Periodontal disease (PD) ranks as the world's second most prevalent oral condition, and it remains a significant and ongoing public health concern [1]. Gingivitis represents a mild and reversible stage of PD, but it tends to progress into periodontitis [2]. The onset of PD starts with an imbalance in bacterial equilibrium, resulting in heightened colonization by periodontopathogens and triggering an inflammatory response in the host, ultimately leading to tissue damage [3], [4], [5]. PD results from the buildup of bacterial plaque biofilm on the teeth, along with the ensuing immune responses that manifest in the tissues as a reaction to this presence [6]. The destructive process affecting the supporting tissues encompasses the ligaments and the alveolar bone [7,8]. Inflammatory and immune responses triggered by oral microorganisms propagate the progression of PD, which is regarded as one of the primary causes of tooth loss in both developing and developed countries [9]. Nevertheless, the inflammatory response of the periodontal tissues to infection is influenced and adjusted by a range of genetic and environmental factors [10]. The underlying causes of PD have not been fully elucidated. Numerous factors contribute to the origin and development of PD [11]. It is widely recognized that a combination of environmental factors, microbiological influences, and host genetics can influence the onset and progression of the condition [12]. Numerous risk factors can be categorized into modifiable and non-modifiable categories [12]. Modifiable risk factors encompass elements such as socio-economic status, stress, osteoporosis, diabetes, obesity, smoking, particular periodontopathogens, and inadequate oral hygiene, while non-modifiable risk factors encompass aspects such as genotype, race, age, and sex [12].

A substantial body of clinical and scientific evidence supports the significance of genetic factors as crucial determinants of both susceptibility to and the progression of PD [13]. Backing for this assertion is derived from studies involving both humans and animals, which demonstrate that genetic factors have a notable impact on immune and inflammatory responses in a broader sense, and particularly on the experience of PD [14]. The heritability of periodontitis was evaluated at 0.38 (95% confidence interval [95% CI]: 0.34 to 0.43) in twin investigations and 0.15 (95% CI: 0.06 to 0.24) in other family-based investigations [15]. Individuals may exhibit varying responses to common environmental challenges, and this diversity in response is shaped by the unique genetic profile of each individual [14]. Particularly, distinct forms of genes, known as allelic variants, can lead to differences in tissue structure (related to innate immunity), antibody responses (linked to adaptive immunity), and inflammatory mediators (associated with non-specific inflammation) [16]. Likely, allelic variants at multiple, and possibly numerous, gene loci exert an influence on susceptibility to PD [12]. Although certain genetic variants may have substantial and clinically significant effects, others are likely to have minor and non-clinically significant impacts [17]. To grasp the possible clinical significance of genetic variability regarding PD, it is essential to comprehend how various genes can play a role in the development of the disease.

Salivary protein polymorphism plays a crucial role in the context of periodontal disease. Within saliva, there exists a variety of proteins that can serve as indicators for periodontitis, such as salivary gelatinases (such as matrix metalloproteinase-2 [MMP-2] and MMP-9) and elastase [18]. These proteins have been observed at significantly higher levels in individuals with periodontitis compared to those who are healthy. Furthermore, a study identified 11 proteins with altered concentrations in patients afflicted with generalized aggressive periodontitis, including proteins already known to be linked to inflammation [18]. However, the study did not find any associations between salivary proteins and the examined polymorphisms [19]. In a study conducted in 2018 [20], researchers investigated the potential association between the risk haplotype of the major histocompatibility complex (MHC) class III region, specifically HLA-B-associated transcript 1, nuclear factor of light chain gene enhancer in inhibitor-like 1 B cells, lymphotoxin-alpha (BAT1-NFKBIL1-LTA), and polymorphisms in lymphotoxin-α, with salivary biomarkers and periodontal parameters. The findings of the study revealed myeloperoxidase (MPO) concentration associated with the risk haplotype, and LTA concentration correlated with specific genetic variants (rs2857708, rs2009658, and rs2844482) [20]. Although direct causation between salivary protein polymorphism and periodontitis may or may not be established, however, the analysis of saliva can prove valuable for the screening and ongoing monitoring of the disease [19]. In essence, salivary protein polymorphism can offer valuable insights into comprehending the development of periodontitis and the formulation of efficient diagnostic and therapeutic approaches.

Considering the possible role of salivary proteins in the pathophysiology of PD, it is plausible to consider that the genes associated with these proteins may serve as robust candidates for elucidating genetic disparities in PD susceptibility within human populations. Nonetheless, the proliferation of genetic association investigations in past decades has led to irreproducible and conflicting outcomes, primarily attributed to variations in methodological design, statistical methodologies, sample type, saliva collection procedure, and the interpretation of research findings. Concerning salivary proteins and PD, it is worth noting that while certain findings indicate a potential link between genetic polymorphisms and susceptibility to PD [21,22], there are also studies that have failed to detect such associations [23,24]. To address this, the current study was undertaken with the primary objective of conducting a systematic review and meta-analysis to compile and analyze the principal findings that pertain to the specific question: whether genetic polymorphisms in salivary proteins serve as a predisposing factor for PD including gingivitis and periodontitis.