106270. doi:10.1371/journal.pone.0106270 An Updated Meta-Analysis of the Association between Tumor Necrosis Factor-a -308G/A Polymorphism and Obstructive Sleep Apnea-Hypopnea Syndrome Anyuan Zhong 0 Xiaolu Xiong 0 Huajun Xu 0 Minhua Shi 0 Elias Zintzaras, University of Thessaly School of Medicine, Greece 0 1 Department of Respiratory Diseases, the Second Affiliated Hospital of Soochow University , Suzhou , China , 2 Department of Endocrinology, the Affiliated Drum Tower Hospital, Nanjing Medical University , Nanjing , China , 3 Department of Otolaryngology, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Otolaryngology Institute of Shanghai Jiao Tong University , Shanghai , China Background: Several studies have reported that the tumor necrosis factor-a (TNF-a) -308G/A polymorphism is associated with susceptibility to obstructive sleep apnea-hypopnea syndrome (OSAHS). However, these results are controversial and conflicting. Objective: To evaluate the association between TNF-a-308G/A and OSAHS risk by meta-analysis. Methods: Electronic databases, including PubMed, Embase, China National Knowledge Infrastructure (CNKI), Wanfang, and Weipu, were searched to identify relevant studies. Data were extracted from the included studies. A model-free approach using odds ratio (OR), generalized odds ratio (ORG) and 95% confidence interval (CI) of the allele contrast to assess the association between the -308G/A polymorphism and OSAHS risk. Cumulative and recursive cumulative meta-analyses (CMA) were also carried out to investigate the trend and stability of effect sizes as evidence accumulated. Results: Seven studies including 1369 OSAHS patients and 1064 controls were identified in this meta-analysis. Significant associations were derived from the variants of the allele contrast [(OR, 1.78; 95% CI, 1.45-2.18) or (ORG, 2.01; 95% CI, 1.273.19). CMA showed a trend of an association. Recursive CMA indicated that more evidence is needed to conclude on the status of significance. No significant publication bias was found. Conclusions: Our meta-analysis suggested that the TNF-a-308G/A polymorphism contribute to the risk of OSAHS. Further studies with larger sample should be performed to confirm our findings. - . These authors contributed equally to this work. Introduction Obstructive sleep apnea-hypopnea syndrome (OSAHS) becomes a major public health problem all over the world recently. OSAHS is a respiratory disorder characterized by upper airway obstruction during sleep, breathing pauses with oxygen desaturation, and arousal from sleep. The prevalence of OSAHS is 2% in females and 4% in males of middle-aged groups [1]. Studies show that OSAHS is an independent risk factor for development of cardiovascular, thrombotic and metabolic events [23]. Inflammation plays a central role in this pathophysiological process. Tumor necrosis factor (TNF)-a is a potential pro-inflammatory cytokine elevated on OSAHS patients and exerted multiple physiologic effects on sleep fragmentation [4,5]. Also, chronic intermittent hypoxia (CIH) impairs endothelium-dependent vasodilator mechanism by stimulating NF-kB-mediated TNF-a generation [6]. Apparently, understanding the interaction between OSAHS and TNF-a is essential for developing therapeutic strategies. Epidemiological studies confirmed that OSAHS is a chronic complex disease with strong genetic components [7,8]. Among OSAHS-related candidate genes, TNF-a has been studied extensively. TNF-a gene is located on chromosome 6 (6p21), with several polymorphisms [e.g., -238 G/A (rs361525), -308 G/A (rs1800629), -857G/A (rs1799724) and -1031 T/C (rs1799964)] in the promoter region has been identified [9]. Among all the gene loci, -308 G/A was mostly studied [1016]. However, the association between TNF-a-308 G/A polymorphism and OSAHS susceptibility still remained unclear, with inconsistent results from different studies. Also, each study has limitations in small sample sizes and low statistical power. In order to shed some light on this controversy, a meticulous meta-analysis, including a cumulative and a recursive cumulative meta-analysis Figure 1. Flow chart of literature search and study selection. doi:10.1371/journal.pone.0106270.g001 [17], was performed for GAS-related variants in the TNF-a gene and OSAHS. Materials and Methods We performed the present meta-analysis according to the guidelines of Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA). Publication search strategy To identify all eligible studies that address the association between the TNF-a-308 G/A polymorphism and OSAHS, we systematically searched major electronic literature databases, including PubMed, Embase, China National Knowledge Infrastructure (CNKI), Wanfang and Weipu. The last search was updated to March 2013. The following search terms were used: obstructive sleep apnea hypopnea syndrome or OSAHS or obstructive sleep apnea syndrome or OSAS or obstructive sleep apnea or OSA and tumor necrosis factor or TNF or tumor necrosis factor-a or TNF-a in combination with gene or polymorphism or variants or alleles. Additionally, we manually searched for relevant published studies and review articles. No language restrictions were applied. Inclusion and exclusion criteria Included studies met the following criteria for the present metaanalysis: (1) evaluation of the TNF-a-308 G/A polymorphism and OSAHS susceptibility, (2) case-control or cohort design, and (3) sufficient data to determine the genotype distributions. Studies were excluded for the following reasons: (1) absence of control subjects, (2) non-clinical studies, (3) reviews, abstracts, or conference papers, (4) no reported genotype distribution or allele frequency data and participants were not adults (Age #18 years old). We accepted the definition of OSAHS provided by authors in each included study. Data extraction Two investigators (Drs. Zhong and Xiong) independently extracted required data from all the eligible studies. The following data were collected from each included study: first authors name and publication year, country, ethnicity, genotyping method; age, body mass index (BMI), gender distribution, and apnea-hypopnea index (AHI) of OSAHS and controls; genotype frequency in cases and controls. We also extracted the following additional information: case definition, case and control selection. In addition, it was Irscaeend Irscaeend Irscaeend Irscaeend recorded whether the genotyping in each study was blinded to clinical status. If a discrepancy existed in data collecting, it was resolved by group discussion. If queries or further study details were needed regarding the included studies, the respective authors were contacted via electronic mail. Quantitative data analysis This meta-analysis (...truncated)