Cytokine Polymorphisms Research Articles

Associations between cytokine gene polymorphisms and rheumatoid arthritis in Turkish population.

OBJECTIVE:Various cytokine polymorphisms have been associated with genetic risk factors predisposing to Rheumatoid Arthritis (RA) in different populations. To predict the clinical outcome as well as response to therapy in RA, studies aimed to describe genetic markers. The present study aims to search for polymorphisms of 13 cytokine coding genes in the Eastern Black Sea Region of Turkey.METHODS:DNAs of 49 patients and 96 healthy bone marrow and kidney donors were isolated from peripheral blood samples. Genotyping was performed using the Heidelberg Cytokine Typing Tray kit. PCR products were visualized on an agarose gel, and results were analyzed using the interpretation scheme provided with the kit. Arlequin 3.5 software was used for statistical analysis.RESULTS:No positive association was found between allele frequencies and the disease. However, a negative association was found for the IL-A -889 C allele (p=0.02, OR=0.533, Wald’s 95% CI=0.318–0.893). IL-12 -1188 CC (p=0.01, OR=3.667, Wald’s 95% CI=1.246–10.786), IL-4 -1098 GT (p=0.02, OR=2.405, Wald’s 95% CI=1.129–5.125) genotypes were found positively associated with the RA, while IL-4 -590 CT (p=0.02, OR=0.422, Wald’s 95% CI=0.201–0.886) was found negatively associated with the disease. In addition, IL-6 GG haplotype was found positively associated with the RA (p=0.02, OR=1.880, Wald’s 95% CI=1.086–3.254).CONCLUSION:Our findings suggest that some polymorphisms of the IL-1A, IL-2, IL-4, IL-6 and IL-12 could be responsible for the susceptibility or protective to RA in our study population. Multi-centered and large numbers of subjects containing studies that search for cytokine polymorphisms will gather more information regarding the susceptibility to RA of Turkish patients.

The risk of atopic dermatitis may be affected by IL-1B +3954 C/T and IL-18 -137G/C polymorphisms: evidence from a meta-analysis.

IntroductionWhether Th1-related cytokine polymorphisms influence the risk of atopic dermatitis (AD) remain inconclusive.AimThe authors performed a meta-analysis to robustly explore relationships between Th1-related cytokine polymorphisms and the risk of AD by merging the results of eligible publications.Material and methodsThe authors strictly adhere to the PRISMA guidelines in study design and implementation. A thorough literature search in Medline, Embase, Wanfang, VIP and CNKI was performed by the authors to identify eligible publications. Relationships between TNF-α/IL-1/IL-6/IL-18 polymorphisms and the risk of AD were estimated with odds ratio and its 95% confidence interval. The statistically significant p value was set at 0.05. The quality of eligible publications was assessed by the Newcastle-Ottawa scale (NOS).ResultsIn total twenty-one publications with a NOS score of 7-8 were selected for merged quantitative analyses. We have noticed that genotypic frequencies of IL-1B +3954 C/T and IL-18 -137G/C polymorphisms among cases with AD and population-based controls differed significantly. Moreover, we have found that genotypic frequency of IL-1B +3954 C/T polymorphism among cases with AD and population-based controls of Caucasian origin differed significantly, and genotypic frequency of IL-18 -137G/C polymorphism among cases with AD and population-based controls of both Caucasian and Asian origins also differed significantly. However, we did not observe such genotypic distribution differences for TNF-α -238 G/A, TNF-α -308 G/A, IL-1A -889 C/T, IL-1B −511 C/T and IL6 -174 G/C polymorphisms.ConclusionsThe present meta-analysis shows that IL-1B +3954 C/T and IL-18 -137G/C polymorphisms may affect the risk of AD.

Impact of IL-18 gene promoter polymorphisms on renal cell carcinoma occurrence and prognosis in Chinese Han population*

Abstract Objective Genetic polymorphisms in various inflammatory cytokines have been associated with the risk and growth or invasiveness of renal cell carcinoma (RCC). However, the molecular basis of RCC pathogenesis is unclear. The aim of this study was to explore a possible association between two IL-18 gene promoter polymorphisms, -137G/C and -607C/A, and RCC occurrence and prognosis in a Chinese Han population. Methods Chinese Han patients with RCC (n = 175) and age-matched healthy controls (n = 200) were analyzed by single nucleotide polymorphism genotyping during follow-up. Results IL-18-137G allele frequency was significantly higher in patients with lymph node metastasis (Odds ratio [OR], 3.52; 95% confidence interval [CI], 0.97-16.17; P = 0.045). The IL-18-607 CC genotype was associated with distant metastasis (OR, 2.81; 95% CI, 1.35-6.24; P = 0.025). The IL-18-137 G allele was correlated with more advanced tumor stage (OR, 1.83; 95% CI, 1.05-3.72; P = 0.026) and higher tumor grade (OR, 2.23; 95% CI, 0.78-4.12; P = 0.041). The IL-18-607 CC genotype frequency was significantly higher in patients with more advanced cancer stage (OR, 2.92; 95% CI, 1.80-6.87; P = 0.001) and higher tumor grade (OR, 2.21; 95% CI, 1.25-12.25; P = 0.035). The IL-18-607 allele was associated with more advanced cancer stage (OR, 2.47; 95% CI, 1.38-3.83; P = 0.002).Carriers of the GG genotype with the -137G/ C polymorphism had a 2.165-times higher risk of RCC progression than carriers of the GC genotype (Hazard ratio = 2.15, 95% CI, 1.270-3.687). Conclusion The IL-18-137 G allele was correlated with more advanced stage, higher tumor grade, and lymph node metastasis. IL-18 gene promoter polymorphism -137G/C may thus influence the prognosis of RCC patients.

Th1 Cytokine Polymorphism Gene: TNF-Alpha -857C/T Affects the Pathogenesis and Progression of Acute Myeloid Leukemia

Background: Acute myeloid leukemia (AML) is a hematological malignancy characterized by the autonomous growth of immature myeloid cells with impaired differentiation and maturation. Cytokines are low-molecular-weight proteins that play a basic and fundamental role in communication within the immune system. Cytokines induce various effects such as differentiation, proliferation, hematopoiesis, and inflammation of target cells. AML is also closely associated with cytokine networks in terms of proliferation, apoptosis, and differentiation of leukemic cells. Cytokines produced by Th1 involved in cell-mediated immunity are called Th1 cytokines. Th1 cytokine includes TNF-α and IL-2. Several studies have reported that TNF-α is highly expressed in leukemia cells with AML patients. Other studies have also reported that high serum level of TNF-α of AML patients is associated with poor survival outcome. However, the association between Th1 cytokine polymorphisms: TNF-α -857C/T and IL-2-330T/G and the pathogenesis of AML is unclear. Therefore, we investigated the role of these polymorphisms in AML. Materials and Methods: This study included 101 patients with AML [male/female, 56/45; age, 15-86 years; median age, 58 years; MRC classification favorable (n = 38), intermediate (n =56), and adverse (n = 7)] and 202 healthy race-matched controls. All participants provided written informed consent. This study was approved by the Institutional Review Board of Gunma University Hospital. Genotyping was performed by the polymerase chain reaction (PCR)-restriction fragment length polymorphism method. Genotype and allele frequency were compared between patient group and control group by χ2-test. Clinical features were compared using Student's t and χ2 tests. Overall survival (OS) and leukemia free survival (LFS) were calculated using the Kaplan-Meier method. Survival curves were compared using the log-rank test. Analyses were performed using the SPSS software package ver. 25 (IBM, Armonk, NY, USA). P < 0.05 was considered to represent statistical significance. Results: TNF-α -857 C/T nonCC genotype (higher producer type) increases the risk of AML (AML vs. controls = 39.6% vs. 28.2%, OR = 1.67, 95% CI = 1.01-2.75, p = 0.045). Moreover, the frequency of TNF-α -857 C/T T allele (higher producer type) was higher in AML patients compared to controls (AML vs. controls = 24.8% vs. 16.8%, OR = 1.625, 95%CI = 1.078-2.451 p = 0.02). There was no significant difference between AML patients and controls in genotype and allele frequencies of IL-2 -330 T/G. In the analysis of clinical features, the average platelet count was significantly lower in TNF-α -857 C/T TT genotype (higher producer type) (TT vs. nonTT = 2.4±1.4 vs. 4.4±5.9, p < 0.01). TT genotype (higher producer type) was also significantly higher in frequency of MRC classification adverse (TT vs. nonTT = 30.0% vs. 4.4%, p = 0.02) and history of tumor (TT vs. nonTT = 30.0% vs. 6.6%. p =0.04). Moreover, in survival time analysis, patients with TNF-α -857 C/T TT genotype (higher producer type) had significantly shortened OS compared with patients with nonTT genotype (lower producer type) (TT vs. nonTT = 17.2 months vs not reached, p < 0.01). Patients with TT genotype (high producer type) also experienced significantly shortened LFS (TT vs. nonTT = 24.0 months vs not reached, p = 0.04). Furthermore, multivariate analysis of OS revealed TNF-α -857 C/T TT genotype (higher producer type) as an independent prognostic factor (HR = 3.01, 95% CI = 1.04-8.69, p = 0.04), like age and white blood cell count. Conclusion: These results suggest that TNF-α-857 C/T T allele (higher producer type) increases the risk of AML. Furthermore, TNF-α-857 C/T TT genotype (higher producer type) affects the poor prognosis. Therefore, these data suggest the new role of TNF-α polymorphism in AML leukemogenesis. Figure Disclosures Handa: Ono: Research Funding.

TNF-α (-308) Gene Polymorphism and Type 2 Diabetes Mellitus in Ethiopian Diabetes Patients.

BackgroundType 2 diabetes mellitus (T2DM) is a metabolic disorder resulting from insulin insufficiency or function. Predisposing factors for T2DM are mainly genetic and environmental. Genetic polymorphism of cytokines like tumor necrosis factor-alpha (TNF-α) is suggestive of interference with insulin-sensitive glucose uptake and induces insulin resistance that ultimately could lead to T2DM. In this study, we assessed the effect of TNF-α (−308) G/A gene polymorphism and its association with the development of T2DM in an Ethiopian population.MethodsAn institutional-based cross-sectional study was conducted on study subjects with T2DM and non-diabetic healthy controls. DNA was extracted and genotyping was carried out by using amplification refractory mutation system polymerase chain reaction. A genetic-polymorphism on TNF-α (−308) G/A with T2DM was evaluated by logistic regression and Student’s t-test. A P-value <0.05 was considered as statistically significant.ResultsIn the present study, we observed a significant association between T2DM and TNF-α (−308) gene polymorphism’s GG genotype [χ2 test P = 0.005, OR (95% CI) =2.667 (1.309–5.45d8)]. In contrast, no statistically significant differences were observed in the frequencies of genotypes AA and AG (χ2 test P=0.132 and 0.067, respectively). Moreover, T2DM individuals had higher concentrations of lipid profiles for those carrying the TNF-α (−308) GG genotype as compared to the control group.ConclusionTNF-α (−308) genetic polymorphism may be implicated in the genetic susceptibility for, as well as the development of T2DM and lipid metabolism in the Ethiopian population. Therefore, a large-scale study and early screening of TNF-α (−308) genetic polymorphism may help in early management and control of diabetes and related outcomes.

Polymorphisms of Proinflammatory Cytokines in Relation to APOE Epsilon 4 and Risk of Alzheimer's Disease in the Lithuanian Population.

Background and objective: Neuroinflammation is one of the pathological pathways of Alzheimer’s disease (AD), mediating the progression of neurodegeneration. Polymorphisms of proinflammatory cytokines have been linked to increased AD risk. Identification of certain combinations of polymorphisms could help predict disease in its preclinical stage. The aim of the study was to evaluate differences in the prevalence of TNFα –850T (rs1799724), IL1A –889T (rs1800587), and IL6 –174C (rs1800795, Intron type) polymorphisms between AD patients and healthy controls (HC) and determine the impact of these SNPs in combination with the APOEε4 allele on AD risk. Materials and Methods: The study population is comprised of 107 patients with sporadic AD (AD group) and age- and gender-matched 110 persons without impaired cognitive functions (control group). TNFα –850C > T polymorphism was revealed by a PCR and restriction fragment length polymorphism (RFLP) method. Real time PCR was used for IL1A and IL6 SNP genotyping. APOEε genotyping was done via hybridization method. Results: The frequencies of TNFα –850T, IL1A –889T, IL6 –174C allele and genotype did not differ between the AD and HC groups (p > 0.05). IL6 –174C was not in HWE, and it was not analysed further. APOEε4 allele (p = 0.001) and 3/4 and 4/4 genotypes (p = 0.005) were more prevalent in AD patients. APOEε4 carriage increased the risk of AD (OR 2.65, p = 0.001), while TNFα –850T and IL1A –889T polymorphisms were not found as significant independent risk factors for AD. The presence of at least one IL1A –889T allele in combination with APOEε4+ was associated with a lower risk of AD (OR 2.24, p = 0.047) than the carriage of APOEε4+ alone (OR 2.70, p = 0.015). Conclusions: No significant differences of TNFα –850, IL1A –889, and IL6 –174 polymorphisms frequencies were found between AD and control groups. In APOEε4 carriers IL1A –889T polymorphism was found to reduce the AD risk determined by APOEε4 alone.

CD4 recovery is associated with genetic variation in IFNγ and IL19 genes

Not all HIV-infected patients receiving cART are able to recover optimal CD4-T cell levels despite achieving undetectable viremia. We evaluated the potential association between polymorphisms (SNPs) in cytokines involved in immune response (IL15, IFNγ and IL19) and the failure to achieve optimal CD4 T-cells restoration after cART. For this, we carried out a retrospective study in 412 HIV-infected patients starting cART with CD4<200 cells/μL. These patients were classified as immunological non-responders (INR) if having a CD4 increase (ΔCD4) below 200 cells/μL after two years on successful cART. IL15, IFNγ and IL19 polymorphisms were genotyped using Sequenom's MassARRAY platform. We found 134 INR patients with a median [IQR] ΔCD4 = 133[73–174] cells/μL. In the multivariate analysis adjusted for age, sex, infection route, ethnic origin, hepatitis co-infection and HIV infection length, the AA genotype of the SNP rs2430561 in IFNγ (OR:2.01[1.13–3.56], p = 0.017) and the TT genotype of polymorphism rs2243191 in IL19 (OR:2.58 [1.17–5.68], p = 0.019) showed significant association with the INR status. Our results show that polymorphisms in IFNγ and IL19 genes significantly impacts in the probability of not achieving an optimal immune recovery in HIV-patients starting cART with CD4 T-cells <200 cells/μL. Thus, these SNPs could represent potential predictive markers of the immunodiscordant response.

The association between gene polymorphism of certain cytokines (IL-6, IL-10) and hepatitis C virus infection locally

Thirty blood samples were collected from people infected with HCV and collected 30 blood samples from healthy individuals as a control group. The samples were collected from the virus department at Diwaniyah Teaching Hospital, Women's Hospital and Educational Children and the Blood Bank in Diwaniyah Governorate, during the period from July 2018 until February 2019. Antibodies (Anti-HCV ) to HCV were detected in the infected serum using ELISA technique, and the diagnosis was confirmed Using the polymerase chain reaction test. Select gene polymorphism of interleukin -6 at site 174, which represents 3 genotypes GG, GC, CC in patients with HCV and control group. GG was significantly increased in patients with hepatitis C virus (63.3%) compared to the control group (30 %). The genotypes GC, CC were significantly decreased in patients with hepatitis C virus (16.7% and 20%) compared with the control group (43.3% and 26.7%), respectively. It also identified gene polymorphism of interleukin -10 at site 592, which represented 3 genotypes AA, AC, CC in patients with hepatitis C virus and control group. Genotype AC was significantly increased in patients with hepatitis C virus (53%) compared with the control group (30%). The genotypes CC, AA were significantly decreased in patients with hepatitis C virus (26.7% and 20%) compared with the control group (26.7% and 43.3%) respectively. Conclude from our current study that genotypes or alleles of IL-6 and IL-10 may play an essential role in increasing the risk of HCV in humans or play a vital role for prevention against.

Polymorphisms in Adipokines in Mexican Children with Obesity.

The high prevalence of childhood obesity in Mexico is alarming in the health-science field. We propose to investigate the contribution of adipokines and cytokines polymorphisms and common BMI/obesity-associated loci, revealed in genome-wide association studies in Caucasian adult cohorts, with childhood obesity. This study included 773 Mexican-Mestizo children (5-15 years old) in a case-control study. The polymorphisms included were ADIPOQ (rs6444174), TNF-α (rs1800750), IL-1β (rs1143643), IL-6 (rs1524107; rs2069845), NEGR1 (rs34305371), SEC16B-RASAL2 (rs10913469), TMEM18 (rs6548238; rs7561317), GNPDA2 (rs16857402), LEP (rs2167270), MTCH2 (rs10838738), LGR4-LIN7C-BDNF (rs925946), BCDIN3D-FAIM2 (rs7138803), FTO (rs62033400), MC4R (rs11872992), MC4R (rs17782313), and KCTD15 (rs29942). No significant contribution was found with adipokines and cytokines polymorphisms in this study. Only both TMEM18 (rs6548238; rs7561317) polymorphisms were found associated with obesity (OR=0.5, P=0.008) and were in linkage disequilibrium (r2=0.87). The linear regression showed that the rs7561317 polymorphism of TMEM18 is negatively associated with obesity. This report highlights the influence of TMEM18 in Mexican-Mestizo children obesity, while adipokine and cytokine polymorphisms were not associated with it.

Association of polymorphisms in inflammatory cytokines encoding genes with severe cases of influenza A/H1N1 and B in an Iranian population

BackgroundThe increased levels of blood cytokines is the main immunopathological process that were attributed to severe clinical outcomes in cases of influenza A, influenza B and people with influenza-like illness (ILI). Functional genetic polymorphisms caused by single nucleotide polymorphisms (SNPs) in inflammatory cytokines genes can influence their functions either qualitatively or quantitatively, which is associated with the possibility of severe influenza infections. The aim of the present case-control study was to investigate the association of polymorphisms in inflammatory cytokines genes with influenza patients and ILI group in an Iranian population.MethodsTotal number of 30 influenza B, 50 influenza A (H1N1) and 96 ILI inpatient individuals were confirmed by Real-time RT-PCR and HI assays. The genotype determination was assessed for defined SNPs in IL-1β, IL-17, IL-10 and IL-28 genes.ResultsThe frequencies of the IL-1β rs16944 (P = 0.007) and IL-17 rs2275913 (P = 0.006) genotypes were associated with severe influenza disease, while the frequencies of IL-10 rs1800872 and IL-28 rs8099917 were not associated with the disease (P > 0.05). Also, the absence of A allele in IL-17 rs2275913 SNP increased the risk of influenza A (H1N1) infection (P = 0.008).ConclusionsThis study demonstrated that influenza A- (H1N1) and B-infected patients and also ILI controls have different profiles of immune parameters, and individuals carrying the specific cytokine-derived polymorphisms may show different immune responses towards severe outcome.

PB1853 IMMUNOREGULATORY CYTOKINES (IL1β‐3954 AND IFNγ‐874) GENE POLYMORPHISMS IN NORTH INDIAN PATIENTS AFFECTED BY ACQUIRED APLASTIC ANEMIA.

Background:The etiopathogenesis of Acquired aplastic anemia is not clear. However immune mediated mechanisms are implicated in the genesis of this disease.Aims:The purpose of the study was to evaluate the polymorphisms in cytokine (IL1β‐3954 and IFN‐γ 874) genes in patients with acquired Aplastic Anemia (AA).Methods:In this observational case‐control study, 120 cases of AA &amp; 120 healthy controls were taken under the standard criteria of Camitta's et al for AA. Genotyping for IL1β‐3954 and IFN‐γ 874 was performed using polymerase chain reaction and restriction fragment length polymorphism (PCR‐RFLP). Peripheral venous blood was collected in EDTA vial from all participants and DNA was extracted. Primer sequences of IL1β‐3954 and IFNγ‐ 874 genes were used under specific PCR conditions. PCR products were then digested with restriction enzymes at 37 °C for overnight. The digested products were run for gel electrophoresis and gel images were taken using the gel doc.Results:The frequency of homozygous (TT) variant genotypes of IL‐1β‐3954 was significantly associated with the higher susceptibility of developing AA when compared with the healthy controls (OR = 2.35, 95% CI = 1.10‐5.00, p = 0.0383). The mutant allele frequency (T) of IFN‐γ 874 showed a significant association with the lower susceptibility of developing AA when compared with the healthy controls (OR = 5.89, 95% CI = 3.97‐8.74, p = 0.0001).Summary/Conclusion:These findings suggest that IL‐1β‐3954 and IFN‐γ 874 gene polymorphisms may be implicated in the pathophysiology of Alastic Anemia.

PS1489 TH1 CYTOKINE IFN‐GAMMA+874T/A AND TNF‐ALPHA‐857C/T POLYMORPHISMS AFFECT THROMBOCYTOPENIA IN CHRONIC IMMUNE THROMBOCYTOPENIA (CITP)

Background:Chronic immune thrombocytopenia (cITP) is an acquired autoimmune disorder characterized by the production of anti‐platelet antibodies, resulting in the destruction of platelets and inhibition of their production. Th1 polarization is involved in the pathogenesis and disease status of cITP. Many investigators have reported IFN‐γ was upregulated at both the mRNA and protein levels in cITP patients. Several investigators have also reported that the Th1/Th2 ratio is inversely correlated with disease severity. These findings demonstrate that Th1 polarization is consistent with characteristics of cITP. However, it remains unclear that whether genetic factors of Th1 cytokines/chemokines affect the clinical features of cITP.Aims:We investigated the impact of Th1 cytokines/chemokine polymorphisms, including IL‐2, TNF‐α, CXCL10, IL‐18, IFN‐γ, and IFN‐γR on the severity of cITP.Methods:We examined 114 Japanese cITP patients (85 females and 29 males with a median age of 63.2 [range: 17.4–86.7] years). cITP was defined as isolated thrombocytopenia (platelet count &lt;100 × 109/L) in the absence of other causes or disorders that may be associated with thrombocytopenia according to the criteria of the ITP International Working Group. “Severe thrombocytopenia” was defined as a platelet count &lt;20 × 109/L. Genotyping of IL‐2–330T/G, TNF‐α‐857C/T, CXCL10–1447A/G, IL‐18–607C/A IL‐18–137G/C, IFN‐γ+874T/A, IFN‐γR‐611G/A polymorphisms were determined by polymerase chain reaction‐restriction fragment length polymorphism (PCR‐RFLP) method. “Severe thrombocytopenia” and bleeding tendency were compared using the χ2‐test. Multivariate analysis for “severe thrombocytopenia” and bleeding tendency performed using the logistic regression model. P &lt; 0.05 was considered to represent statistical significance. All patients were provided written information about the study. This study was approved by the Institutional Research Board of Gunma University Hospital.Results:The platelet count ranged from 1 × 109/L to 96 × 109[t1] /L with a median of platelet count of 21 × 109/L at the initial diagnosis. In addition, 70 patients (61.4%) had bleeding tendency. Steroid treatment was given to 74 patients (64.9%), and eradication of Helicobacter pylori (H. pylori) was performed in 40 patients (35.4%), while splenectomy was performed in only 18 patients (15.8%). cITP patients with IFN‐γ+874 non‐AA genotype (high expression type) showed a significantly higher frequency of severe thrombocytopenia at diagnosis than AA genotype (low expression type) (73.3% vs 42.4% respectively, odds ratio [OR] = 3.73, 95% confidence interval [CI] = 1.11–12.54, p = 0.025). ITP patients with IL‐18–607 nonCC genotype showed a significantly higher frequency of bleeding tendency than CC genotype (65.3% vs 60.0% respectively, OR = 3.14, 95% CI = 1.05–9.37, p = 0.034). Multivariate analysis showed that the IFN‐γ+874 nonAA genotype was an independent predictor of “severe thrombocytopenia” at diagnosis (HR = 4.781, 95% CI = 1.27–18.0, p = 0.02). Furthermore, “severe thrombocytopenia” during observed period showed that the TNF‐α‐857 nonCC genotype (high producer type) was an independent significantly affecting factor (HR = 3.067, 95%CI = 1.17–8.03, p = 0.02).Summary/Conclusion:Our study revealed that IFN‐γ+874T/A and TNF‐α‐857C/T is associated with thrombocytopenia in cITP. These findings indicate that Th1 cytokine polymorphisms affect the severity of cITP.

The effect of tumor necrosis factor alpha (-308G/a) and interferon gamma (+874T/a) polymorphisms on susceptibility to coronary heart disease

Background: Coronary heart disease (CHD) is a chronic inflammatory disease, which is still regarded as a major cause of morbidity and mortality worldwide. Several studies have suggested that polymorphisms in cytokine genes are associated with the pathogenesis of CHD. The genotype distribution of Tumor necrosis factor alpha (TNF-α) and interferon gamma (IFN-γ) genes polymorphisms have been shown to be different in various ethnic populations. This study was aimed to investigate the association of TNF-α-308 G/A and IFN-γ + 874T/A polymorphisms with risk of CHD in an Iranian population.Methods: A total of 187 unrelated subjects comprised 96 CHD patients and 91 healthy controls were enrolled in this cross-sectional study. The TNF-α-308 G/A and IFN-γ + 874T/A polymorphisms were genotyped using amplification refractory mutation system-PCR (ARMS-PCR). The chi-square and logistic regression tests were used to calculate the odds ratios (ORs) as a measure of differences in genotype frequencies.Results: A significant differences in the allelic and genotypic distribution of TNF-α-308 G/A and IFN-γ + 874T/A polymorphisms was found between CHD patients and healthy controls (P = 0.017, P = 0.011, P = 0.006 and P = 0.002, respectively). Logistic regression analyses were also revealed statistically significant risk for CHD with respect to TNF-α-308 A and IFN-γ + 874 T carriers either in crude or after adjustment for potential confounders (P = 0.003 and P = 0.006, respectively).Conclusion: This study provides strong evidence supporting the association of TNF-α-308G/A and IFN-γ + 874T/A polymorphisms with the increased risk of CHD. Therefore, these two cytokine polymorphisms may play a role in predisposition to coronary heart disease.

The features of immunogenetic profile and biochemical indicators in patients with chronic hepatitis B

The aim of the work is to conduct a comprehensive assessment of immunogenetic and biochemical parameters in patients with chronic hepatitis B living in the Odessa region.Material and methods. A total of 41 patients with chronic hepatitis B were examined. The traditional biochemical and immunological parameters, the content of cytokines IL‑4, IL‑10, TNFα and the gene polymorphism of cytokines IL‑4, IL‑10, TNFα were determined.Results. To assess the relationship of non-parametric and parametric indicators (changes in the immunological status, biochemical parameters and cytokine profile), the patients were divided into groups in accordance with the identified polymorphisms of cytokine genes. With the use of the Spearman's rank correlation coefficient, certain relationships have been established. In patients with homozygous SS polymorphism of IL‑4, more pronounced changes in the cytokine profile, immunological status and a higher level ofALA and AsAt activity were noted.Conclusions. The revealed relationship between the AlAt and Asat levels, the immunological status and cytokine profile indicators with certain TNFα and IL‑4 genotypes suggests a genetic predisposition of certain patients with chronic hepatitis B to a more severe course. The information obtained canbe applied as one of the additional criteria for the activity of inflammatory changes in the liver tissue.

English

The promoter region of human interleukin-10 (IL-10) gene is highly polymorphic while the first intronic region of interferon gamma (IFN-) gene is also highly polymorphic. These polymorphisms are associated with susceptibility or resistance to Schistosoma haematobium infection. Schistosomiasis is known to be a highly inflammatory disease that requires the delicate balance of pro- and anti-inflammatory cytokines. The polymorphisms are associated with low, moderate or high cytokine production resulting in exacerbation of the infection leading to pathological severity. Urine filtration technique was used for diagnosis the S. haematobium. Whole blood samples were collected from 400 children aged between 6 to 13 years. Molecular determination of polymorphism related to resistance or susceptibility to infection was performed using the allele-specific polymerase chain reaction. SNPs in the IL-10 and IFN- cytokine genes were examined in blood samples from 400 school-aged children. Schistosomiasis was detected in 49.8% (199). For IFN- +874A/T, the distribution of TT, TA and AA was 7, 41 and 51% respectively. An analysis of the polymorphisms on IL-10 -1082G/A showed that most of the samples were heterozygous (47% GA) whereas AA (32%) and GG (21%) were monozygous. SNPs within the promoter region of IL-10 gene and in the intronic region of IFN- have been associated with altered profiles of circulating IL-10 and IFN-. Our findings suggest that IL-10 and IFN- polymorphisms participate in the progression of schistosomiasis rather than in its initial development in school aged children. It is recommended to study more polymorphisms in the other cytokines implicated in schistosomiasis. Key words: Polymorphism, cytokine, Schistosoma haematobium, interleukin-10, interferon gamma. &nbsp; &nbsp

TGF-β1 polymorphism in American tegumentary leishmaniasis in a Southern Brazilian population.

Genetic polymorphisms define the cytokine production leading to susceptibility or resistance to diseases. We studied the cytokine polymorphism in the development of tegumentary leishmaniasis (TL). Genotyping of TNF-α, TGF-β1, IFN-γ, IL-6, and IL-10 were performed by polymerase chain reaction assay. G and C alleles of TGF- β1 (codon 25) were the most common in controls and patients, respectively. G/G was the most frequent genotype in controls, and G/C and C/C in patients. G/G genotype of codon 25 in TGF-β1 appeared to confer resistance, and G/C and C/C genotypes, susceptibility to TL in this population.

Impact of Interleukin-6 and Interleukin-10 Gene Polymorphisms on Inhibitor Development in Patients with Moderate and Severe Hemophilia a

Background:An important complication of administration of factor VIII concentrates to treat or prevent bleeding,is the development of autoantibodies that block the activity of the relevant factor (inhibitors). These inhibitory antibodies occur in approximately 25 % of patients with severe hemophilia A. Inhibitors are much less common in patients with mild or moderate disease. Recently, significant progress has been made in our understanding of the mechanisms that lead to inhibitor formation. Polymorphisms of the immune response genes have been suggested to be contributing determinants of the inhibitor risk. Previous immunogenetic studies have shown the implication of human leukocyte antigen (HLA) alleles and some of the cytokine polymorphisms in inhibitors formation such as IL-6 and IL-10.Aim:This study aimed to investigate the associations between interleukin-6 gene promoter polymorphism at position (−174 G/C), interleukin-10 gene promoter polymorphism at position (-1082G/A) and susceptibility of patients with hemophilia A to develop factor VIII inhibitors.Methods and subjects:After medical ethical committee approval, the present study was conducted on 50moderate and severehemophilia A males aged ≤ 18 years who are attending hematology outpatient clinic of Alexandria University Children's Hospital at El-Shatby. The 50 children were undergoing a)Detailed history taking, with special emphasis on: Age of the patient at the time of diagnosis, clotting activity of factor VIII, Age at first exposure to factor VIII, Type and dose of administered factor VIII concentrate. Exposure days (EDs), Age at first surgical intervention, Detection of factor VIII inhibitors b)Laboratory investigations: Identification of genetic variant IL-6 (rs1800795) , IL-10 ( rs1800896 ) using real time PCR.Results:Thirtyone (72.1%) patients had severe hemophilia and 19 (27.9%) had moderate Hemophilia. Eight (16%) of the studied patients were inhibitor positive.As regard interleukin-6 gene promoter polymorphism at position (−174 G/C), the frequency of G allele was greater than C allele in patients who developed inhibitors (χ2= 0.63) with P value = 1.000. regarding interleukin-10 gene promoter polymorphism at position (-1082G/A), the frequency of G allele was greater than A allele in patients who developed inhibitors (χ20.75) with P value = 0.891.There was no statistically significantdifference as regards interleukin-6 polymorphism at position (−174 G/C), interleukin-10 polymorphism at position (-1082G/A) between inhibitor positive and inhibitor negative patients.Conclusion:There was no relation between interleukin-6 polymorphism at position (−174 G/C) , interleukin-10 polymorphism at position (-1082G/A)and the development of factor VIII inhibitors in patients with hemophilia A despite of the high frequency of G allele among inhibitors corresponding to the previous studies done . Further studies are recommended with larger cohort and other SNPs. DisclosuresHassab:Global Blood Therapeutics: Research Funding.

Lack of association between single-nucleotide polymorphisms of pro- and anti-inflammatory cytokines and HTLV-1-associated myelopathy / tropical spastic paraparesis development in patients from Rio de Janeiro, Brazil

BackgroundHTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP) is a progressive neurological and inflammatory disease, associated with HTLV-1 infection. HAM/TSP neurological disease is a consequence of an inflammatory reaction, and adaptive immune responses, through the secretion of anti-inflammatory and pro-inflammatory cytokines, play an important role in the outcome of infection and disease progression. Studies addressing the association between cytokines functional single nucleotide polymorphisms and HAM/TSP development are scarce.MethodsThe genetic polymorphisms of cytokine genes were evaluated in HAM/TSP patients (n = 68) and in asymptomatic HTLV-1 positive carriers (n = 83) from Rio de Janeiro, Brazil, in a case-control study. HTLV-1 infected patients were genotyped for SNPs in five cytokine genes: TNFA-308G/A, IL6-174G/C, IFNG + 874 T/A, TGFB at the codons + 10 T/C and + 25G/C, IL10-592C/A and -819C/T, and -1082A/G and proviral load (PVL) was quantified. Associations between genotypes, haplotypes, clinical outcome and pro viral load were evaluated.ResultsLack of association between the cytokine polymorphisms and disease outcome was observed. The genotypes TNFA-308GG, IL6-174GG/GC, IL10-592AA and -819CC and TGFb1 high producers phenotypes were correlated with higher PVL in HAM/TSP patients versus asymptomatic carriers.ConclusionsWe did not observe association between cytokine polymorphisms and risk for HAM/TSP development in Brazilian HTLV-1 infected individuals, regardless of differences in PVL between HAM/TSP versus asymptomatic carriers in specific cytokine polymorphisms.

Genetic influence of cytokine polymorphisms on the clinical outcome of Japanese gastrointestinal cancer patients in palliative care.

Gastrointestinal cancer is one of the most common causes of mortality globally. The present study examined the influence of cytokine genetic polymorphisms [interleukin (IL)-1B C-31T, IL-1RN VNTR, IL-6 C-634G, IL-8 T-251A, IL-10 T-819C and IL-10 A-1082G] on clinical outcomes in patients with gastrointestinal cancer in palliative care. A total of 59 patients with gastrointestinal cancer who were admitted to Iga City General Hospital were analyzed. Genotyping was conducted using a polymerase chain reaction with confronting two-pair primers. Patients with at least one IL-1RN 2 allele demonstrated a significantly better survival (P=0.0275) while those with IL-6-634 G/G demonstrated a worse survival (P=0.0024). Multivariate analyses using the Cox proportional hazard model revealed that those with at least one IL-1RN 2 allele, IL-6-634 G/G or IL-10-1082 A/G had a significantly elevated adjusted hazard ratio of 9.20 (P=0.014), 41.01 (P=0.001) or 6.49 (P=0.046), respectively, compared with those with each homozygous wild-type polymorphism. In addition, the evaluation of weight loss by genotype revealed the potential influence of IL-10 T-819C genotype (P=0.072). IL-1RN, IL-6 and IL-10 polymorphisms were associated with the survival of patients with gastrointestinal cancer, suggesting the clinical feasibility of genetic testing in patients with gastrointestinal cancer in palliative care.

Polymorphisms in TH1-TH2 cytokine and receptor genes associated with risk of vertical HIV transmission, in Mumbai, India.

Vertical HIV transmission does not occur in all exposed infants. Many infants remain HIV uninfected even after exposure. This is partly attributed to the host genes involving cytokine production, which is rarely documented in vertical transmission. Here, an observational cohort study evaluated whether polymorphisms in cytokine, receptor and antagonist genes are associated with perinatal HIV transmission. Single nucleotide polymorphism (SNP) genotyping was performed via the polymerase chain reaction with sequence-specific primers method. Haplotype block structure was determined and statistical analysis was performed using appropriate software in each case. Twenty-two SNPs were analysed in 30 seropositive and 61 seronegative children. Confounding factors such as mother's viral load, treatment regimen, breast feeding options, etc., were documented. Analysis revealed the association of two SNPs: IL1R1 (rs2234650) and TNFA (rs1800629) with vertical HIV transmission. CT genotype at IL1R1 was observed at a higher frequency in positive children (76.66% versus 42.62%, p=0.002), whereas the CC genotype was significantly increased in exposed uninfected children (47.54% versus 16.66%, p=0.004). Similarly, the GG genotype of TNFA was significantly higher in uninfected children compared to infected ones (76.66% versus 46.66%, p=0.005), whereas the GA genotype frequency was higher among infected children (53.33% versus 21.66%, p=0.003). The frequency of the 'G' allele of TNFA and 'C' allele of IL1R1 was significant (p=0.018) in negative children. Haplotypes of SNPs belonging to IL1, TNFA and IL4 were also found to associate with transmission. The present study confirms the association of SNPs IL1R1 (rs2234650) and TNFA (rs1800629) with the risk of vertical transmission. These SNPs can be exploited as possible predictive markers of HIV transmission.