TLR4 and IL-18 gene polymorphisms in rheumatoid arthritis and periodontitis

Objective: Recent literature has indicated that patients with rheumatoid arthritis (RA) are at higher risk of developing moderate to severe periodontitis than non-RA patients. In both diseases, genetic variants influence inflammatory immune responses, and polymorphisms of the interleukin18 (IL-18) and toll-like receptor4 (TLR4) genes, e.g., could play a role. We therefore evaluated known polymorphisms of these two genes in RA patients and healthy individuals with or without periodontitis. Methods: 68 RA patients and 203 non-RA control subjects were genotyped for c.896A>G and c.1196C>T polymorphisms in the TLR4 gene as well as for c. 368G>C and c.-838C>A IL-18 variants. Allele frequencies and genotype distribution were compared between the study groups. Clinical periodontal examination included probing depth (PD) and clinical attachment level (CAL). The presence of periodontitis was defined as proposed by the CDC Periodontal Disease Surveillance Workgroup (Page and Eke, 2007). Results: The genotype and allele frequencies of the two IL-18 promoter variants were not statistically different between the RA patients and healthy individuals. In contrast, TLR4 variants occurred in complete linkage disequilibrium, and were associated with RA, with an increased carrier rate of the c.896G and c.1196T allele in the RA patients (25% versus 9.9% in controls, p=0.004, Fisher's exact test; adjusted odds ratio [OR] for age and gender: 2.29; 95% confidence interval [CI]: 1.07-4.92). There was no significant association between any of the analyzed gene variants and periodontal status in univariate analysis. However, in a multiple logistic regression model, carriage of a TLR4 c.896G/c.1196T allele increased the risk of the occurrence of both RA and severe periodontitis together (adjusted OR: 3.67; 95% CI: 1.5-8.9). Conclusion: TLR4 gene variants could contribute to the susceptibility to developing RA and to developing severe periodontitis in RA patients. These findings support the hypothesis of a shared genetic background between RA and periodontitis. Keywords: rheumatoide arthritis, periodontitis, TLR4 gene polymorphism