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  • We searched PubMed and EMBASE in all languages for relevant studies. The final date for inclusion was March 10, 2013. Comprehensive search themes included Medical Subject Headings (MeSH) terms and keywords: “sleep apnea”; “obstructive sleep apnea Syndrome”; “sleep apnea/hypopnea syndrome” and “serotonin 2A receptor(5-HT2A)”; “serotonin transporter protein(5-HTT)”; “leptin receptor (LEPR)”; “polymorphism”; ”variant”; and “genotype”. Inclusion criteria for this study were: (1) OSAS patients must be clearly diagnosed; (2) the study must be a case-control study; (3) the study should report enough genotyping information to extract and estimate odds ratios (ORs) with a 95% confidence interval (CI). Studies were excluded if: (1) the diagnosis was unclear; (2) the study did not contain sufficient data for extraction; (3) the study design was based on case, family or sibling pairs; or (4) no control group was included in the study. When overlapping reports occurred, the study with largest number of patients was selected. All included studies were retrieved and the required information was extracted separately, in duplicate, by two authors (BDQ and SZ). Any discrepancies were resolved by discussion and agreement. The characteristics collected from each study were: author, year of publication, country, age, AHI, sample size, diagnosis criteria, genotype, allele frequency, and specific technique of analysis. If the allele frequency was not given, it was calculated from the corresponding genotype distributions. The OR with its 95%CI was extracted or calculated for each study. There is no standard quality criteria for single nucleotide polymorphism (SNP) studies, so we employed a modified Newcastle-Ottawa scale (NOS) score system to assess the quality of these non-randomized studies [16]. A total of eight items are included in the NOS. These are divided into three categories describing selection, comparability and exposure. A maximum of two stars was given for each of these items. A study awarded 0–3 stars was classified as a low quality study, while 4–6 stars and 7–9 stars were moderate and high quality studies, respectively [17]. We performed a systematic review and meta-analysis following a predetermined protocol in accordance with the Meta-analysis of Observational Studies in Epidemiology (MOOSE) reporting guidelines [18]. A meta-analysis was performed of polymorphisms of the 5-HT2A, 5-HTT, and LEPR genes, to examine their association with OSAS using additive, recessive and dominant models. The pooled ORs with 95%CIs were calculated in random-effects or fixed-effects models to measure the strength of the associations between these polymorphisms and OSAS risk. Heterogeneity of effects across studies was evaluated using the means of χ2-based Q test and I2 test. P<0.10 was considered to be representative of significant heterogeneity with the Q test. The I2 statistic represented quantification of heterogeneity ranging from 0% to 100%. Hundred percent represented a high degree of heterogeneity and 50%-<100% represented substantial heterogeneity [19]. If there was significant heterogeneity (P<0.10 for Q test; I2>50% for I2 test), a random-effects model was used to pool the data. Otherwise, a fixed-effects model was used. A funnel plot was employed to visually assess potential publication bias in meta-analyses including more than five studies. The Egger's regression asymmetry test and Begg's rank correlation test were used to statistically examine publication bias. A sensitivity analysis was performed to assess the impact of each individual study upon the overall ORs, using the one-study removal approach [20]. Hardy-Weinberg Equilibrium was assessed using χ2 tests for the polymorphism investigated in each study. All analyses were conducted using STATA 11.0 (StataCorp, College Station TX, USA). P<0.05 was considered statistically significant.
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