Polymorphism of the Serotonin Transporter Gene and the Peripheral 5-Hydroxytryptamine in Obstructive Sleep Apnea: What Do We Know and What are We Looking for? A Systematic Review of the Literature.

Background: Obstructive sleep apnea (OSA) is a highly prevalent disease with substantial public health burden. In most of the cases, there is a genetic predisposition to OSA. Serotonin/T-HydroxyTriptamine (5-HT) plays a key role in ventilatory stimulation, while the polymorphism of the serotonin transporter gene (STG) leads to alterations in serotonin level, making it important in OSA.

Objective: To examine whether the 5-HydroxyTriptamine and the genetic predisposition influence the incidence and evolution of OSA, we reviewed randomized, controlled trials and observational studies on the selected topic. The secondary objective was to determine the metabolic effects of the circulating serotonin in other tissues (liver, pancreas, gut, brown adipose tissue, and white adipose tissue) and its role in the development of obesity.

Data Sources: A systematic review of English articles was performed based on PubMed and the Cochrane Library databases. Search filters included randomized controlled trial, controlled clinical trial, random allocation, double-blind method, and case-control studies and used the following keywords: Brain Serotonin OR Serotonin Transporter Gene Polymorphism OR Peripheral 5-HydroxyTryptamine AND Obstructive Sleep Apnea OR Sleep Disorder Breathing OR brain serotonin AND OSA OR serotonin transporter gene OR Peripheral 5-Hydroxytryptamine AND Sleep.

Study Eligibility Criteria: The inclusion criteria for the current review were previous diagnosis of OSA, age above 18 years, and articles including quantitative data about serotonin transporter gene or peripheral serotonin. Language and time criteria were added - English articles published in the last 15 years. Studies that were not included were reviews and case reports.

Study Appraisal And Synthesis Methods: In order to study the serotonin function, a literature research was conducted in the databases Pubmed and Cochrane Library. The following search terms were used: serotonin, 5-hydroxytryptamine, serotonin transporter gene. A critical appraisal of the included studies was performed with the Newcastle-Ottawa scale (NOS) and Delphi list.

Results: The search yielded 1210 articles, from which 43 were included. The included studies suggest that the two polymorphisms of serotonin transporter gene (5HTT) - variable number of tandem repeats (VNTR) and linked polymorphic region (LPR) - are strong candidates in the pathogenesis of OSA. The allele 10 of 5HTTVNTR and the long/long (L/L) allele genotype were associated with a higher prevalence of OSA and the L allele with a higher apnea-hypopnea index and a longer time during sleep with oxygen desaturation.

Limitations: The main limitation of the present study consists of heterogeneity of the information. Being a less studied subject, randomized trials are not widely available and most data were obtained from case-control trials. Moreover, the included material indirectly approached the subject by demonstrating the effects of serotoninergic system over the metabolism, the connection between serotonin and obesity, factors which are implied in the pathogenesis of OSA.

Conclusion And Implications Of Key Findings: The two polymorphisms of serotonin gene can be considered important factors in the diagnosis and management of OSA.