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
Bibliographic record
Abstract
Anca Diana Maierean,1,* Ioana Roxana Bordea,2,* Tudor Salagean,3 Reem Hanna,4,5 Teodora Gabriela Alexescu,6 Ana Chis,1 Doina Adina Todea1,* 1Department of Pneumology, “Iuliu Hatieganu” University of Medicine and Pharmacy, Cluj-Napoca, Romania; 2Department of Oral Rehabilitation, “Iuliu Hatieganu” University of Medicine and Pharmacy, Cluj-Napoca, Romania; 3Department of Land Measurements and Exact Sciences, University of Agricultural Sciences and Veterinary Medicine, Cluj-Napoca, Romania; 4Department of Surgical Sciences and Integrated Diagnostics, Laser Therapy Centre, University of Genoa, Genoa, 16132, Italy; 5Department of Oral Surgery, Dental Institute, King’s College Hospital NHS Foundation Trust, London, SE5 9RS, UK; 6Department of Internal Medicine, “Iuliu Hatieganu” University of Medicine and Pharmacy, Cluj-Napoca, Romania*These authors contributed equally to this workCorrespondence: Tudor Salagean Email tudor.salagean@usamvcluj.roandIoana Roxana Bordea Cluj-Napoca County, Gheorghe Lazar Street, No. 4, Building D4, Ap 4, Tel +40744919391Email roxana.bordea@ymail.comBackground: 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.Keywords: 5-HTTLPR, 5-HTTVNTR, sleep disorder breathing, obesity
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How this classification was reachedexpand
Full frame machine prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. The Gemma side is a direct model label for every work in the frame, read from the title-only record. The Codex side is a classifier learned from the 10,348 direct Codex labels and calibrated to design-weighted sample rates; fields without enough sample support carry no Codex call. Candidate is the union of the two sides; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels.
Distilled classifier scores by category (both heads)
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.006 | 0.025 |
| Meta-epidemiology (narrow) | 0.001 | 0.001 |
| Meta-epidemiology (broad) | 0.008 | 0.008 |
| Bibliometrics | 0.006 | 0.007 |
| Science and technology studies | 0.000 | 0.001 |
| Scholarly communication | 0.002 | 0.002 |
| Open science | 0.001 | 0.001 |
| Research integrity | 0.002 | 0.001 |
| Insufficient payload (model declined to judge) | 0.002 | 0.000 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one source (direct Gemma or distilled Codex), not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".