A Systematic Review and Meta-Analysis of the Association between Serotonergic Gene Polymorphisms and Obstructive Sleep Apnea Syndrome

<div><p>Background</p><p>5-Hydroxytryptamine receptor (5-HTR) and 5-hydroxytryptamine transporter (5-HTT) gene polymorphisms have been reported to be associated with susceptibility to obstructive sleep apnea syndrome (OSAS). The associations, derived from sporadic, inconsistent, small-sample-size studies, need to be evaluated further in a meta-analysis.</p><p>Methods</p><p>Relevant studies were identified by searching PubMed, Embase, The Cochrane Library, China National Knowledge Infrastructure (CNKI), Wanfang, and Weipu. Eligible data were extracted from each included study. Odds ratios (ORs) were calculated using a fixed-effects or a random-effects model. The ORs and 95% confidence interval (CI) were used to assess the strength of the association between serotonergic gene polymorphisms and OSAS in the dominant and recessive models, as well as alleles. The Q statistic was used to evaluate homogeneity and Begg’s test was used to assess publication bias.</p><p>Results</p><p>Eight studies were finally included in the meta-analysis of the association between 5-HTR2A gene variants (including 102T/C and 1438G/A), 5-HTT gene polymorphisms (including 5-HTT gene-linked promoter region (5-HTTLRP), and serotonin transporter intron 2 variable number tandem repeat (STin2VNTR) and OSAS risk. The G allele of 5-HTR2A 1438G/A, long 5-HTTLPR, and 10-tandem-repeats STin2VNTR were shown to increase OSAS susceptibility, with ORs of 2.33 (A vs. G, 95% CI 1.48–3.66), 1.24 (L vs. S, 95% CI: 1.04–1.49), and 2.87 (10 vs. 12, 95% CI: 1.38–5.97), respectively. These significant differences were determined in both dominant and recessive models. Of the 5-HTR2A 1438G/A gene polymorphism, the AA genotype increased the OSAS risk, with an OR of 4.21 (95% CI: 2.83–6.25) in a recessive model in male OSAS patients, but no significant association was found in females.</p><p>Conclusions</p><p>Our meta-analysis demonstrated that polymorphisms in the 5-HTR2A 1438G/A and 5-HTT genes contributed to susceptibility to OSAS. The A allele of the 1438G/A gene polymorphism is predominantly distributed in males and increased the OSAS risk significantly.</p></div

Forest plots for the association between 5-HTR2A 1438 G/A and OSAS risk in male and female groups.

<p>The squares correspond to the study specific OR and 95% CI. The area of the squares reflects the weight. The diamond represents the summary OR and 95% CI.</p

Forest plots for the associations between 5-HTR2A 102 T/C, 5-HTR2A 1438 G/A, HTTLRP and HTTVNTR gene polymorphisms and OSAS risk.

<p>The squares correspond to the study specific OR and 95% CI. The area of the squares reflects the weight. The diamond represents the summary OR and 95% CI.</p

Flow chart of literature search and study selection.

<p>6, 5, 3 and 3 studies were eligibly included in the meta-analysis of 5-HTR2A 102 T/C, 5-HTR2A 1438 G/A, HTTLRP and HTTVNTR, respectively.</p

Meta-analysis of the association between gene polymorphisms and OSAS risk.

<p>Abbreviation: L or S, long or short 5-HTT gene-linked polymorphic region;10 or 12, serotonin transporter intron 2 variable number tandem repeat; F, fixed-effects model; R, random-effects model; OR, odds ratios; 95%CI, 95% confidence interval.</p

Tests for publication bias in overall population.

<p>Abbreviation: 5-HTTLPR L/S, long or short 5-HTT gene-linked polymorphic region; STin2VNTR 10/12, 10 or 12 tandem repeats of serotonin transporter intron 2 variable number tandem repeat.</p

HPV GenoArray and genotyping assay.

<p>(<b>A</b>) The genotyping results were evaluated by means of a colorimetric change on the chip under direct visualization. Spots of “Biotin” indicate the hybridization-positive control gene, and “IC” indicates the inner control gene. (<b>B</b>) HPV-16 positive.</p

Treatment with curative intent received by 674 patients with LSCC.

<p>Treatment with curative intent received by 674 patients with LSCC.</p

Explanatory variables for 674 patients with LSCC in three hospitals.

<p>Explanatory variables for 674 patients with LSCC in three hospitals.</p

Clinical parameters of 674 patients with LSCC according to HPV status.

<p>Clinical parameters of 674 patients with LSCC according to HPV status.</p