Cytokines and Their Genetic Polymorphisms Related to Periodontal Disease.

Periodontal disease (PD) is a chronic inflammatory disease caused by the accumulation of bacterial plaque biofilm on the teeth and the host immune responses. PD pathogenesis is complex and includes genetic, environmental, and autoimmune factors. Numerous studies have suggested that the connection of genetic and environmental factors induces the disease process leading to a response by both T cells and B cells and the increased synthesis of pro-inflammatory mediators such as cytokines. Many studies have shown that pro-inflammatory cytokines play a significant role in the pathogenesis of PD. The studies have also indicated that single nucleotide polymorphisms (SNPs) in cytokine genes may be associated with risk and severity of PD. In this narrative review, we discuss the role of selected cytokines and their gene polymorphisms in the pathogenesis of periodontal disease.

Ficolin-2 Gene rs7851696 Polymorphism is Associated with Delayed Graft Function and Acute Rejection in Kidney Allograft Recipients.

Ficolin-2 is an activator of the complement system that acts via the lectin pathway. Complement activation plays a substantial role in the renal injury inherent to kidney transplantation. In this study, we examined the associations between ficolin-2 gene polymorphisms in exon 8 and kidney allograft function. This study comprised 270 Caucasian deceased-donor renal transplant recipients. The following parameters were recorded in each case: delayed graft function (DGF), acute rejection (AR), and chronic allograft dysfunction. Among patients with DGF, we observed a significantly increased frequency of rs7851696 GT and TT genotypes as well as T allele (TT + GT vs GG OR 1.98, 95% CI 1.12-3.48, p = 0.02; T vs G OR 2.08, 95% CI 1.27-3.41, p = 0.005). There was also an increased frequency of rs4521835 GG and TG genotypes as well as G alleles; however, these differences were on the borderline of statistical significance (GG + TG vs TT, OR 1.75, 95% CI 0.98-3.12, p = 0.07; G vs T OR 1.45, 95% CI 1.00-2.09, p = 0.050). In addition, we observed an increased frequency of acute allograft rejection in carriers of ficolin-2 rs7851696 T alleles on the borderline of statistical significance (TT + GT vs GG OR 1.75, 95% CI 0.97-3.16, p = 0.08), but the frequency of T allele was significantly higher in patients with AR (T vs G OR 1.71, 95% CI 1.02-2.87, p = 0.048). The results of our study suggest that ficolin-2 rs7851696 gene polymorphism influences kidney allograft functions, with T allele increasing the risk of DGF and AR.

STAT4 gene polymorphism in patients after renal allograft transplantation.

INTRODUCTION: STAT4 (signal transducer and activator of transcription 4) is involved in the regulation of innate and adaptive immune responses. Some studies have suggested that STAT4 may be involved in the immune response after graft transplantation. Several polymorphisms in the STAT4 gene have been identified. The most commonly studied polymorphism in the STAT4 gene is rs7574865. In our study, we examined whether this polymorphism is associated with the early and late functions of renal allografts. MATERIAL AND METHODS: A total of 270 recipients of first renal transplants were included in the study. Single nucleotide polymorphisms (SNPs) within the STAT4 gene were genotyped using TaqMan genotyping assays. RESULTS: There were no statistically significant associations between the STAT4 gene rs7574865 polymorphism and delayed graft function, acute rejection, chronic allograft dysfunction, post-transplant diabetes mellitus, or creatinine serum concentrations after transplantation. CONCLUSIONS: Our results suggest a lack of association between the STAT4 rs7574865 SNP and kidney allograft function in the Polish population.

CCL2 gene polymorphism is associated with post-transplant diabetes mellitus.

Post-transplant diabetes mellitus (PTDM) is a common complication after solid organ transplantation, especially in recipients treated with calcineurin inhibitors. Previous studies suggest that chronic inflammation and chemokines play an important role in the pathogenesis of diabetes. Single-nucleotide polymorphisms (SNPs) can increase or decrease transcriptional activity and can change the production of chemokines. The aim of this study was to examine the association between CCL2 and CCL5 gene polymorphisms and the development of post-transplant diabetes mellitus. The study included 315 patients who received kidney transplants and were treated with calcineurin inhibitors. Patients were divided into two subgroups: with PTDM (n=43) and without PTDM (n=272). An additive model of univariate Cox regression analysis showed that the hazard of PTDM development was significantly positively associated with the number of CCL2 rs1024611 G alleles (HR 1.65; 95%CI 1.08-2.53; p=0.021). Multivariate Cox regression analysis, taking into the account the recipient's sex, age and BMI, as well as the number of G alleles of the CCL2 rs1024611 polymorphism, revealed that this polymorphism is an independent risk factor for post-transplant diabetes. The results of our study suggest an association between the CCL2 gene rs1024611 G allele and PTDM in patients treated with tacrolimus or cyclosporine.

The effect of gene polymorphisms on patient responses to rheumatoid arthritis therapy.

INTRODUCTION: Rheumatoid arthritis (RA) is a systemic disease leading to joint destruction. The therapy of RA is mainly based on disease-modifying anti-rheumatic drugs (DMARDs) and biological drugs. The response to treatment is different among patients. Therefore, we have searched for factors that may predict the efficacy and toxicity during therapy in individual patients. AREAS COVERED: This review presents the role of genetic polymorphisms as predictors of the efficacy and toxicity during the therapy of RA patients with DMARDs (methotrexate, leflunomide, sulfasalazine) and biological drugs (anti-TNF-alpha antagonists, Tocilizumab, Rituximab). EXPERT OPINION: Despite studies having shown an association between genetic polymorphisms and response to therapy in RA patients, the majority of these findings are still inconclusive and inconsistent. We are still far from applying pharmacogenetic tests in routine clinical practice that can predict the outcome of treatment. Several factors, such as small sample size with low statistical power, variability in the outcome definitions and the heterogeneity of the cohorts, limited number of tested single nucleotide polymorphisms (SNPs), small effect for the selected variant, and a lack of consideration of epigenetic factors, may contribute to the inconsistency observed and may lead to limited success in personalizing therapy.

Association between the CX3CR1 gene V249I polymorphism and delayed kidney allograft function.

BACKGROUND: Fractalkine is a member of the chemokine family that acts as an adhesion molecule and as an extracellular chemoattractant promoting cellular migration. In this study, we analysed the association between the CX3CR1 gene V249I (rs3732379) SNP and renal allograft function. METHODS: The study enrolled 270 Caucasian kidney allograft recipients. The following parameters were recorded in each case: the recipient's age and gender, delayed graft function (DGF) defined as the need for dialysis in the first 7 days after transplantation, occurrence and number of episodes of acute rejection (AR), and chronic allograft dysfunction (CAD). RESULTS: Delayed graft function was diagnosed in 39.2% of individuals with the CC genotype, 22.7% with CT and 23.5% of those with the TT genotype. The differences were statistically significant (CC vs. TT+CT: OR = 2.17; 95% CI = 1.28-3.70, p = 0.0042). In multivariate analysis the CC genotype was an independent and significant predictor of higher risk of DGF. The distribution of genotypes and alleles of the CX3CR1 gene polymorphism among patients with and without AR as well as CAD did not differ significantly. CONCLUSIONS: The results of this study suggest that the CX3CR1 gene V249I (rs3732379) SNP CC genotype is associated with increased risk of DGF.

Renalase gene polymorphism in patients after renal allograft transplantation.

BACKGROUND/AIMS: Renalase is a recently discovered protein, which is likely involved in regulation of blood pressure in humans and animals. Previous studies suggest that renalase reflects kidney functioning. A common missense polymorphism in the flavin-adenine dinucleotide-binding domain of human renalase (Glu37Asp) has been described. In this study we examined the association between (Glu37Asp) polymorphism (rs2296545) in renalase gene and kidney allograft function. METHODS: The study enrolled 270 Caucasian kidney allograft recipients. SNP within the renalase was genotyped using TaqMan genotyping assays. RESULTS: There were no statistically significant associations between renalase gene rs2296545 polymorphism and delayed graft function, acute rejection, chronic allograft dysfunction as well as creatinine serum concentrations and blood pressure values after transplantation. CONCLUSIONS: The results of this study suggest, that renalase gene rs2296545 polymorphism is not important factor determining renal allograft function.

Association between IVS3 +17T/C CD28 gene polymorphism and the acute kidney allograft rejection.

CD28 is a costimulatory molecule which plays an important role in T cell-mediated immune response and transplantation. The aim of the present study was to examine the association between the IVS3 +17T/C (rs3116496:T/C) polymorphism in the CD28 gene and the development of delayed renal graft function (DGF), as well as the acute rejection and chronic allograft nephropathy. A total of 270 recipients of the first renal transplants were included in the study. SNP within the CD28 gene was genotyped using TaqMan genotyping assay. Acute rejection was diagnosed in 21.74% of the carriers of the TT genotype, 33.33% of CT carriers and 60.00% of CC homozygotes. The odds of acute rejection were statistically significantly higher in carriers of the C allele (with CT or CC genotype) compared with TT homozygotes (CC+CT vs TT: OR = 1.93, 95%CI = 1.10-3.39, p = 0.026). There were no statistically significant associations between CD28 gene polymorphism and DGF as well as chronic allograft nephropathy. The results of our study suggest an association between IVS3 +17T/C polymorphism in the CD28 gene and acute kidney allograft rejection.

[Association between AIF-1 gene polymorphisms and response to rheumatoid arthritis treatment with sulphasalazine]. / Wplyw polimorfizmów genu AIF-1 na skutecznosc leczenia sulfasalazyna reumatoidalnego zapalenia stawów.

INTRODUCTION: AIF-1 is an inflammatory cytokine influencing the immune system. There are increased levels of AIF-1 in the synovial fluid of patients with rheumatoid arthritis (RA). Sulfasalazine still remains the mainstay for the treatment of RA. It has an anti-inflammatory effect, inhibiting the action of inflammatory mediators. The aim of our study was to examine the association between AIF-1 (rs2269475:C>T, rs2736182:G>A, rs2259571:A>C) polymorphisms and response to sulfasalazine treatment in RA patients. MATERIAL: A total of 112 RA patients were enrolled in the study. RESULTS: There were no statistically significant associations between AIF-1 polymorphisms and response to sulphasalazine treatment. CONCLUSION: The results of this study suggest a lack of association between AIF-1 gene polymorphisms and response to sulphasalazine treatment.

The association between cytokine gene polymorphisms and kidney allograft survival.

BACKGROUND: Cytokines regulate cellular and humoral immune responses. One determinant of the variable cytokine production observed among individuals is genetic polymorphism in cytokine genes. These polymorphisms represent normal allelic variations in the cytokine genes; usually single base changes. Homozygous genotypes for high producer alleles are generally associated with high cytokine production, heterozygotes with intermediate production, and homozygotes for the low producer alleles with low cytokine production. Cytokines have been implicated in the regulation of acute and chronic rejection of allografts. The aim of the study was to evaluate the promoter polymorphism of TNF-alpha gene (-308 promoter polymorphism), IL-2 gene (-330 promoter polymorphism), IL-4 gene (-590 promoter polymorphism), and IL-6 gene (-174 promoter polymorphism) in renal transplant recipients with allograft duration under and over 10 years to establish whether aforementioned polymorphism are involved in kidney allograft survival. MATERIAL/METHODS: The study included 197 renal transplant recipients with well-functioning grafts for 2 to 18 years. The patients were divided into two subgroups: recipients with allograft duration under 10 years and recipients with allograft duration over 10 years. RESULTS: Among renal transplant recipients with allograft duration over 10 years we observed the prevalence of subjects with the T1T1 genotype of TNF alpha (low expression of TNF alpha) and GG of IL-6 (high expression of IL-6). There was no difference in relation to IL-2 and IL-4 promoter polymorphism. CONCLUSIONS: The results of present study suggest that the TNF-alpha -308 and the IL-6 -174 promoter polymorphisms may be the genetic factors influencing the renal allograft survival.

677C > T and 1298A > C MTHFR polymorphisms affect arechin treatment outcome in rheumatoid arthritis.

Despite the availability of several new agents for the treatment of rheumatoid arthritis (RA), arechin (hydroxychloroquine) remains the mainstay because of both cost-effectiveness and experience with its use. However, there is considerable variation in response to this drug, with toxicity limiting treatment in some patients. Methylenetetrahydrofolate reductase (MTHFR) is involved in the folate metabolism and has been shown to be polymorphic what affects the enzyme activity. To examine the association between 677C > T and 1298A > C MTHFR polymorphisms and arechin efficacy in the treatment of RA, a total of 50 RA patients, treated with arechin were analyzed. In univariate regression analysis model, MTHF R 677T allele was associated with significantly higher frequency of remission, whereas 1298C allele carriers showed a tendency to higher remission rate. In univariate regression analysis model, the presence of MTHFR 677T allele was associated with 2.3-fold higher frequency of remission. Multivariate regression analysis taking into the account the combined effect of MTHFR 677T and 1298C alleles revealed that both alleles were independent factors associated with increased frequency of remission. The results of our study suggest that 677T and 1298C alleles are independent factors associated with increased frequency of remission and the evaluation of C677C > T and A1298A> C MTHFR polymorphisms may be a useful tool to predict arechin treatment outcome in RA patients.

[The influence of IL-6 polymorphism on efficacy of treatment of rheumatoid arthritis patients with methotrexate and prednisone]. / Wplyw polimorfizmu interleukiny-6 na skutecznosc leczenia chorych na reumatoidalne zapalenie stawów metotreksatem i prednizonem.

Rheumatoid arthritis (RA) is a chronic inflammatory disease in which cytokines play an important role. The therapy of RA is associated with application of the drugs modulating the immune response via inhibiting the cytokine production. The common drugs used in RA therapy are methotrexate and prednisone. Recent investigations showed the importance of genetically determined differences in cytokine production in RA activity and therapy. The aim of the present study was to examine the influence of - 174 interleukin-6 (IL-6) promoter polymorphism on the efficacy of treatment of RA patients with methotrexate and prednisone. Polymerase chain reaction amplification was used for analysis of the polymorphism at IL-6 gene. Seventy patients with RA diagnosed according to the criteria of the American College of Rheumatology were investigated. The patients were divided into two subgroups. The first subgroup included patients who have obtained remission for at least 6 months after therapy with methotrexate and glucocorticosteroids. The second subgroup included patients with active disease despite at least 6 months of therapy with methotrexate and glucocorticosteroids. It has been shown that the incidence of remission after therapy with methotrexate and glucocorticosteroids was significantly lower in patients with GG genotype as compared with GC and CC genotypes p< 0.05. We suggest that -174 IL-6 promoter polymorphism may be a genetic risk factor determining the effectiveness of RA treatement with methotrexate and glucocorticosteroids.

[The influence of FcgammaRIIa polymorphism on rheumatoid arthritis]. / Rola polimorfizmu FcgammaRIIa w przebiegu reumatoidalnego zapalenia stawów.

The FcgammaRIIa receptor is most widely distributed of the Fcgamma receptors and is expressed on the most types of immunocomponent cells. Polymorphism of the FcgammaRIIa receptors may modulate immune complex mediated inflammation, particularly when immune complex contains IgG. The aim of the study was to evaluate the influence the FcgammaRIIa polymorphism on disease parameters activity in patients with rheumatoid arthritis (RA). The study included 75 patients with RA diagnosed according to the American College of Rheumatology criteria. In each patient the following parameters of disease activity were evaluated during one-year period: number of swollen and tender joints, morning stiffness duration, CRP, ESR as well as the disease activity in global physical assessment. There was no correlation between disease activity parameters and FcgammaRIIa polymorphism. Our results suggest, that FcgammaRIIa polymorphism does not represent an important genetic risk factor for RA activity.

Increased genotype frequency of N-acetyltransferase 2 slow acetylation in patients with rheumatoid arthritis.

OBJECTIVES: Acetylation polymorphism can alter therapeutic responses and toxicity to certain xenobiotics and may also be a factor that influences a patient's susceptibility to certain diseases. We investigated whether patients with rheumatoid arthritis (RA) differed from healthy individuals with regard to genotype of the polymorphic enzyme N-acetyltransferase 2 (NAT2). METHODS: NAT2 polymorphism was compared in 118 healthy subjects and 82 patients with RA. NAT2 alleles (*4, *5, *6, and *7) were determined by polymerase chain reaction-restriction fragment length polymorphism methods with deoxyribonucleic acid extracted from peripheral blood. RESULTS: A statistically significant increase in the proportion of homozygous slow acetylators with 2 mutated alleles (84.1%) was found among patients with RA in comparison with healthy subjects (52.5%; P <.0001). The risk of development of RA was almost 5-fold greater in slow acetylators than in fast acetylators (odds ratio, 4.79; 95% confidence interval, 2.28-10.21). There was no correlation between NAT2 polymorphism and presence of rheumatoid factor, extra-articular manifestations, and age at first occurrence of disease symptoms. CONCLUSIONS: NAT2 slow acetylation genotype may be a risk factor of individual susceptibility to RA.