Polymorphisms of the serotonin receptors genes in patients with bruxism: a systematic review

Abstract This study aimed to investigate if SNP rs6313, SNP rs2770304, SNP rs4941573, and SNP rs1923884 of the 5-HT2A receptor gene and SNP rs6295 of the 5-HT1A receptor gene are associated with bruxism etiology. Methodology This systematic review was registered in PROSPERO (CRD42018094561). A search was conducted for articles published in or before May 2021. To qualify for eligibility in this review, the studies had to be case-controls, cohort or cross-sectional. The inclusion criteria were the articles with a group of patients with bruxism and a control group in which the presence of these SNPs was evaluated. The exclusion criteria were the investigations of other polymorphisms, the studies that did not consider a control group for comparison, case reports, and reviews. The NOS and JBI were used to evaluate the methodological quality of studies. Results We conducted this study with databases, such as Web of Science, Scopus, Embase, PubMed/MEDLINE, and ProQuest. We considered four studies eligible. A total of 672 participants were included,187 with sleep bruxism, 105 with awake bruxism, 89 with sleep and awake bruxism, and 291 controls. One study found a strong association between the SNPs rs6313, rs2770304 and rs4941573 of the 5-HT2A receptor gene and sleep bruxism. In one study, we considered the C allele of the SNP rs2770304 a risk factor for sleep bruxism. We found no significant results of other SNPs in sleep bruxers compared to controls. We found no positive association concerning the SNPs and groups of awake bruxism and sleep and awake bruxism. Conclusion The different results regarding the SNPs in sleep bruxers could be explained by the genetic distinction between Chilean, Mexican, Japanese, and Polish population. More clinical trials and prospective studies must be conducted with larger sample size and in different ethnicities to confirm the results of this review.


Introduction
Bruxism is defined as a repetitive jaw-muscle activity characterized by clenching or grinding of the teeth and/or by bracing or thrusting of the mandible. 1 It has two different circadian manifestations: sleep bruxism occurring during sleep, characterized as rhythmic (phasic) or non-rhythmic (tonic); and awake bruxism, manifesting during wakefulness. 2 Bruxism can cause damages, such as loss of tooth structure, cracked teeth, tooth hypersensitivity, pain in tooth, masticatory muscles, joint and face. It also affects 20% of the population and is more common in women than in men. 3 The complete knowledge about the risk factors of bruxism is still unclear. 4 Studies showed the involvement of genetic polymorphisms of ACTN3, DRD2, ANKK1, 5-HTT and COMT genes with Bruxism risk. [5][6][7] Serotonin (5-HT) is a neurotransmitter involved in the etiology of Bruxism. 8 It is considerably the most important neurotransmitter that controls endogenous mechanisms of pain 9 and it plays a role both in activation of the muscles 10 and in the maintenance of chronic orofacial pain. 11 The activity of 5-HT is mediated by 5-HT receptors. 12 5-HT1A and 5HT2A receptors are highly expressed in the prefrontal cortex. 13 5-HT receptors single nucleotide polymorphisms (SNP) have been associated with mood disorders, 14 sleep quality 15 and it is known to alter 5-HT mechanism of action. 14 5-HT1A is located on chromosome 5q11.2-q13 and presents the SNP rs6295 of the 5-HT1A receptor gene. 16 5HT2A is located on chromosome 13q14-21 and present in the first exon the T102C SNP rs 6313. 17 It has a base in nucleotide position 102, which can be thymine (T) or cytosine (C) and that determine three possible genotypes TT, TC, or CC. 18 5-HT2A also presents the SNPs rs2770304 in intron 2 of the gene, 19 rs4941573 in intron 3 of the gene 20 and rs1923884. 6 Previous investigations showed that some 5-HT receptors gene polymorphisms were positively associated with bruxism, 6,21   To qualify for eligibility in this review, the studies had to be case-controls, cohort or cross-sectional.
The inclusion criteria were the articles with a group of patients with awake or sleep bruxism, and a control group in which the presence of the SNPs of the 5-HT1A and 5-HT2A receptors genes was evaluated, regardless of the method since it does not modify the individual's genetic code.
The exclusion criteria were the investigations of other polymorphisms, studies that did not consider a control group for comparison, case reports and reviews.

Search methods
Two independent investigators (C.P.C and C.A.A.L) conducted a search in Web of Science, Scopus, Embase, and PubMed/MEDLINE databases ( Figure   1), for articles published in or before May 2021. Moreover, the search in the grey literature for search J Appl Oral Sci. 2021;29:e20210262 3/11 used to perform these steps. The authors considered the exclusion of duplicate and reading the titles and summary of the articles. If there was not enough data in the title and summary, the whole article was acquired. Studies were excluded when they did not attend the inclusion criteria. All differences in selection process between the investigators were resolved by a third author (M.T.C.M.) to obtain a consensus through discussion.

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Along with the three categories of the NOS for cohort studies (selection, comparability, and outcome), eight items were analyzed. Selection presents four items: (1) Representativeness of the exposed cohort; (2) Selection of the non-exposed cohort; (3) Ascertainment of exposure; (4) Demonstration that outcome of interest was not present at the beginning of the study. Comparability corresponds to one item: (1) Comparability of cohorts based on the design or analysis. The outcome category is evaluated with three questions: (1)  and both. Univariate analyses using Chi-square tests at a 5% significance level were performed to verify if the genotypic frequencies of each SNP were associated to sleep bruxism, awake bruxism, and both compared with controls for the studies (Oporto,et al. 21 (2016), Cruz-Fierro, et al. 22 (2018) and Wieckiewicz,et al. 23 (2020)). The other data were described as they are reported in the articles. The Kappa coefficient was estimated to find the inter-reader agreement at the time of inclusion of the articles of Web of Science, Scopus, Embase, PubMed/MEDLINE and ProQuest databases.

Literature search
We presented the details of the search strategy Description of the studies Quality assessment and risk of bias of studies included We analyzed the risk of bias through the NOS ( Figure 4). We also associated the mostly absence of stars with a deficiency in terms of ascertainment of   6 We also found a meaningful association between the CC genotype of the SNP rs2770304 (p=0.004) and CC genotype of the SNP rs4941573 of the 5-HT2A receptor gene (p=0.006) and sleep bruxism. 6 We observed no significant difference in sleep bruxers compared to controls concerning the SNPs rs1923884 of the 5-HT2A receptor gene (p=0.327) and the SNP rs6295 of the 5-HT1A receptor gene (p=0.841). 6 Different from the other investigations, this study excluded people without occlusal contact to the posterior teeth or with orofacial dysfunction, acute symptoms, systemic diseases, and everyone who use or used medication that modify the serotonergic system or sleep/wake regulation or treat disorders of movement. 6 This research evaluated all participants (cases and controls) following Johansson, et al. 28 (1993) and Lavigne, Rompré and Montplaisir. 29 (1996) criteria.
When this evaluation process could not identified sleep bruxers, they evaluated the participants using a miniature electromyograph. Wieckiewicz,et al. 23 (2020)     We also observed controversial findings when the SNP rs4941573 of the 5-HT2A receptor gene was analyzed in Japanese (p=0.006) 6 and Chilean population (p=0.7113). 21 The SNP rs1923884 of the 5-HT2A receptor gene was not related with sleep bruxism in Japanese (p=0.327) 6  according to the JBI Critical Appraisal Checklist for Analytical Cross-Sectional Studies. However, the studies did not estimate the minimal sample size for the research. Cruz-Fierro, et al. 22 (2018) reported a lack of accurate data on the prevalence of bruxism in Mexican population. This is the reason why this study was estimated in an infinitive population.
Other limitations of this systematic review were the study design, the low number of studies included, and the lack of standardization in diagnosis criteria, because the studies had different methodologies to diagnose bruxism (possible/probable bruxism or definitive bruxism) and it could influence the results.

Conflict of interest
The authors declare no conflict of interest.