Interferon Gamma +874T/A Polymorphism Increases the Risk of Hepatitis Virus-Related Diseases: Evidence from a Meta-Analysis

Sun, Yifan; Yu, Lu; Li, Taijie; Xie, Li; Deng, Yan; Li, Shan; Qin, Xue

doi:10.1371/journal.pone.0121168

Cited by 15 publications

(14 citation statements)

References 51 publications

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“…IFN-g expression levels are affected transcriptionally by polymorphisms in the IFN-g gene as well as translationally by metabolic mechanisms. [42][43][44]52 Indeed, multiple factors contribute to a T-cell cytokine expression profile, however, a common link for IL-2, IL-4, and IL-10 production is the transactivation of CXCR4 by the TCR to maintain cytokine mRNA stability.…”

Section: Discussionmentioning

confidence: 99%

TCR-CXCR4 signaling stabilizes cytokine mRNA transcripts via a PREX1-Rac1 pathway: implications for CTCL

Kremer¹,

Dinkel²,

Sterner

et al. 2017

Blood

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As with many immunopathologically driven diseases, the malignant T cells of cutaneous T-cell lymphomas (CTCLs), such as Sézary syndrome, display aberrant cytokine secretion patterns that contribute to pathology and disease progression. Targeting this disordered release of cytokines is complicated by the changing cytokine milieu that drives the phenotypic changes of CTCLs. Here, we characterize a novel signaling pathway that can be targeted to inhibit the secretion of cytokines by modulating either CXCR4 or CXCR4-mediated signaling. We demonstrate that upon ligation of the T-cell antigen receptor (TCR), the TCR associates with and transactivates CXCR4 via phosphorylation of S339-CXCR4 in order to activate a PREX1-Rac1-signaling pathway that stabilizes ,, and messenger RNA (mRNA) transcripts. Pharmacologic inhibition of either TCR-CXCR4 complex formation or PREX1-Rac1 signaling in primary human T cells decreased mRNA stability and inhibited secretion of IL-2, IL-4, and IL-10. Applying this knowledge to Sézary syndrome, we demonstrate that targeting various aspects of this signaling pathway blocks both TCR-dependent and TCR-independent cytokine secretion from a Sézary syndrome-derived cell line and patient isolates. Together, these results identify multiple aspects of a novel TCR-CXCR4-signaling pathway that could be targeted to inhibit the aberrant cytokine secretion that drives the immunopathogenesis of Sézary syndrome and other immunopathological diseases.

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Section: Discussionmentioning

confidence: 99%

TCR-CXCR4 signaling stabilizes cytokine mRNA transcripts via a PREX1-Rac1 pathway: implications for CTCL

Kremer¹,

Dinkel²,

Sterner

et al. 2017

Blood

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“…However, the pattern of association between the IFN‐γ +874 T/A gene polymorphism and viral hepatitis is inconclusive . Based on this polymorphism, three genotypes are possible: T/T, T/A, and A/A .…”

Section: Discussionmentioning

confidence: 99%

“…Another study on Asian and Caucasian populations discovered that the T allele is a protective gene in liver disease and is more powerful than the A allele, where the +874 AA genotype is associated with a 1.350‐fold increased risk of hepatitis virus‐related disease, especially in the Asian population; the IFN‐γ +874 TT genotype increases the level of IFN‐γ production; and the AA and TA genotypes result in a decrease in IFN‐γ production . On the other hand, it was reported that the IFN‐γ +874 AA genotype was associated with an increased risk of mild and/or moderate/severe chronic hepatitis and cirrhosis, but the +874 TA genotype was associated with reduced risk, although the IFN‐γ +874 T/A alleles did not differ between any of the groups .…”

Section: Discussionmentioning

confidence: 99%

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Association of interferon gamma gene polymorphism and susceptibility to hepatitis C virus infection in Egyptian patients: A multicenter, family‐based study

et al. 2017

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Background and AimPolymorphisms in some genes may influence the persistence of hepatitis C virus (HCV) infection, clinical outcome, HCV replication, and liver damage. This study was conducted to investigate the role of the interferon gamma (IFN‐γ) gene at (+874 T/A, −764 G/C, −179 C/A) single‐nucleotide polymorphisms (SNPs) and its receptor (IFN‐γR2) at (rs 2786067 A/C) SNP in the susceptibility of Egyptian families to HCV infection with high‐resolution techniques.MethodsIn total, 517 Egyptian families, with 2246 subjects, were recruited to this study from the Upper and Lower Egypt governorates and were classified into three groups: 1034 patients with chronic hepatitis C virus, 108 subjects with spontaneous virus clearance (SVC), and 1104 subjects as a healthy control group. All subjects were genotyped for (+874 T/A, rs2430561, −764 G/C, rs2069707, −179 C/A, rs2069709, and rs 27860067, A/C) SNPs of the IFN‐γ gene using the allelic discrimination real‐time polymerase chain reaction technique and were confirmed using sequence‐based typing.ResultsThe carriage of T allele of (+874) IFN‐γ is a risky allele and was significantly higher in chronic hepatitis C more than other two groups (odds ratio [OR]: 2.6646, P < 0.0002). On the other hand, the C allele of (−764, rs2069707) is a protective allele and was higher in SVC than the other two groups (OR: 0.2709, P < 0.0001). However, both (−179 C/A, rs 2069709) and (rs 27860067, A/C) SNPs are not polymorphic enough to be studied in the Egyptian population.ConclusionsHCV infection is associated with the T allele of (+874 rs2430561), while SVC of HCV is associated with the C allele of (−764, rs2069707) of the IFN‐γ gene.

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“…[2] Major risk factors for HCC include chronic hepatitis B virus (HBV) and hepatitis C virus (HCV) infections, aflatoxin exposure, Type 2 diabetes, cirrhosis related to heavy alcohol consumption, nonalcoholic fatty liver disease (associated with obesity), and smoking. [1345] In general, approximately 75–85% of HCC patients are attributable to chronic HBV infections, especially in less developed countries such as China. [67]…”

Section: Introductionmentioning

confidence: 99%

Role of superoxide dismutase in hepatitis B virus-related hepatocellular carcinoma

Zhang

Rong

et al. 2016

J Res Med Sci

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Background:Reactive oxygen species (ROS) play important roles in hepatocarcinogenesis. Superoxide dismutase (SOD) is involved in the repair of ROS. Serum alpha-fetoprotein (AFP) is the “golden marker” for diagnosing hepatocellular carcinoma (HCC), and one major shortcoming of its use is that it is insensitive for the early detection of HCC. Therefore, we evaluated serum SOD levels and their association with AFP in hepatitis B virus (HBV)-related HCC.Materials and Methods:A total of 279 subjects were divided into three groups: 99 HBV patients with HCC, 73 HBV patients without HCC, and 107 sex- and age-matched healthy controls. Serum levels of SOD were assayed using colorimetry, while AFP levels were measured by electrochemiluminescence immunoassay.Results:A highly significant elevation was found in AFP in HBV-with HCC patients compared to HBV-without HCC patients and control subjects (P < 0.001). Alternatively, serum SOD levels were significantly decreased in patients with HCC compared to HBV patients without HCC and healthy controls (P < 0.001). Furthermore, serum SOD was negatively correlated with AFP (r = −0.505, P < 0.001) in HBV-with HCC patients.Conclusion:SOD and AFP might be simultaneously evaluated to improve the HCC detection rate.

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Interferon Gamma +874T/A Polymorphism Increases the Risk of Hepatitis Virus-Related Diseases: Evidence from a Meta-Analysis

Cited by 15 publications

References 51 publications

TCR-CXCR4 signaling stabilizes cytokine mRNA transcripts via a PREX1-Rac1 pathway: implications for CTCL

TCR-CXCR4 signaling stabilizes cytokine mRNA transcripts via a PREX1-Rac1 pathway: implications for CTCL

Association of interferon gamma gene polymorphism and susceptibility to hepatitis C virus infection in Egyptian patients: A multicenter, family‐based study

Role of superoxide dismutase in hepatitis B virus-related hepatocellular carcinoma

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