Genetic insights into the relationship between anti-inflammatory drug target genes and oral diseases

Glucocorticoids and nonsteroidal anti-inflammatory drugs (NSAIDs) are cornerstones in the management of oral inflammatory pathologies. However, their precise causal effects on a range of oral diseases and the underlying genetic mechanisms remain poorly understood. Concurrently, emerging evidence on the gut-brain axis suggests a potential connection between intestinal inflammation and the pathogenesis of oral diseases. Although preliminary data point to the gut microbiota's role in disease progression, the specific causal pathways and genetic underpinnings remain largely unexplored. Therefore, this investigation was designed to elucidate the potential causal relationships between exposure to anti-inflammatory medications and oral disease risk.

This study systematically investigates the causal effects of anti-inflammatory medications on oral disease risk through a comprehensive Mendelian randomization (MR) strategy. Our approach integrates a primary two-sample MR using Genome-wide association study (GWAS) summary statistics with a multivariable MR leveraging gene expression quantitative trait locus (eQTL) data to assess specific drug targets from DrugBank. Furthermore, we investigate the gut microbiota as a potential mediator to elucidate the complete mechanistic pathway connecting the drug target to the disease outcome.

Our Mendelian randomization analysis revealed distinct, and often opposing, causal effects of different anti-inflammatory drug classes on oral disease risk. Genetically proxied glucocorticoid use was associated with an increased risk for acute periodontitis (IVW: odds ratio = 1.4786, 95% CI 1.0341-2.114, p = 0.032), Oral and oropharyngeal cancer (IVW: odds ratio = 1.0006, 95% CI 1.00004-1.0011, p = 0.033), and Cellulitis (odds ratio = 1.149, 95% CI 1.0003-1.3199, p = 0.0495). Conversely, paracetamol, a widely used NSAID, demonstrated a protective effect against acute periodontitis (IVW: odds ratio = 0.3338, 95% CI 0.1527-0.7293, p = 0.0059) but was concurrently identified as a risk factor for Oral and oropharyngeal cancer (odds ratio = 1.0016, 95% CI 1.0004-1.0028, p = 0.011), Disease of pulp and periapical tissues (odds ratio = 1.2486, 95% CI 1.0228-1.5242, p = 0.0291), and Dental caries (odds ratio = 1.6037, 95% CI 1.2179-2.1118, p < 0.001). To explore the genetic basis of these associations, we further investigated the role of specific drug target genes. Our findings implicated CASP3 (odds ratio = 1.25004, 95% CI 1.09498-1.42706, p < 0.001) and CCND1 (odds ratio = 1.55479, 95% CI 1.33389-1.81227, p < 0.001) as being significantly associated with the progression of acute periodontitis. In relation to oral and oropharyngeal cancer, significant associations were observed for a suite of genes including HSPA5, TNFAIP6, AKR1C1, CASP1, ANXA1, and MYC. Furthermore, CCND1 also demonstrated a significant association with the progression of dental caries (odds ratio = 1.15564, 95% CI 1.05554-1.26523, p = 0.0018), while SLC6A4, CASP3, NR3C1, and ANXA1 were linked to diseases of the pulp and periapical tissues. Of particular note, our mediation analysis provided initial evidence for a specific biological mechanism underlying these genetic links. The gene CCND1 appears to increase the risk of acute periodontitis via a reduction in the relative abundance of the genus Eubacterium coprostanoligenes group, and similarly increases the risk of dental caries through a decreased abundance of the family Rikenellaceae.

The results of this study suggest that the use of common anti-inflammatory medications may have significant implications for the risk and progression of oral diseases. These findings offer new insights into the clinical management of oral health and warrant further investigation into the underlying genetic mechanisms and drug-target interactions.