Genetic polymorphisms and periodontal disease in populations of African descent: A review.

Aggressive periodontitis is a rare but rapidly progressing form of periodontal disease that usually affects otherwise systemically healthy individuals, at a young age. It usually affects first molars and incisors, which are usually lost if treatment is not properly and early rendered. Although of low prevalence, it affects individuals of African descent at a higher prevalence, and usually multiple members within the same family. Several studies have been performed in the attempt to evaluate specific single nucleotide polymorphisms (SNPs) that could be associated with this disease. To the best of our knowledge, the present article provides the first review of the literature focusing on studies that evaluated SNPs in patients of African descent with aggressive periodontitis. Several SNPs have been evaluated in different genes according to their role in the pathogenesis of the disease, with positive and negative associations (such as IL1, FCGR3B, FPR1, LTF, CYBA, GLT6D1, TLR4) with both the localized and generalized forms of aggressive periodontitis. Given the complexity of periodontitis, the difficulty in gathering large cohorts diagnosed with this rare form of disease, and the fact that candidate gene studies may only determine part of the genetic risk of a disease, the search for specific SNPs associated with aggressive periodontitis seems to be a long one, most likely to result in the combination of multiple SNPs, in multiple genes.

Associations of P2RX7 Functional Diplotypes with Localized Aggressive Periodontitis.

AIM: The purpose of this study was to test for the role of the P2X7 receptor in localized aggressive periodontitis (LAP). METHODS: Peripheral blood was obtained from 95 subjects with LAP and 76 healthy unrelated controls (HUCs). Three P2RX7 single-nucleotide polymorphisms (rs1718119, rs2230911, and rs3751143) were genotyped from these subjects, and their peripheral blood samples were stimulated with lipopolysaccharide (LPS) from Escherichia coli and tested for inflammatory markers. The 3 P2RX7 single-nucleotide polymorphisms were in found to be in perfect linkage disequilibrium, and a total of 4 haplotypes and 9 diplotypes were identified among all subjects. For both subject populations, the 9 diplotypes were grouped into 4 functional groups and tested for association with subject inflammatory response. To specifically study the effects of extrinsic activation of the P2X7 receptor in LAP, peripheral blood samples from were stimulated under 3 treatments: LPS, LPS + ATP, and LPS +ATP+ P2X7 selective inhibitor. The effects of these treatments on P2X7 receptor activity were measured through Luminex protein assay. Last, to test whether receptor stimulation was related to P2RX7 expression, relative mRNA levels of P2RX7 were quantified with real-time quantitative polymerase chain reaction. RESULTS: Several associations between the P2RX7 diplotypes and LPS-stimulated blood chemokine/cytokine levels were found between the LAP and HUC populations (P < 0.05). P2X7 activation resulted in statistically significant differences in IL-1ß and IL-12p40 concentrations for both subject populations. The relative P2RX7 mRNA levels increased significantly after addition of its inhibitor for both LAP and HUC populations. CONCLUSIONS: This study detected an association between P2RX7 functional diplotypes and in vitro immune response of whole blood from subjects with LAP. In addition, we found that inhibition of the activated P2X7 receptor leads to increased P2RX7 mRNA levels, suggesting a feedback loop ( ClinicalTrials.gov NCT01330719). KNOWLEDGE TRANSFER STATEMENT: The results of this study suggest that P2RX7 functional diplotypes are associated with LAP and their in vitro immune response to bacteria. Ongoing studies to uncover the mechanistic link between P2RX7 and LAP phenotypes could lead to the development of preventive approaches for susceptible subjects.

Evaluation of kynurenine pathway metabolism in Toxoplasma gondii-infected mice: implications for schizophrenia.

Toxoplasma gondii, an intracellular protozoan parasite, is a major cause of opportunistic infectious disease affecting the brain and has been linked to an increased incidence of schizophrenia. In murine hosts, infection with T. gondii stimulates tryptophan degradation along the kynurenine pathway (KP), which contains several neuroactive metabolites, including 3-hydroxykynurenine (3-HK), quinolinic acid (QUIN) and kynurenic acid (KYNA). As these endogenous compounds may provide a mechanistic connection between T. gondii and the pathophysiology of schizophrenia, we measured KP metabolites in both the brain and periphery of T. gondii-treated C57BL/6 mice 8 and 28 days post-infection. Infected mice showed early decreases in the levels of tryptophan in the brain and serum, but not in the liver. These reductions were associated with elevated levels of kynurenine, KYNA, 3-HK and QUIN in the brain. In quantitative terms, the most significant increases in these KP metabolites were observed in the brain at 28 days post-infection. Notably, the anti-parasitic drugs pyrimethamine and sulfadiazine, a standard treatment of toxoplasmosis, significantly reduced 3-HK and KYNA levels in the brain of infected mice when applied between 28 and 56 days post-infection. In summary, T. gondii infection, probably by activating microglia and astrocytes, enhances the production of KP metabolites in the brain. However, during the first two months after infection, the KP changes in these mice do not reliably duplicate abnormalities seen in the brain of individuals with schizophrenia.