IFN-γ Polymorphisms Research Articles

The Relationship of Interferon Gamma +874T/A and Interleukin-10 -1082G/A Gene Polymorphism to The Recovery of Multidrug Resistant Tuberculosis Patients

Background: Multidrug resistant (MDR) TB caused by the M.Tb strain is resistant toward at least rifampicin and isoniazid. Interferon Gamma is responsible for activating macrophages and phagocytosis for M.Tb destruction. Interleukin 10 causes a significant decrease in reactive nitrogen intermediates, increased arginase 1, and overall decreased macrophage function. Gene mutation causes IFN production by CD4 - T cells less effective and disrupts the immune response against M.Tb. There has been no research on the relationship between IFN-γ and IL-10 gene polymorphisms with TB recovery in Indonesia, especially in patients with MDR-TB. The aim of this study is to determine gene polymorphism relationship of IFN-γ +874T/A and IL-10 -1082G/A with MDR-TB recovery. 
 Methods: This study was a non-experimental clinical trial with a retrospective cohort design. The study was conducted on 105 MDR-TB patients treated in dr. Moewardi Hospital between January 2011-June 2014 consists of 84 recovered patients and 21 patients died/failed.
 Results: Gene polymorphism of IFN-γ +874T/A was obtained OR=0.703 (0.265-1.863) and P=0.477 which mean IFN-γ +874 T/A gene was not related to recovered case of MDR-TB. The IL-10 -1082G/A gene obtained the value of OR=0.657 (0.173-2.491) and the value P=0.785 which means that IL-10 -1082G/A is not related to the MDR-TB case recovery.
 Conclusions: There is no relationship of IFN-γ + 874T/A and IL-10 -1082G/A gene polymorphisms in the recovery of MDR-TB patients. (J Respir Indo. 2017; 37(4): 299-306)

Association between TNF, IL1B, IL6, IL10 and IFNG polymorphisms and recurrent miscarriage: a case control study

BackgroundApproximately half of recurrent miscarriages have unexplained etiology. Recent evidences suggest that cytokines are important determinants in pregnancy maintenance and as such, cytokine gene polymorphisms, which can affect cytokine production and/or functionality, could play a role in the disorder. Thus, we aimed to investigate the association of selected cytokine gene polymorphisms with risk of recurrent miscarriage among Chinese.MethodsTNF -238G > A, TNF -308G > A, IL1B -511 T > C, IL1B 3954C > T, IL6 -174G > C, IL6 -634C > G, IL10 -1082A > G and IFNG 874A > T polymorphisms were genotyped on 775 women with idiopathic recurrent miscarriage and 805 healthy parous control women. Logistic regression analysis was performed to determine the odds ratios (ORs) of the association between the polymorphisms and recurrent miscarriage risk.ResultsAmong the eight polymorphisms studied, only the IL1B -511 T > C and IL6 -634C > G polymorphisms showed statistically significant associations with recurrent miscarriage risk. For the former, a significantly increased risk of recurrent miscarriage was observed for the mutant (CC) genotype (OR: 1.377; 95% CI: 1.039–1.824; P = 0.026). However, for the IL6 -634C > G polymorphism, a decreased recurrent miscarriage risk was observed for the heterozygous (CG) genotype (OR: 0.614; 95% CI: 0.493–0.765; P < 0.001) and the mutant (GG) genotype (OR: 0.414; 95% CI: 0.251–0.684; P = 0.001).ConclusionsThe IL1B -511 T > C polymorphism may serve as important risk factor for recurrent miscarriage while the IL6 -634C > G polymorphism may protect against the risk of recurrent miscarriage.

Susceptibility to Mycobacterium ulcerans Disease (Buruli ulcer) Is Associated with IFNG and iNOS Gene Polymorphisms

Buruli ulcer (BU) is a chronic necrotizing disease of the skin and subcutaneous fat tissue. The causative agent, Mycobacterium ulcerans, produces mycolactone, a macrolide toxin, which causes apoptosis of mammalian cells. Only a small proportion of individuals exposed to M. ulcerans develop clinical disease, as surrounding macrophages may control the infection by bacterial killing at an early stage, while mycolactone concentration is still low. Otherwise, bacterial multiplication leads to in higher concentrations of mycolactone, with formation of necrotizing lesions that are no more accessible to immune cells. By typing a cohort of 96 Ghanaian BU patients and 384 endemic controls without BU, we show an association between BU and single nucleotide polymorphisms (SNPs) in iNOS (rs9282799) and IFNG (rs2069705). Both polymorphisms influence promoter activity in vitro. A previously reported SNP in SLC11A1 (NRAMP, rs17235409) tended to be associated with BU. Altogether, these data reflect the importance of IFNG signaling in early defense against M. ulcerans infection.

Effect of Interferon-γ Polymorphisms on Ankylosing Spondylitis: A Case-Control Study.

BackgroundThis research aimed to explore the effects of interferon-γ (IFN-γ) polymorphisms and expression profile on susceptibility to ankylosing spondylitis (AS) in a Chinese population.Material/MethodsBlood samples were collected from 89 AS patients and 106 healthy controls. IFN-γ polymorphisms were genotyped by polymerase chain reaction (PCR) and sequencing methods. The genotype distribution of polymorphism in the control group was detected by Hardy-Weinberg equilibrium (HWE). Odds ratios (OR) with 95% confidence intervals (95%CI) were calculated using the χ2 test to evaluate the association between AS susceptibility and IFN-γ polymorphisms. Moreover, serum IFN-γ level was measured by ELISA.Resultsrs1861493 and rs2430561 polymorphisms were conformed to be in HWE in genotypes distribution of the control group (P>0.05 for both). However, only TT genotype and T allele of rs2430561 presented significantly higher frequencies in AS patients than in healthy controls (P=0.04 and 0.03, respectively), indicating that they obviously increased the risk of AS in a Chinese population (OR=2.54, 95%CI=1.01–6.40; OR=1.60, 95%CI=1.04–2.46). In AS patients, serum IFN-γ level was higher than in controls, and its expression patterns showed significant association with genotypes of rs2430561.ConclusionsIFN-γ rs2430561 polymorphism may contribute to the risk of AS through influencing IFN-γ expression.

Interaction effects among IFN-γ+874, IL-2-330, IL-10-1082, IL-10-592 and IL-4-589 polymorphisms on the clinical progression of subjects infected with hepatitis B virus and/or hepatitis C virus: a retrospective nested case–control study

BackgroundThe natural outcomes of hepatitis B virus (HBV) and/or hepatitis C virus (HCV) infections vary considerably among individuals The infection may heal naturally, or patients may succumb to chronic liver...

Genetic variants of interferon-gamma and its mRNA expression and inflammatory parameters in the pathogenesis of vitiligo.

Although genetics plays an essential role in the pathogenesis of vitiligo, vitiligo pathogenesis is still unclear. Our aim was to investigate the role of IFN-γ expression and polymorphism in vitiligo susceptibility and whether intercellular adhesion molecule-1 (ICAM-1), tumor necrosis factor (TNF)-α, and TNF-β play a role in vitiligo pathogenesis as important inflammatory parameters. Eighty-five patients with vitiligo and 90 controls were investigated for IFN-γ gene expression by quantitative real-time PCR and genotyped for IFN-γ +874T/A (rs2430561) and IFN-γ +2109A/G (rs1861494) gene polymorphisms by sequence-specific primer (SSP)-PCR and PCR-restriction fragment length polymorphism (RFLP), respectively. Serum levels of inflammatory parameters were measured using ELISA. Frequencies of the +874 TT genotype and T allele were significantly higher in patients with active vitiligo than in stable patients (P = 0.01 and 0.03, respectively). Calculation of odds ratio suggested a 1.7-fold increased risk of vitiligo in individuals having the TA haplotype. We observed overexpression of IFN-γ mRNA with elevated serum levels of IFN-γ, ICAM-1, TNF-α, and TNF-β in patients with vitiligo when compared with the control group (P = 0.001, for all). In addition, these levels were elevated in patients with active vitiligo compared with stable patients with vitiligo (P = 0.008, 0.006, 0.01, 0.01, and 0.03, respectively), which suggests the involvement of these cytokines in disease activity. In conclusion, IFN-γ is a promising immunological marker in vitiligo pathogenesis.

Polymorphism of IFN-γ (+874 T/A) in Syrian patients with chronic hepatitis B.

This study aimed to investigate the association of IFN- γ +874 (T/A) polymorphism with susceptibility to chronic HBV infection in the Syrian population. Accumulating evidence indicate that the inadequate immune responses are responsible for HBV persistency. Therefore, polymorphisms in genes encoding the cytokines, which are responsible for regulation of the immune response, can affect the course and outcome of the infection. The IFN-γ +874 T/A polymorphism affects the expression of IFN-γ, which has been shown to be crucial to HBV clearance. In this case-control study, 140 samples were collected (70 healthy individuals, 70 chronic HBV patients), and genomic DNA was isolated. Sequencing and ARMS-PCR were performed to genotype the IFN-γ +874 T/A polymorphism. Results of this study showed an association between IFN- γ +874 T/A polymorphism and the susceptibility to chronic HBV infection (P < 0.05). In addition, results showed that the AA genotype increased the risk of chronicity (OR = 3.05, 95% CI = 1.35 - 6.89), whereas the AT and TT genotypes reduced the risk of chronicity (OR = 0.33, 95% CI = 0.150 - 0.753). Results of this study conclude that the IFN- γ +874 T/A polymorphism may be associated with the chronic HBV infection, according to the genetic model AA vs. AT&TT.

Single nucleotide polymorphisms of IL-2, but not IL-12 and IFN-γ, are associated with increased susceptibility to chronic spontaneous urticaria

BackgroundA clear picture of interaction of Th1/Th2 cytokines in pathogenesis of chronic spontaneous urticaria (CSU), remains elusive. Impaired IFN-γ production and decreased levels of IL-2 have been reported. The aim of this study was to evaluate the association of Th1 cytokines; IL-2, IL-12 and IFN-γ polymorphisms with CSU. Methods90 patients with CSU and 140 age-sex matched subjects were included in this study. DNA samples were evaluated through PCR-SSP assay in order to detect single nucleotide polymorphisms of IL-12 (A/C −1188) or (rs3212227), IFN-γ (A/T UTR5644) or (rs2069717) and IL-2 (G/T −330 and G/T +166) or (rs2069762 and rs2069763). ResultsG allele at −330 at promoter region of IL-2 gene was overrepresented in CSU. Heterozygotes (GT) at this locus and heterozygotes at +166 of IL-2 gene (GT) were more prevalent in CSU group. Additionally, the haplotype GT for loci −330 and +166 of IL-2 gene was powerfully associated with CSU (OR (95%CI)=57.29 (8.43–112.7)). ConclusionsSNP at position −330 and +166 of IL-2 gene are differently expressed in CSU. The haplotype GT of IL-2 at −330 and +166 might confer vulnerability to a number of immunological disorders in Iranian region.

Association Between IFN-γ Gene Polymorphisms and IgA Nephropathy in a Chinese Han Population

Background/Aims: IFN-γ was reported to be involved in the development and progression of Immunoglobulin A nephropathy (IgAN), however, few studies have investigated the association between IFN-γ polymorphisms and IgAN. Therefore, we performed a case-control study to assess the association between IFN-γ polymorphisms and the risk of IgAN. Methods: Sequenom MassARRAY was used to genotype two SNPs (rs1861494 and rs2430561) in 351 patients with IgAN and 310 healthy controls. Associations were evaluated as odd ratios (OR) with 95% confidence intervals (CI). Results: No association was found between IFN-γ rs1861494 and IgAN risk or clinical parameters. For rs2430561, the AA genotype was more common in patients with IgAN, compared with controls (AT vs. AA: OR = 0.57, P = 0.035). IFN-γ-rs2430561 T allele may be a protective factor for IgAN susceptibility (T vs. A: OR = 0.59, P = 0.04). Subgroup analysis based on clinical features revealed no significant association between rs2430561 polymorphism and clinical data such as gender, 24-h urine protein, blood pressure, Oxford classifcation and estimated glomerular fltration rate. IgAN patients had a higher IFN-γ serum level than healthy controls and patients with rs1861494 AA genotype had a higher IFN-γ serum level compared with those with AG/GG genotypes. Conclusions: IFN-γ polymorphisms may be involved in the development and progression of IgAN.

Interferon-Gamma +874 (T/A) Polymorphism and Susceptibility to Aplastic Anemia: A Systematic Review and Meta-Analysis

Background: Many studies have assessed the relation between IFN-γ +874(T/A) polymorphism and risk of aplastic anemia. However, the results of these studies were inconclusive. In the current study, we performed a metaanalysis to evaluate the association between IFN-γ +874(T/A) polymorphism and susceptibility to aplastic anemia. Methods: All publications were searched precisely to find eligible articles on IFN-γ polymorphism +874(T/A) and aplastic anemia. Odds ratios (ORs) and their corresponding 95% confidence intervals (CIs) were calculated to evaluate the strength of association in the dominant model, recessive model, allelic model, homozygotes contrast, and heterozygotes contrast. Results: A total of 4 case-control studies, including 210 cases and 537 healthy controls were elegble for this metta-analysis. Combined analysis of these studies showed no significant association between the IFN-γ polymorphism +874(T/A) and aplastic anemia risk in the overall population (dominant model: OR=1.52, 95% CI=0.57-2.46; recessive model: OR=1.27, 95% CI=0.47-2.08; allelic model: OR=0.98, 95% CI=0.63-1.34; TT vs. AA: OR=3.68, 95% CI=0.21-7.15, and AT vs. AA: OR=1.20, 95% CI=0.43-1.97). No heterogeneity or publication bias was observed in this study. Conclusion: This meta-analysis showed that the IFN-γ +874(T/A) polymorphism was not associated with the risk of aplastic anemia.To confirm our results, further studies are needed.

Pharmacologic Co-Blockade of IFNγR and IL6R Pathways to Prevent and Treat GvHD

The therapeutic benefits of allogeneic hematopoietic stem cell transplantation (allo-HSCT) for hematologic malignancies are primarily derived from an anti-leukemia effect that is mediated by T cells in donor grafts. Unfortunately, these T cells also mediate graft-versus-host disease (GvHD), the major complication of allo-HSCT.We have previously published that in vivo administration of JAK1/JAK2 inhibitors to murine allo-HSCT recipients of interferon gamma receptor deficient (IFNγR-/-) T cells results in 100% survival in a fully MHC-mismatched B6 to Balb/c allo-HSCT model (Choi et al., 2014, PLoS ONE). Since the infusion of IFNγR-/- T cells alone is associated with only ~70% survival, we hypothesize that JAK1/JAK2 inhibitors have either additional off-target effects or are inhibiting other non-IFNγR signaling pathways which are themselves dependent on JAK1/JAK2. The major other cytokine receptor signaling pathway mediated via both JAK1 and JAK2 is the interleukin 6 receptor (IL6R) signaling pathway. Thus, it is possible that JAK1/JAK2 inhibitors also block signaling through IL6R in addition to IFNγR. In addition, Alam et al. have recently reported that single nucleotide polymorphisms of donor IFNγ and IL6 are closely linked to gastrointestinal GvHD in patients (2015, BMT). Therefore, we examined if blockade of both IFNγR and IL6R signaling results in complete elimination of GvHD after a fully MHC-mismatched allo-HSCT in which B6 (H-2b) T cell-depleted bone marrow cells (5x106) along with B6 pan T cells (5x105) are intravenously injected into lethally irradiated Balb/c mice (H-2d). As shown in Fig. 1, we have found that blocking both IFNγR (IFNγR-/- T cells) and IL6R (α-IL6R Ab) signaling dramatically reduces GvHD and results in >95% survival. In addition, we found that blocking both IFNγR and IL6R signaling significantly increased regulatory T cells (Tregs) in peripheral blood (23.2% Foxp3+ in CD4+ T cells (n=17) vs 2.5% in WT T cell control (n=16) at day 27 after allo-HSCT), suggesting that increase in Tregs might be a potential mechanism underlying the reduced GvHD after dual blockade of IFNγR and IL6R signaling.Baricitinib is a potent and balanced JAK1/JAK2 inhibitor currently being clinically developed by Eli Lilly for the treatment of inflammatory diseases. We hypothesize that baricitinib will optimally block both IFNγR and IL6R signaling pathways and prevent GvHD. We found that that baricitinib is a potent suppressor of GvHD in B6 to Balb/c allo-HSCT models (100% survival), superior to ruxolitinib and similar to blockade of both IFNγR and IL6R signaling (Fig. 2A). Baricitinib increases Tregs in vivo (Fig. 2B) and reduces the ratio of IL5 (Th2 cytokine) to IL2 (cytokine for Treg induction) in plasma (p=0.0046), a potential diagnostic marker for GvHD (Fujii et al., 2006, Int J Mol Med), significantly better than ruxolitinib. Lastly, we found that baricitinib inhibits the expression of T-bet (Fig. 2C), which is the master transcription factor of Th1 cells, that are primary effector T cells in inducing GvHD. These data suggest that the suppression of GvHD by baricitinib results from increased Tregs and decreased Th1 and Th2 cells.We next examined if the prevention of GvHD by baricitinib is dependent on natural regulatory T cells (Tregs) in donor grafts. Tregs were depleted from donor pan T cells before allo-HSCT (B6 to Balb/c). We found that in vivo administration of baricitinib resulted in 70% survival (0% control, p<0.0001; 100% Treg-replete T cells + baricitinib. In addition, based on clinical GvHD score when recipients of Treg-replete T cells were compared with those of Treg-deplete T cells, the beneficial effect of Tregs in the donor grafts for the prevention of GvHD was observed only for the first two weeks after allo-HSCT (p≤0.01).Lastly, we examined whether baricitinib can cure ongoing GvHD by administering baricitinib starting at day 10 after allo-HSCT when GvHD is established (B6 to Balb/c). We found that baricitinib treatment results in a significant reduction of GvHD and 100% survival (10% control, p<0.0001).All of these data suggest that pharmacologic co-blockade of IFNγR and IL6R pathways is a promising therapeutic strategy to prevent and effectively treat established GvHD. The inhibitory effect of baricitinib, ruxolitinib, and blockade of IFNγR and IL6R on JAK-STAT signaling using JAK/STAT phosphorylation antibody arrays is currently being investigated and will be presented. [Display omitted] [Display omitted] DisclosuresDiPersio:Incyte Corporation: Research Funding.

557P Association of TGFB1 exon 1 129 T/C polymorphism with reduced risk of sporadic breast cancer in older North Indian women population

Background Transforming growth factor beta 1 (TGFB1) is a cytokine secreted by immune cells that plays an important role in breast tumorigenesis. It shows dual characteristics:anti-inflammatoryactivityandgrowthinhibitionofearlytumor cells and growth promoting activityin advanced tumor. Here, we investigated the association between TGFB1 +29 polymorphism and breast cancer risk in North Indian population. Methods We analyzed 285 patients with sporadic breast tumor and 363 healthy controlsinanassociationstudyforTGFB1+29T/C,TRAIL-716C/T,TP53codon72, IFNG CA repeat polymorphism using DNA sequencing or SSLP. The expression levels of TGFB1,TRAIL,DR4,DR5,DCR1,DCR2,CYCS,BCL2,CASP8,CASP8L,FLIPL, FLIPS,CASP3 andCASP3sintheDDRandapoptoticpathwayweremeasuredbyRT- PCR. Results The study of TGFB1 +29polymorphismindicatedasignificantdifferencein the genotype distribution between patients and controls. The predominant TT and TC genotypes, when compared against CC genotype, provided 1.7-fold risk. This association was mainly attributable to higher age group (> 45 years) women. Stratificationofgenotypicdatarevealedthatinpresenceofprotectorgenotypesof TGFB1 +29 CC and TRAIL -716 CT and TT genotypes, a 2.5-fold protection was observed. Studies carried out on TGFB1 +29 and TP53 codon 72 interaction showed that in presence ofthe protector genotypes a 2-fold protection was observed. Combined influence of TGFB1 and IFNG polymorphisms on breast cancer risk revealed that in presenceofprotectorgenotypeofIFNGCArepeat,TGFB1 +29riskgenotypeprovided 2.5-foldprotection.Furthermore,thecomparisonofTGFB1 transcriptlevelsintumors revealed significant difference for TGFB1 expression with different +29 genotype background.Also,TGFB1 +29genotypeinfluencedapoptosisthatoccurredthrough TRAIL mediated extrinsic pathway; CC with increased apoptosis compared to TT+TC in breast tumor patients greater than 45 years in age. Conclusions:Thus,weconcludethatasapotentinhibitorofcellproliferationand apoptosis,TGFB1 +29CCgenotypemaybeoneofthefactorsresponsibleforless aggressive and slow growing tumors in Legal entity responsible for the study: Jawaharlal Nehru University, New Delhi, India Funding Council of Scientific and Industrial Research, University Grants Commission, Department of Biotechnology Disclosure All authors have declared no conflicts of interest.

Association of the IFN-γ (+874A/T) Genetic Polymorphism with Paranoid Schizophrenia in Tunisian Population

ABSTRACTSince growing evidence suggests a significant role of chronic low-grade inflammation in the physiopathology of schizophrenia, we have hypothesized that functional genetic variant of the IFN gamma (IFN-γ; +874A/T; rs2430561) gene may be involved in the predisposition to schizophrenia. This research is based on a case–control study which aims to identify whether polymorphism of the IFN-γ gene is a risk factor for the development of schizophrenia. The RFLP-PCR genotyping of the IFN-γ gene was conducted on a Tunisian population composed of 218 patients and 162 controls. The IFN-γ (+874A/T) polymorphism analysis showed higher frequencies of minor homozygous genotype (TT) and allele (T) in all patients compared with controls (11.5 vs. 4.9%; p = 0.03, OR = 2.64 and 30.7 vs. 24.1%, p = 0.04, OR = 1.4, respectively). This correlation was confirmed for male but not for female patients. Also, the T allele was significantly more common among patients with paranoid schizophrenia when compared with controls (25.8 vs. 4.9%, p = 0.0001; OR = 6.7). Using the binary regression analysis to eliminate confounding factors as age and sex, only this last association remained significant (p = 0.03; OR = 1.76, CI = 1.05–2.93). In conclusion, our results showed a significant association between +874A/T polymorphism of IFN-γ and paranoid schizophrenia, suggesting that this single nucleotide polymorphism (SNP) or another at proximity could predispose to paranoid schizophrenia. Since the minor allele of this polymorphism was correlated with an increased expression of their product, our study validates the hypothesis of excessive pro-inflammatory cytokine in the physiopathology of paranoid schizophrenia.

Single nucleotide polymorphisms of IFNγ (+874 A/T) and IFNγR1 (-56 C/T) in Iranian patients with TB.

Two important genes for controlling TB are IFNγ and IFNγR1. However, little information exists regarding genetic susceptibility of the Iranian TB population. We investigated the single nucleotide polymorphisms (SNPs) in genes of IFNγ (+874 A/T) and IFNγR1 (-56 C/T) and serum level of IFNγ and their influence on TB in patients; 300 patients with TB and 300 healthy controls were enrolled in this study. PCR-restriction fragment length polymorphism was used to identify SNPs and serum level of IFNγ was measured by ELISA. The allelic and the genotypic form of IFNγ+874 A/T SNP of the studied population were not significant (p>0.05). Allele T frequencies of IFNγR1 -56 C/T promoter region in patients with pulmonary TB (PTB) or extrapulmonary TB (EPTB) were significantly greater than allele C. The -56 TT motif of IFNγR1 is associated with both forms of TB (p<0.05). The serum level of IFNγ was significantly higher in patients with TB than in controls, but there was no significant difference between serum level of IFNγ and the studied genotypes (p>0.05). The cause of active TB in the patients seems to be due to the lack of effective IFNγ function or the lack of effective signaling connection between IFNγ and its receptor in presence of -56 C/T polymorphism in promoter region of IFNγR1 gene.

Association of genetic polymorphisms in interferon-γ, interleukin-6 and transforming growth factor-β1 gene with oral lichen planus susceptibility.

BackgroundOral lichen planus (OLP) is a premalignant mucocutaneous disease in which genetic factors and immune responses play a major role. Cytokines play an important role in the pathogenesis and disease progression of OLP. The aim of this study was to investigate the impact of gene polymorphisms of T helper cell subtype Th1 and Th2 cytokines, interferon-gamma (IFN-γ), interleukin-6 (IL-6) and transforming growth factor (TGF)-β1 on OLP susceptibility in a Saudi cohort.MethodsForty two unrelated patients with OLP and 195 healthy controls were genotyped for IFN-γ (874A/T), IL-6 (174G/C) and TGF-β1 (509C/T) polymorphisms.ResultsThe frequency of genotype AT of IFN-γ (874A/T) was significantly higher while genotype AA was lower in OLP patients as compared to controls (P < 0.05). The frequency of T containing genotypes (AT + TT) was also higher in OLP patients as compared to that in controls (P = 0.003). The frequencies of allele T was higher while that of allele A lower in patients than the controls however the difference was not statistically significant (P = 0.07). There was no significant difference in the frequencies of alleles and genotypes of IL-6 (174G/C) and TGF-β1 (509C/T) polymorphisms between patient and control groups. These results indicated that genotype AT of IFN-γ (874A/T) polymorphism is associated with OLP risk and genotype AA is protective to OLP. On the other hand the polymorphisms IL-6 (174G/C) and TGF-β1 (509C/T) may not be associated with OLP risk in our population.ConclusionIt is concluded that IFN-γ (874A/T) polymorphism is associated with the susceptibility of OLP, however further studies with large sample size involving different ethnic populations should be conducted to strengthen our results.

Gene Polymorphisms and Serum Levels of Pro- and Anti-Inflammatory Markers in Dengue Viral Infections.

Pro- and anti-inflammatory markers (tumor necrosis factor [TNF]-α, TNF-β, interferon [IFN]-γ, interleukin [IL]-6, IL-8, IL-10, and C-reactive protein [CRP]) were investigated in 80 patients infected with dengue viruses, 100 patients presenting with febrile illness but negative for dengue, and 99 healthy subjects. Immunoenzyme methods were used for quantitative assays in the plasma. Polymorphisms of TNF-α, TNF-β, IL-6, IL-8, and IL-10 genes were assessed by polymerase chain reaction (PCR)-restriction fragment length polymorphism and allele-specific oligonucleotide (ASO)-PCR for the IFN-γ. The highest mean serum levels of TNF-α, IFN-γ, IL-8, and CRP were observed in dengue-positive individuals. TNF-β, IL-6, and IL-10 levels were significantly higher in the dengue-negative individuals. No cytokine expression pattern was evidenced according to virus serotype. Genotypic frequency distributions were statistically significant for the polymorphisms of TNF-α and IFN-γ among positive, negative, and control dengue groups and IFN-γ among groups DENV-1, DENV-2, DENV-3, and controls. Modulation of cytokine expression and polymorphisms is a complex matter and needs further explanation considering the ethnic origins of the Brazilian population.

Evaluation of cytokine genetic polymorphisms in adult patients with common variable immunodeficiency: A single-center study

Common variable immunodeficiency (CVID) is a heterogeneous disease characterized by impaired B-cell differentiation and maturation accompanied with the defective antibody production. Several investigators addressed the possibility that disturbed cytokine production of TNF, IL-6, IFN-γ and IL-10, among a variety of others, may be implicated in CVID. The aim of this study was to test the hypothesis that genetic polymorphisms involving TNF (−308G/A), IFNG (+874 T/A), IL10 (−1082G/A, −819T/C and −592A/C), and IL6 (−174G/C) cytokine genes might contribute to susceptibility to CVID. Thirty five patients with CVID and 250 healthy controls were genotyped for indicated single nucleotide polymorphisms (SNP) in TNF, IL6, IFNG and IL10 using Taqman-based assays. CVID patients had significantly higher frequency of TNF A allele and AA genotype than in healthy subjects (p=0.006; OR=2.27; 95%CI=1.24-4.17 and p=0.038, OR=15.64; 95%CI=1.38-177.20, respectively). In addition, the frequency of GG genotype was significantly higher in healthy controls than in patient group (p=0.019, OR=0.43, 95%CI=0.21-0.89). Genetic analysis of IL6 SNP showed that allele G confers increased risk for CVID (p=0.037, OR=1.78, 95% CI=1.03-3.08) while IFNG allele T was associated with splenomegaly in CVID (p=0.032; OR=2.86; 95% CI=1.08-7.56). We observed no association between genotypes, alleles and haplotypes of IL-10 gene and CVID or its clinical complications. In conclusion, our results indicated association between CVID and cytokine gene polymorphisms −308G/A TNF and −174G/C IL6. In addition, we demonstrated that splenomegaly, one of the most common complications in this disease, is associated with +874T/A IFNG polymorphism. These findings add further support to the notion that cytokines may play significant role in pathogenesis of this primary antibody deficiency. However, further investigation that would involve a larger study group of CVID patients is warranted to confirm our findings.

Polymorphisms of IFN-γ (+874A/T) and IL-12 (+1188A/C) in tuberculosis patients and their household contacts in Hyderabad, India

Several cytokine gene variants have shown to be associated with host susceptibility to infectious diseases including tuberculosis (TB). High rates of transmission were identified within household members of TB patients. In this study, we examined whether single nucleotide polymorphisms of IFN-γ +874A/T and IL-12 +1188A/C affect susceptibility to TB. Genomic DNA from patients with active disease, their household contacts HHC and healthy controls HC was genotyped for IFN-γ +874A/T and IL-12 +1188A/C SNPs by amplification refractory mutation system-polymerase chain reaction (ARMS-PCR). IFN-γ +874 AA and AT genotypes were significantly with different frequencies in patients and total HHC as compared to HC (p<0.0001). In patients IL-12 +1188 AC and CC genotypes were associated with TB (p<0.003, p<0.008). In total HHC AC, CC genotypes and both alleles (A&C) were significantly different as compared to HC (p<0.004, p<0.001, p<0.034) and the same result was obtained when HHC were stratified into related (p<0.02, p<0.001) and unrelated (p<0.009, p<0.017) individuals. Allelic frequencies, however, were significant only in related contacts (p<0.021). Generalized multifactor dimensionality reduction method (GMDR) testing revealed high risk combinations of several genotypes in IFN-γ & IL-12 genes. Our findings suggest an important role of genetic variations of IFN-γ and IL-12 for susceptibility to TB.

CD38+CD8+ and CD38+CD4+ T Cells and IFN Gamma (+874) Polymorphism Are Associated with a Poor Virological Outcome

ABSTRACTThe main objective of the work was to evaluate the use of CD38 on T lymphocytes, IFNγ (+874 A/T), and IL-10 (−1082 A/G) polymorphisms in HIV-infected patients under antiretroviral (ARV) therapy. Sixty-one patients were selected at the outpatient clinic for HIV infection at the Hospital São José de Doenças Infecciosas, Fortaleza, Ceará, Brazil. The patients were classified into two groups, according to viral load after one year of ARV therapy. In the aviremic group (group I), a reduction of 35.5% of CD38+CD4+ T cells was observed (p = 0.02) and 49.3% of CD38+CD8+ T cells (p = 0.001). In the viremic group (group II), a reduction of 37.2% of CD38+CD4+ T cells (p = 0.067), and 21.4% of CD38+CD8+ T cells (p = 0.60) occurred. No association was found between IL-10 (−1082) polymorphism and the type of response to ARV therapy. Regarding the gene polymorphism on IFNγ (+874 T/A), 73.34% of group I and 33.3% of group II presented the AA genotype. The relative risk of the individuals carrying AA genotype or the A allele and not being able to suppress the viral load level after one year of ARV therapy was 3.44 (1.25–9.45; p = 0.014) or 2.35 (1.05–5.26; p = 0.027), respectively. Our data suggested that an augmented frequency of activated CD38+CD8+ T cells as well as the presence of the A allele of IFNγ polymorphism could contribute to a reduced virological suppression in patients under antiretroviral therapy.

Association of IFN-γ and P2X7 Receptor Gene Polymorphisms in Susceptibility to Tuberculosis Among Iranian Patients.

Interferon-gamma (IFN-γ) and P2X7 receptor are crucial for host defence against mycobacterial infections. Recent studies have indicated that IFN-γ, IFN-γ receptor 1 (IFN-γR1) andP2X7 gene polymorphisms are associated with susceptibility to pulmonary tuberculosis (TB). However, the relationship between IFN-γ and P2X7 polymorphism and TB susceptibility remains inconclusive in Iranian population. For this reason, single nucleotide polymorphisms (SNPs) in IFN-γ (G+2109A), IFN-γR1 (G-611A) and P2X7 genes (at -762, 1513 position) in patients (n = 100) were assessed using PCR-RFLP. Data were analysed with SPSS version 18. For the 2109 loci of IFN-γ gene, the frequency of mutant alleles between patients and controls were not statistically significant. However, there was a significant difference between the TB patient and controls for -611 alleles of IFN-γR1 (P = 0.01). Additionally, the frequency of P2X7 gene polymorphisms (SNP-762 and 1513) between patients and controls was statistically significant. In conclusions, our study revealed a significant association of IFN-γR1 and P2X7 genes polymorphisms with risk of developing TB in Iranian population.