Introduction

Oral diseases, including dental caries, periodontal disease, and oral cancers, remain significant global health concerns affecting individuals across all age groups. According to the World Health Organization (WHO), oral diseases affect nearly 3.5 billion people globally, highlighting the pressing need for effective prevention and management strategies. The development and progression of these diseases are influenced by a combination of genetic and environmental factors, creating a complex web of interactions that determine an individual’s susceptibility. Understanding these factors is crucial for developing personalized prevention strategies and targeted treatment approaches (1).

Genetic predisposition plays a pivotal role in oral disease susceptibility. Variations in genes involved in immune response, inflammation, and tissue repair have been linked to increased risks of conditions such as periodontal disease and oral cancers. For instance, certain genetic polymorphisms in the interleukin-1 gene cluster have been associated with an increased risk of severe periodontitis, suggesting that the immune response is a critical factor in disease progression (2). Similarly, genetic mutations in the p53 tumor suppressor gene have been identified in patients with oral cancer, further demonstrating the importance of genetic factors in disease susceptibility (3).

Environmental factors, including diet, smoking, alcohol consumption, and oral hygiene practices, also significantly impact oral health. These factors can exacerbate or mitigate the effects of genetic predispositions, creating a multifactorial risk profile for oral diseases. For example, smoking has been shown to increase the severity of periodontal disease, particularly in individuals with a genetic predisposition to inflammatory conditions (4). Moreover, poor dietary habits, such as high sugar intake, contribute to the development of dental caries, especially in genetically susceptible individuals.

The interplay between genetic and environmental factors, often referred to as gene-environment interactions, further complicates the understanding of oral disease susceptibility. Epigenetic modifications, such as DNA methylation and histone modification, have emerged as important mechanisms through which environmental factors can influence gene expression and, consequently, disease outcomes. Research into these interactions is ongoing, but it is becoming increasingly clear that both genetics and the environment must be considered when assessing an individual’s risk for oral diseases (5). This review aims to explore the current understanding of genetic and environmental factors in susceptibility to oral diseases, with a focus on how these factors interact to influence disease development and progression.

Review

The connection between genetic and environmental factors in the development of oral diseases is a key area of research. Genetic predisposition plays a crucial role in determining an individual’s susceptibility to conditions such as dental caries, periodontitis, and oral cancer. For instance, genetic polymorphisms in immune-related genes, such as those coding for interleukins, have been linked to increased inflammatory responses, thereby exacerbating the progression of periodontal disease. These findings highlight the importance of genetic factors in shaping oral health outcomes (6). Environmental factors such as smoking, alcohol consumption, diet, and oral hygiene habits further modulate these genetic predispositions. Smoking, in particular, has been shown to significantly increase the risk of periodontitis and oral cancers, especially in individuals with a genetic susceptibility to these conditions (7). Poor dietary habits, including high sugar intake, contribute to the formation of dental caries, especially in genetically susceptible individuals who may have variations in genes related to enamel development or saliva composition. Understanding the complex interactions between these factors is essential for improving oral disease prevention and management. Personalized approaches that consider both genetic predispositions and environmental risk factors may offer more effective prevention and treatment strategies for at-risk populations.

Role of Genetic Predisposition in Oral Disease Development

Genetic predisposition is a critical factor in the susceptibility to oral diseases such as dental caries, periodontitis, and oral cancers. Recent research has shown that variations in specific genes can influence how the body responds to bacterial infections, inflammation, and other pathogenic processes associated with oral disease. These genetic variations, known as polymorphisms, can alter immune function, tissue repair mechanisms, and other key biological processes involved in oral health (7). One well-studied example is the association between genetic polymorphisms in the interleukin-6 (IL-6) gene and periodontitis. IL-6 plays a central role in the body’s immune response, and individuals with certain IL-6 gene variants may exhibit a heightened inflammatory response to bacterial infection, increasing their risk of developing severe periodontitis (7, 8).

Further evidence of genetic predisposition can be seen in research on the role of MMPs in oral diseases. MMPs are enzymes that break down extracellular matrix components, and their activity is crucial in tissue remodeling and wound healing. However, polymorphisms in the MMP-1 and MMP-3 genes have been associated with increased enzyme activity, leading to excessive tissue breakdown in individuals with periodontitis. This genetic variation can lead to the rapid progression of periodontal disease, even in individuals who practice good oral hygiene (9). In addition to inflammatory and tissue remodeling genes, genetic mutations affecting enamel formation have been implicated in the development of dental caries. Amelogenin, a critical protein in enamel development, is encoded by the AMELX gene. Mutations in this gene can lead to defects in enamel structure, making teeth more susceptible to decay. Studies have shown that individuals with amelogenesis imperfecta, a condition caused by AMELX mutations, have a significantly higher risk of developing early and severe dental caries (10). Genetic predisposition to oral cancers has also been widely studied. For example, mutations in the TP53 tumor suppressor gene have been linked to an increased risk of oral squamous cell carcinoma. The TP53 gene plays a critical role in regulating cell growth and preventing tumor formation. Individuals with mutations in this gene are at greater risk of developing oral cancer, particularly when environmental risk factors such as tobacco and alcohol use are present (11). Understanding these genetic factors is essential for identifying individuals at higher risk for oral diseases and could potentially lead to the development of targeted prevention and treatment strategies based on genetic profiles.

Environmental Influences on Oral Health: Diet, Smoking, and Lifestyle

Environmental factors, particularly diet, smoking, and overall lifestyle choices, significantly influence oral health and contribute to the onset and progression of oral diseases. Among these factors, diet plays a key role, with high sugar intake being a well-established risk factor for dental caries. Frequent consumption of sugary foods and beverages provides a substrate for acidogenic bacteria such as Streptococcus mutans, which metabolize sugars and produce acids that demineralize tooth enamel, leading to decay. Studies have consistently shown a strong correlation between sugar consumption and caries prevalence, particularly in populations with limited access to fluoride or dental care (10). In contrast, a balanced diet rich in calcium, phosphorus, and vitamin D supports enamel strength and resilience against caries.

Smoking is another major environmental factor that adversely affects oral health. Tobacco use is strongly associated with periodontal disease, oral cancers, and tooth loss. The chemicals in tobacco smoke impair immune responses, making the gums more susceptible to infection and slowing down the healing process after dental procedures. Smokers are at higher risk of developing periodontal pockets, bone loss, and eventual tooth loss. Additionally, smoking increases the likelihood of oral cancer, particularly when combined with alcohol use, which can have a synergistic effect in promoting carcinogenesis (1, 11). The relationship between smoking and oral disease progression is dose-dependent, meaning that the risk increases with the duration and intensity of smoking.

Lifestyle factors, including alcohol consumption and poor oral hygiene practices, further compound these risks. Alcohol is a known risk factor for oral cancer due to its ability to act as a solvent, enhancing the penetration of carcinogens such as those found in tobacco smoke. Additionally, alcohol may irritate the mucosal lining of the mouth, increasing the likelihood of malignant transformations in cells exposed to carcinogenic agents (12). Lifestyle factors also extend to hygiene practices, where irregular brushing and infrequent dental visits contribute to the development of both dental caries and periodontal disease. Regular oral hygiene, including twice-daily brushing with fluoride toothpaste and routine dental check-ups, is essential for mitigating the impact of environmental risks on oral health. Environmental influences such as diet, smoking, and lifestyle choices interact with genetic factors to shape individual risk profiles for oral diseases, highlighting the importance of a comprehensive approach to prevention and management.

Gene-Environment Interactions and Oral Disease Risk

The intricate relationship between genetic predisposition and environmental exposures has emerged as a pivotal area of study in understanding oral disease risk. Gene-environment interactions (GEIs) play a fundamental role in modulating an individual’s susceptibility to oral diseases, such as periodontitis and oral cancers. These interactions occur when environmental factors, such as smoking, diet, or microbial exposure, differentially affect individuals depending on their genetic makeup. A growing body of evidence demonstrates that these interactions significantly influence the pathogenesis and progression of oral diseases.

One of the most studied gene-environment interactions in periodontal disease involves polymorphisms in the interleukin-1 (IL-1) gene cluster. Individuals carrying the IL-1 gene variant associated with hyper-responsiveness to inflammation are more susceptible to severe periodontitis, particularly when exposed to environmental risk factors like smoking. Smoking not only increases the burden of oral bacteria but also amplifies the inflammatory response in genetically predisposed individuals, accelerating the progression of periodontal destruction (13). This synergy between a genetic pro-inflammatory state and an environmental toxin illustrates the profound impact of GEIs in periodontal disease outcomes.

Similarly, oral cancer development is heavily influenced by gene-environment interactions, particularly those involving genes responsible for the detoxification of carcinogens. Polymorphisms in genes encoding enzymes such as glutathione S-transferases can impair the detoxification of carcinogens found in tobacco smoke, increasing the risk of oral squamous cell carcinoma (14). In individuals with GST gene polymorphisms, tobacco exposure results in an accumulation of carcinogenic metabolites, leading to increased DNA damage and a higher likelihood of malignant transformation. This highlights the interplay between genetic susceptibility and carcinogen exposure in oral cancer etiology.

Moreover, recent studies have explored how epigenetic mechanisms, such as DNA methylation, mediate gene-environment interactions in oral diseases. Environmental factors like diet and smoking can induce epigenetic modifications that alter gene expression without changing the underlying DNA sequence. For instance, hypomethylation of the CDKN2A gene promoter has been associated with increased susceptibility to oral cancers in smokers (15). These epigenetic changes can enhance the expression of oncogenes or suppress tumor suppressor genes, thereby facilitating the carcinogenic process in individuals exposed to harmful environmental factors. Understanding the complexities of gene-environment interactions is crucial for developing personalized approaches to oral disease prevention and treatment, as these interactions underscore the variability in individual responses to environmental risk factors.

Implications of Epigenetic Modifications in Oral Disease Susceptibility

Epigenetic modifications, including DNA methylation, histone modifications, and non-coding RNA regulation, are increasingly recognized as pivotal mechanisms in modulating gene expression and contributing to oral disease susceptibility. Unlike genetic mutations, epigenetic changes do not alter the DNA sequence but instead affect gene activity in response to environmental and biological stimuli. These modifications can profoundly influence the pathogenesis of oral diseases, including periodontitis and oral squamous cell carcinoma (OSCC), by altering cellular processes such as inflammation, cell proliferation, and apoptosis.

DNA methylation, particularly hypermethylation of tumor suppressor genes, has been well-documented in the context of OSCC. Hypermethylation of genes such as CDKN2A (p16), which regulates the cell cycle, results in the silencing of these critical regulatory genes, leading to unchecked cellular proliferation and increased cancer risk. Studies have shown that CDKN2A hypermethylation is frequently observed in OSCC tissues and is associated with poor prognosis (16). Furthermore, environmental factors such as tobacco and alcohol exposure can exacerbate these epigenetic alterations, suggesting a synergistic role of environmental triggers and epigenetic dysregulation in oral carcinogenesis.

Histone modifications also play a crucial role in the epigenetic regulation of genes involved in inflammation and tissue destruction, particularly in periodontitis. Histone acetylation, which typically promotes gene expression, has been implicated in the upregulation of pro-inflammatory cytokines such as IL-6 and tumor necrosis factor-alpha (TNF-α) in periodontal tissues (17). These cytokines contribute to the inflammatory cascade, leading to tissue breakdown and bone resorption characteristic of periodontitis. Altered histone acetylation patterns may thus contribute to a heightened inflammatory response in individuals genetically predisposed to periodontal disease.

Non-coding RNAs, especially microRNAs (miRNAs), have emerged as critical regulators of gene expression in oral diseases. miRNAs function by binding to messenger RNA (mRNA) and preventing its translation into protein, thereby fine-tuning gene expression. Dysregulation of specific miRNAs has been implicated in both periodontitis and OSCC. For instance, miR-31 has been shown to be overexpressed in OSCC, where it promotes cell proliferation and invasion by targeting tumor suppressor genes (18). Additionally, miRNAs such as miR-146a are involved in modulating inflammatory responses in periodontitis, suggesting that miRNA dysregulation may exacerbate tissue destruction in this chronic inflammatory condition. Epigenetic modifications thus represent a dynamic and reversible layer of gene regulation that bridges genetic susceptibility and environmental exposure, playing a critical role in the development and progression of oral diseases

Conclusion

In summary, genetic predispositions, environmental exposures, and epigenetic modifications all contribute significantly to oral disease susceptibility. Understanding these intricate relationships provides valuable insights into developing personalized prevention and treatment approaches. Further research into gene-environment interactions and epigenetic influences will enhance early detection and targeted interventions in oral healthcare. These advances hold promise for improving patient outcomes and disease management strategies.

Disclosure

Conflict of interest

There is no conflict of interest.

Funding

No funding

Ethical Consideration

Not applicable.

Data availability

Data that support the findings of this study are embedded within the manuscript.

Author Contribution

The authors contributed to conceptualizing, data drafting, collection and final writing of the manuscript.