IL-17A Polymorphism Research Articles

Interleukin (IL)-23 Receptor, IL-17A and IL-17F Gene Polymorphisms in Brazilian Patients with Rheumatoid Arthritis.

Rheumatoid arthritis (RA) is a progressive, autoimmune disease for which the previous studies have shown that some functional polymorphisms can influence its etiology. Knowing this, the aim of this study was to investigate the association of +2199 A/C IL-23R (rs10889677), -197 G/A IL-17A (rs2275913), and +7488 A/G IL-17F (rs763780) gene polymorphisms with RA susceptibility and clinical features in a Brazilian population. A total of 127 RA patients and 134 healthy controls were recruited for the analyses of polymorphic variants. Genotyping was performed using RFLP-PCR. Logistic regression was used to analyze the genotype distribution of the polymorphisms. Individuals carrying the homozygous CC genotype for the IL-23R polymorphism seem to be at lower risk for RA development (OR 0.22; p=0.004), as well as those carrying the variant C allele (OR 0.56; p=0.002). For the -197 G/A IL-17A polymorphism, the wild-type genotype (GG) was significantly associated with a 3.18-fold (OR 3.18; p=0.033) increased risk for RA. In relation to the +7488 A/G IL-17F polymorphism, no significant difference was found between RA cases and control subjects (p>0.05). Moreover, when investigating the relationship between polymorphisms and clinical features, no evidence of an association was found. Our findings suggest that the variants +2199 A/C IL-23R and -197 G/A IL-17A could contribute to RA development in the studied population. However, larger studies are needed to fully understand this genetic predisposition.

Association between SNPs at IL-17A and IL-17F and susceptibility to accelerated silicosis

The association between single nucleotide polymorphisms (SNPs) in the interleukin (IL)-17 gene and silicosis has been evaluated in different populations. The aim of the present study was to analyze the association between SNPs at IL-17A (-832A/G) and IL-17F (+7488A/G) and susceptibility to accelerated silicosis in the Iranian Kurdish population. We studied 48 patients with accelerated silicosis and 62 controls. Genomic DNA was isolated using the "salting out" method. PCR-RFLP was performed for all SNPs typing. The frequencies of A/A, A/G, and G/G genotypes at IL-17A (-832A/G) were 4 (8.33%), 23 (47.92%), and 21 (43.75%) in patients and 5 (8.06%), 35 (56.45%), and 22 (35.48%) in controls, respectively. The frequencies of A and G alleles at IL-17 (-832A/G) were 31 (32.29%) and 65 (67.71%) in patients, and 45 (36.29%) and 79 (63.71%) in the controls, respectively. The frequencies of A/A, A/G, and G/G genotypes at IL-17F (+7488A/G) were 1 (2.08%), 47 (97.92%), and 0 (0%) in patients, and 11 (17.74%), 51 (82.26%), and 0 (0%) in the controls, respectively. The frequencies of A and G alleles at IL-17F (+7488A/G) were 49 (51.04%) and 47 (48.96%) in patients, and 73 (58.87%) and 51 (41.13%) in the controls, respectively. IL-17F (+7488A/G) genotype was more frequent among the cases compared with controls (97.92% vs. 82.26%). The frequency of the IL-17F (+7488A/G) genotype was significantly greater in patients with accelerated silicosis (odds ratio = 10.13 95%; confidence interval = 1.2-81.5; p = 0.008). The IL-17F (+7488A/G) genotype revealed a significantly increased risk of accelerated silicosis ( p < 0.05). The IL-17F (+7488 G) allele was associated with an increased risk of accelerated silicosis, but in the case of the IL-17A (-832A/G) polymorphism, a significant association was not observed.

IL17A gene polymorphisms: relationship to predisposition for chronic viral hepatitis and progression to liver cirrhosis in kazakh population

This work is the first genetic association study of a potential relationship of single nucleotide polymorphisms rs8193036 and rs2275913 located in the IL17A promoter on chromosome 6p12 to chronic viral hepatitis and its progression in Kazakh population. Evaluation of the effect of IL17A polymorphism on predisposition for chronic hepatitis B and C and its progression to liver cirrhosis. A total of 862 individuals were enrolled in the retrospective case-control association study. Among the participants, 100 patients had chronic hepatitis B and/or C and liver cirrhosis, and 341 patients had chronic viral hepatitis only. Four hundred twenty-one (421) healthy HBV- and HCV-negative donors without liver diseases were recruited as population control. single nucleotide polymorphisms rs8193036[T/C] and rs2275913[G/A] were genotyped by TaqMan assays using genomic DNA extracted from peripheral blood cells. Results. Minor allele frequencies of rs8193036[C] and rs2275913[A] in the groups of patients were very similar to those observed in the control population, 0.4 and 0.3, respectively. Multivariate logistic regression analysis revealed odds ratios close to 1.0 and confidence intervals overlapping with the value of 1.0 and statistical significance p > 0.4 for any groups under comparison in the multiplicative model of inheritance. No significant association between two single nucleotide polymorphisms, rs8193036 and rs2275913 in the IL17A promoter, and susceptibility to chronic viral hepatitis C and/or B and disease progression to liver cirrhosis in Kazakh population were found.

IL17A and IL17F Gene Polymorphism Association with Psoriasis Risk and Response to Treatment in a Polish Population

Background: Recent studies have revealed the pivotal role of Th17 cells and interleukin-17 (IL-17) in plaque psoriasis development and treatment outcome. The IL-17 family consists of 6 structurally related cytokines (IL-17A, IL-17B, IL-17C, IL-17D, IL-17E, IL-17F), of which IL-17A and IL-17F mediate similar biological effects. Objectives: The aim of this study was to evaluate an association between the IL17A (-197G>A; rs2275913) and IL17F (rs763780: T>C; rs11465553: G>A; rs2397084: T>C) polymorphisms with psoriasis susceptibility as well as response to topical and combined topical with narrow-band ultraviolet B (NB-UVB) therapy in a Polish population. Methods: Association study involving 407 psoriasis patients and 205 healthy controls. Treatment efficacy was analyzed in 207 patients with mild psoriasis (Psoriasis Area and Severity Index; PASI 3-12) and moderate psoriasis (PASI 12-18), who were randomly subjected to topical or combined topical and NB-UVB treatment. The polymorphisms were evaluated by RT-PCR. Results: No statistically significant differences between psoriasis patients and controls were found in the frequency of the evaluated IL17A and IL17F genotypes and haplotypes. The IL17A or IL17F polymorphisms were not associated with treatment outcome measures: efficacy of treatment at the eighth week of the study and PASI change after topical or combined topical and NB-UVB therapy. However, IL17F rs2397084 variant allele C carriers required a significantly higher number of NB-UVB irradiations in comparison to TT homozygotes (15.5 ± 11.4 vs. 11.1 ± 11.9, p = 0.047) to produce a positive clinical response. Conclusion: It can be stated that the IL17A and IL17F polymorphisms are not markers of susceptibility to psoriasis. However, the IL17F polymorphism may affect the response to NB-UVB therapy.

RS8193036 POLYMORPHISM OF IL-17A GENE IN A KAZAKH POPULATION AND ITS ASSOCIATION WITH PLASMA IL-17A AMONG ERYSIPELAS PATIENTS

We studied associations between rs8193036 polymorphism of IL-17A gene (C737T) and plasma levels of IL-17A in patients with erysipelas and healthy subjects in a Kazakh population. The rs8193036 polymorphism was assessed in 95 patients with erysipelas and 383 control subjects. The IL-17A (rs8193036) polymorphism was studied by a real time polymerase chain reaction. Plasma levels of IL-17A were assessed in 90 patients with erysipelas and 90 healthy subjects by enzyme immunoassay. Categorical data were analyzed using Pearson's Chi tests and odds ratios (OR) with 95 % confidence intervals (CI). Continuous data were studied using Kruskal -Wallis and Mann-Whitney tests with Bonferroni correction. We found that T allele occurred more frequently (OR = 1.41; 95 % CI: 0.21-0.92) while allele C (OR = 0.71; 95 % CI: 0.51-0.99) and genotype CC (OR = 0.44; 95% CI: 0.21-0.92) occurred less frequently in cases than in controls. In erysipelas patients with CC genotype the level of IL-17A was significantly higher (p = 0.010) compared to the carriers of CT genotype. Also, the levels of IL-17A in patients with erysipelas was higher than among controls in groups with both CC and CT genotypes (p = 0.023 and p = 0.020, respectively). These data suggest that the rs8193036 polymorphism of IL-17A gene may play a role in the etiology of erysipelas, but other factors are also involved.

Investigation of the role of IL17A gene variants in Chagas disease.

Human host genetic factors have been suggested to be determinants of the prevalence and clinical forms of Chagas disease. In this regard, IL-17A is believed to control parasitemia and protect against heart disease. In this work, we assessed whether IL17A gene polymorphisms are related to infection and/or development of the cardiac form of Chagas disease by genotyping for five IL17A SNPs (rs4711998, rs8193036, rs3819024, rs2275913 and rs7747909) in 1171 individuals from a Colombian region endemic for Chagas disease, classified as seronegative (n=595), seropositive asymptomatic (n=175) and chronic Chagas cardiomyopathy (n=401). Our results showed that SNP rs8193036, which is located upstream of the coding region of the gene, was slightly associated with protection against T. cruzi infection (P=0.0170, P(FDR)=0.0851, odds ratio (OR)=0.80, confidence interval (CI)=0.66-0.96) and associated with protection against the development of cardiomyopathy (P=0.0065, P(FDR)=0.0324, OR=0.75, CI=0.60-0.92). This finding suggests that this IL17A polymorphism could be associated with Trypanosoma cruzi infection and the development of chronic cardiomyopathy due to differential expression of cytokine IL-17A.

Association study between IL-17A and IL-17F gene polymorphism and myasthenia gravis in Chinese patients.

Alleles of IL-17A and IL-17F genes were reported to be associated with many inflammatory and autoimmune disorders in Asian patients. Serum level and mRNA of IL-17A in peripheral blood mononuclear cells were reported to be significantly higher in MG patients than in healthy controls. In experimental autoimmune myasthenia gravis (EAMG) animals, IL-17 may have effects on the severity of MG. This study investigated the association between four SNPs of IL-17A and IL-17F gene (rs8193036, rs2275913 and rs3748067 in IL-17A; rs763780 in IL-17F) and MG in Chinese patients. The allele frequencies were compared between 480 MG patients and 487 healthy controls, between each MG subgroup and the control group, and between each pairs of MG subgroups. Subgroups were specified by clinical features (onset age, gender, thymoma, AChRAb and muscle involvement at onset) and maximal severity during the follow-up. No associations were found between the four SNPs of IL-17A and IL-17F gene and MG in Chinese patients.

Interleukin 17A polymorphism elevates gene expression and is associated with increased risk of nonsmall cell lung cancer.

Interleukin 17 (IL-17), also known as IL-17A, is a proinflammatory cytokine and plays critical roles in tumor immunity. Nonsmall cell lung cancer (NSCLC) is the most common type of lung cancers. The aim of this study was to investigate the correlation between IL-17A genetic polymorphisms and susceptibility to NSCLC. Two single nucleotide polymorphisms (SNPs) in IL-17A gene, rs3819024A/G and rs8193037G/A, were detected in 322 NSCLC patients and 366 healthy donors. Data revealed that prevalence of IL-17A rs8193037GA and AA genotypes were significantly higher in the patients than in controls (odds ratio [OR]: 2.20, 95% confidence interval [CI]: 1.53-3.16, p<0.001; and OR: 3.19, 95% CI: 1.42-7.15, p=0.003). Stratification analyses showed that rs8193037A allele had significantly higher percentage in adenocarcinoma than in squamous cell carcinoma (OR: 1.72, 95% CI: 1.12-2.64, p=0.013). When examining the possible function of the SNPs, we found that in vitro stimulated peripheral blood mononuclear cells from subjects possessing rs8193037A allele produced significantly more IL-17 than those with the GG genotype, and this phenomenon could be observed in both controls and the NSCLC patients. These data indicate IL-17A polymorphism is associated with increased risk of NSCLC probably by elevating gene expression.

IL-17A, IL-17F and IL-23R Gene Polymorphisms in Polish Patients with Rheumatoid Arthritis.

Among the complex network of inflammatory cells involved in the pathogenesis of rheumatoid arthritis (RA), Th17 cells have recently been identified as key cells in the promotion of autoimmune processes, and joint destruction. The IL-23/Th17 signalling pathway, consisting of IL-23/IL-23R, IL-17A and IL-17F encoding genes, represents a candidate way for RA development with possible involvement in disease susceptibility and effect on disease progression. The present study aimed to determine the association between the polymorphic variants of the IL-17A (rs2275913), IL-17F (rs763780) and IL-23R (rs11209026) genes and RA susceptibility, progression and response to therapy with TNF-α inhibitors. Eighty-nine patients and 125 healthy individuals were investigated. The IL-17A polymorphism was found to affect RA progression and response to anti-TNF treatment. Female patients carrying the IL-17A wild-type genotype more frequently presented with stage 4 (8/24 vs. 6/47; p = 0.058) and were characterized by more active disease (the highest DAS28 score >5.1) after 3 months of therapy with the TNF inhibitors (12/23 vs. 15/45; p = 0.040). The IL-17F polymorphism appeared to be associated with susceptibility to the disease. The presence of the IL-17F minor variant (OR 3.97; p < 0.001) and its homozygosity (OR 29.62; p < 0.001) was more frequent among patients than healthy individuals. These results suggest that the polymorphisms within the IL-17A and IL-17F genes play a significant role in RA.

IL-17A (-197G/A) and IL-17F (7488T/C) gene polymorphisms and cancer risk in Asian population: a meta-analysis.

Interleukin (IL)-17 has been shown to play an important role in the pathogenesis of inflammation and cancer. The IL-17A (-197G/A) and IL-17F (7488T/C) polymorphisms have been extensively investigated with cancer risk, but individually published results have been inconclusive. The aim of this study was to clarify the effects of the IL-17A (-197G/A) and IL-17F (7488T/C) polymorphisms on cancer risk in Asian populations. Relevant studies were identified by searching databases extensively. The association between the IL-17A (-197G/A) and IL-17F (7488T/C) polymorphisms and cancer risk was assessed by odds ratios (ORs) together with their 95% confidence intervals (CIs). A total of 12 articles with adequate information satisfied our inclusion criteria; these included 12 studies, with 4,540 cases and 5,875 controls, of IL-17A (-197G/A) polymorphism and seven studies, with 1,960 cases and 3,226 controls, of IL-17F (7488T/C) polymorphism. In the overall analysis, the IL-17A (-197G/A) polymorphism was significantly associated with increased cancer risk (P<0.05), for all genetic models. However, there was no statistically significant association between IL-17F (7488T/C) and cancer risk (P>0.05), for any genetic models. Furthermore, stratification by cancer type revealed a significant correlation between the IL-17A (-197G/A) polymorphism and cancer risk for all cancer types. When stratified by source of controls, a significant correlation was observed between the IL-17A (-197G/A) polymorphism and cancer risk in the population-based control subgroup but not in hospital-based control subgroup. In conclusion, our meta-analysis provides evidence that the IL-17A (-197G/A) polymorphism might be associated with cancer risk, while no evidence suggested a significant association between IL-17F (7488T/C) polymorphism and cancer risk.

Significant association between interleukin-17A polymorphism and colorectal cancer

Interleukin (IL) 17A is an inflammatory cytokine expressed by Th 17 cells and plays a role in tissue inflammation by inducing release of proinflammatory and neutrophil-mobilizing cytokines. We have investigated the association between colorectal cancer and polymorphisms of IL17A (rs2275913. G197A). The study was performed in 241 subjects (102 with colorectal cancer and 139 healthy controls). Genotypes were determined by fluorescent-based restriction fragment length polymorphism method. The association between the molecular features at the gene in relation to tumor and patient clinical characteristics was analyzed. There was a significant difference between the genotype frequencies of IL17A G197A of control subjects (GG 68.34 % and GA + AA 31.65 %) and patients with colorectal cancer (GG 47.05 % and GA + AA 52.94 %) (p = 0.001 with odds ratio (OR) 2.45 (1.43-4.11)). IL17A G197A polymorphism is particularly associated with colon cancer. Indeed, the IL17A GG genotype could be considered as a protective factor against colon cancer (p = 0.00001) with OR 3.77 (2.04-6.99). We have noted a significant association of IL17A G197A polymorphism not only with tumor localization (p = 0.003) but also with tumor differentiation (p = 0.0005) in CRC patients. We have also showed a significant association of G197A variant with an increased risk of advanced stage (p = 0.005). Our result suggests that the A allele of IL17A gene is involved in susceptibility to colorectal cancer and is associated with clinical features as tumor location, tumor differentiation, and TNM stage. IL17A polymorphism may serve as biomarker of disease location and progression.

Association of interleukin-17A and -17F gene single-nucleotide polymorphisms with autoimmune thyroid diseases

Th17 lymphocyte and its relative cytokines have been shown to play an important role in autoimmune thyroid diseases (AITD). The aim of this study was to investigate the association between IL-17A and IL-17F gene polymorphisms and two main types of AITD, Graves' disease (GD) and Hashimoto's thyroiditis (HT). Whole blood specimens and clinical data were collected from 508 AITD patients (326 with GD and 182 with HT) and 224 age- and gender-matched healthy controls, respectively. IL-17A (rs2275913, rs8193037, rs3819025) polymorphism was determined using DNA sequencing method and IL-17F/rs763780 polymorphism was assayed by polymerase chain reaction-restriction fragment length polymorphism (PCR -RFLP). The results indicated that the frequencies of IL-17F/rs763780 genotypes in patients with GD and HT differed significantly from their controls (P = 0.013 and P = 0.005, respectively); the G allele frequencies were also significantly higher in the patient groups than the control groups (P = 0.002 and 0.001, respectively). For IL-17A/rs2275913 and rs8193037 SNP, no significant difference was observed in patients with either GD or HT compared to the control groups (P>0.05). Interestingly, for rs3819025, the frequency of A allele was lower in patients with GD than controls (P = 0.011). The frequencies of haplotype AGGG and GGGG in patients with GD and HT were significantly higher than in controls (P = 0.012, P = 0.019, P = 0.017 and P = 0.029, respectively). In conclusion, the results indicate that IL-17F/rs763780 polymorphisms may affect the susceptibility to AITD, and IL-17A/rs3819025 SNP is likely a protective factor to GD in the Chinese population.

Association between IL-17A, -17F and MIF polymorphisms predispose to CpG island hyper-methylation in gastric cancer

CpG island hyper-methylation (CIHM) is one of the major events in the gastric carcinogenesis. IL-17A, -17F and MIF have a crucial role in the gastric inflammation and carcinogenesis. Recently, we showed that the genetic polymorphisms of MIF-794-CATT repeat are associated with CIHM status in the non-neoplastic gastric mucosa. Consequently, the CIHM status in the gastric cancer tissue, in relation to IL-17A (-197G>A), -17F (7488T>C), and MIF (-173G>C and -794 tetranucleotide repeats) polymorphisms was investigated. Gastric cancer tissues were obtained from 102 patients. CIHM of p14, p16, DAP-kinase and CDH1 genes were determined by methylation-specific polymerase chain reaction (MSP). CIHM high was defined as three or all CpG islands methylated. We employed the PCR-SSCP (multiplex PCR for IL-17A and -17F) method to detect the gene polymorphisms. We did not find significant association between CIHM status and IL-17F (7488T>C) and MIF (-173G>C) polymorphisms. However, concerning the IL-17A (-197G>A) polymorphism, we found that IL-17A G carrier (GG+GA) held a significantly higher risk of CIHM of p16 (OR=11.22, 95% CI=1.38-91.17, p=0.024) and CIHM high (OR=3.51, 95% CI=1.15-10.68, p=0.027). An association was also found between the 7-CATT repeat carrier (5/7 + 6/7 + 7/7) of the MIF polymorphism (-794-CATT) and reduced risk of CIHM of CDH1 (OR=0.36, 95% CI=0.14-0.92, p=0.032). No association was found between CHIM status and homozygote genotypes of each repeat (-794-CATT 5/5, 6/6, and 7/7). The present results provided evidence that the genetic polymorphisms of IL-17A, and MIF-794-CATT repeat are associated with CIHM status in the gastric cancer. Genetic polymorphisms of IL-17A, and MIF-794-CATT repeat may be involved in methylation-related carcinogenesis in the stomach.

Significant Impact of IL-17A Gene Polymorphism On Transplant Outcomes After HLA-Fully-Matched Unrelated Bone Marrow Transplantation.

Abstract 2305Poster Board II-282IL-17 plays an active role in autoimmune diseases and organ transplant rejection through its mediating proinflammatory responses and inducing inflammatory cytokine and chemokine production. This study examined the impact of donor and recipient polymorphism in the IL-17A gene on the clinical outcomes in unrelated HLA-fully-matched myeloablative bone marrow transplantation (BMT) through the Japan Marrow Donor Program. The IL-17A polymorphism (rs2275913, G197A) was retrospectively analyzed in a total 145 recipients with hematologic malignancies and their unrelated donors. In patients with standard risk disease, the donor IL-17A-197A genotype was associated with significantly improved OS (adjusted HR, 0.32; 95% CI, 0.13-0.79; p=0.01) and reduced transplant related mortality (TRM) (adjusted HR, 0.27; 95% CI, 0.11-0.67; p=0.005), but no impact on disease relapse or the development of grades II-IV acute GVHD or chronic GVHD. Patients with standard risk disease receiving transplants from donors with the 197A genotype had better 5-year OS (71% vs. 40%, p=0.02; Figure) and lower 5-year TRM rate (27% vs. 60%, p=0.02). The IL-17A polymorphism did not significantly influence the transplant outcomes in patients with high risk disease. These results suggest transplantation from IL-17A-197A positive donor is advantageous in improving OS and reducing TRM after HLA-matched unrelated BMT for standard risk hematologic malignancies. [Display omitted] Disclosures:No relevant conflicts of interest to declare.

Genetic polymorphisms of molecules associated with inflammation and immune response in Japanese subjects with functional dyspepsia

Inflammatory changes in the gastric mucosa are commonly observed in Japanese patients with functional dyspepsia (FD). However, detailed data regarding the relationship between the genetic regulatory factors of inflammation and FD are not available. We investigated the associations between FD and genetic polymorphisms of molecules associated with inflammation or immune response (IL-17A, -17F and MIF). The study was performed with 278 subjects (188 with no upper abdominal symptoms and 90 with FD according to the Roma III criteria). We employed the PCR-SSCP (multiplex PCR for IL-17A and -17F) method to detect the gene polymorphisms. Overall, the polymorphisms of the IL-17A, -17F and MIF genes were not correlated with the susceptibility to FD. However, the MIF -173C allele carrier had a significantly increased risk for the development of epigastric pain syndrome (EPS) of FD (OR, 2.12; 95% CI, 1.00-4.49; p=0.0497). In Helicobacter pylori (H. pylori)-infected cases, the number of IL-17F 7488T alleles was positively correlated with the development of EPS (OR, 11.3; 95% CI, 1.23-103.2; p=0.032), while the IL-17F T/T homozygote and the MIF -173C carrier had an increased risk for EPS (OR, 10.4; 95% CI, 1.17-92.3; p=0.036 and OR, 3.66; 95% CI, 1.19-11.3; p=0.024, respectively). In addition, a significant interaction between the IL-17F 7488 polymorphism and H. pylori infection was shown to increase the activity and inflammation scores (p=0.043 and 0.042, respectively). There were no significant associations between the IL-17A polymorphism and FD. Our results provide the first evidence that the IL-17F and MIF gene polymorphisms are significantly associated with the development of FD, particularly EPS, a subgroup of FD, in H. pylori-infected subjects. The genetic polymorphisms of inflammation or immune response-related molecules are involved in the development of one of the FD subgroups via H. pylori-induced gastric inflammation.