The temporomandibular joint (TMJ), masticatory muscles, and neighboring structures can be affected by several musculoskeletal and neuromuscular conditions described collectively as temporomandibular disorders (do Nascimento Rechia et al., 2020; Schiffman et al.). These disorders are characterized by diffuse myofascial pain and dysfunction in the orofacial region, particularly affecting the masticatory muscles. Common TMD signs and symptoms are stiffness, joint noises, limited mouth opening, discomfort while chewing, and headaches (Anderson & Athanasiou, 2009). Approximately 10 % of these cases are associated with poor diagnosis, chronicity, and pain spreading to surrounding areas, causing significant individual suffering, and contributing to billions of dollars in healthcare costs annually (Bonato et al., 2021).

The TMD can be classified into masticatory muscle disorders, including myofascial pain, and TMJ disorders (Schiffman et al., 2014). Myofascial TMD involves pain resulting from excessive activity of the masticatory muscles, leading to chronic myalgia. Conversely, disc displacement (DD) represents the most common TMJ internal disorder characterized by abnormal positioning of the articular disc in relation to the mandibular condyle, articular eminence, and glenoid fossa (do Nascimento Rechia et al., 2020). In this condition, the articular disc is displaced anteriorly within the joint and can be categorized as with reduction or without reduction. In cases of reduction, the disc returns to its original position upon mouth closure, while in cases without reduction, this movement does not occur (Young, 2015). Additionally, when pain co-occurs with DD, the additional diagnosis of arthralgia may be applied (Schiffman et al., 2014). In this condition, the pain is perceived unexpectedly by nociceptors situated in the surrounding soft tissues during joint movement (do Nascimento Rechia et al., 2020).

TMD is a complex condition influenced by environmental, biological, and psychological factors. The multifactorial nature of the TMD pathology suggests that environmental exposure and diverse genetic risk factors could contribute to the disease pathogenesis (Furquim et al., 2016). However, the precise pathophysiological mechanisms underlying these conditions are still unclear. TMJ inflammation, peripheral and central sensitization, uncontrolled autonomic nervous system stimulation, inefficient descending pain modulation, and neuroendocrine/immunologic systems dysregulations are recognized as significant risk factors that initiate and sustain the disorder (Furquim et al., 2016).

The influence of genetic risk factors has been extensively explored, particularly focusing on the genetic impact of single nucleotide polymorphisms (SNPs) on essential biological pathways associated with TMD pathogenesis. The presence of SNPs in specific genes related to pain sensitivity, such as catechol-O-methyltransferase (COMT), adrenoceptor beta 2 (ADBR2), and 5-hydroxytryptamine (HTR1A) (Bonato et al., 2021) was correlated with TMD. Polymorphisms in the COMT gene can reduce enzyme function, increasing catecholamine levels that stimulate beta-adrenergic receptors involved in pain sensation (Nackley et al., 2007). The Val158Met (rs4680) polymorphism, the most studied, alters codon 158, replacing valine with methionine and producing a defective enzyme. Studies have linked rs4680 to painful TMJ clicking (Poluha et al., 2022), arthralgia or myalgia (Smith et al., 2014a, Smith et al., 2014b), and pain intensity in TMD patients (Pinto Fiamengui et al., 2020, Zlendić et al., 2023).

A genetic predisposition to an abnormal inflammatory response may trigger and maintain TMD (Campello et al., 2023). Genes related to proinflammatory responses, such as tumor necrosis factor-alpha (TNFα), transforming growth factor β (TGFβ), interleukin (IL) 6, and IL8 (Pinto Fiamengui et al., 2020), and anti-inflammatory responses, like IL10 (Poluha et al., 2022), have been linked to TMD. The TNFα gene, a key player in inflammation, includes the −308 (rs1800629) polymorphism, where a G-to-A substitution in the promoter region increases TNF-α secretion (Furquim et al., 2016). Elevated TNF-α concentrations are notably higher in TMD cases compared to controls (Kaneyama et al., 2005a, Kaneyama et al., 2005b)

Extracellular matrix degradation, involving matrix metallopeptidase 1 (MMP1) (Poluha et al., 2022), and fibrous tissue formation, mediated by collagen type V (COL5A1) and collagen type II alpha 1 (COL2A1) (Dalewski et al., 2021, do Nascimento Rechia et al., 2020), have been also linked to TMD. The −1607 1 G/2 G polymorphism in the MMP1 gene increases local MMP1 concentration, accelerating extracellular matrix degradation(Rutter et al., 1998). This polymorphism has been associated with DD with reduction (Rosales et al., 2020) and painful TMJ clicking (Poluha et al., 2022).

Despite the previously described evidence linking genetic polymorphisms to TMD, conflicting data still exist regarding their role in the etiology of this condition (Campello et al., 2023, Dalewski et al., 2020). This highlights the need to clarify these associations to better understand the genetic contributions to TMD. The investigation of genetic characteristics associated with TMD can provide new insights into the risk of TMD onset or its severity (Campello et al., 2023). Additionally, identifying genetic polymorphisms in TMD patients could contribute to a mechanistic understanding and facilitate the development of individualized treatment strategies (Poluha et al., 2022).

Based on that, this systematic review and network meta-analysis (NMA) aims to compare and rank the effects of different genetic polymorphisms on susceptibility to TMD. It enables the identification of which genetic polymorphisms may significantly impact TMD etiology and provides direction for future investigations.