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The reduced predictive value of interleukin 28b gene polymorphisms in a cohort of patients with thyroiditis developed during antiviral therapy for chronic hepatitis C: a preliminary study.

Tran HA, Jones TL, Ianna EA, Gibson RA, Reeves GE - Hepat Mon (2012)

Bottom Line: Single nucleotide polymorphism in the interleukin28B (IL28B) gene was recently shown to be associated with a significant increase in response to interferon-α and ribavirin treatment in patients with chronic hepatitis C.Similarly, thyroid disease (TD) occurring during treatment confer an improved sustained virologic response (SVR).This suggests that TD in this clinical context may be a critical factor in the achievement of SVR, probably above that of the genetic predisposition.

View Article: PubMed Central - PubMed

Affiliation: Hunter Area Pathology Service, John Hunter Hospital, Newcastle, Australia.

ABSTRACT

Background: Single nucleotide polymorphism in the interleukin28B (IL28B) gene was recently shown to be associated with a significant increase in response to interferon-α and ribavirin treatment in patients with chronic hepatitis C. Similarly, thyroid disease (TD) occurring during treatment confer an improved sustained virologic response (SVR).

Objectives: To determine the role of IL28B genotypes in a cohort of hepatitis C patients who develop TD during treatment and its relationship to SVR.

Patients and methods: IL28B gene profiles including rs12979860, rs12980275 and rs 8099917 and their genotypes were determined in a cohort of 23 hepatitis C patients who developed TD during treatment and their relationship to SVR.

Results: Out of 23 studies cases, 19 has one or more favorable genotypes, of which 15 (78.9%) achieved SVR. Eleven has all three unfavorable genotypes and yet achieved 72.7 % SVR. The presence of more than one favorable genotype only correctly predicts SVR vs. non- SVR in ~50 % of cases, i.e. by chance.

Conclusions: Despite the small number of subjects, the presence of one or more unfavorable IL28B genotype does not portend a poor SVR prognostic outcome. This suggests that TD in this clinical context may be a critical factor in the achievement of SVR, probably above that of the genetic predisposition.

No MeSH data available.


Related in: MedlinePlus

The Cellular Mechanism of the Synergy Between Thyroxin and InterferonsAbbreviations: IFN: Interferon, T4: Thyroxin, STAT: Signal Transducer and Activation of Transcription, MAPK: Mitogen–Activated Protein Kinase, MEK: MAPK Kinase, ISRE: Interferon Stimulated Response Element
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Related In: Results  -  Collection

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fig107: The Cellular Mechanism of the Synergy Between Thyroxin and InterferonsAbbreviations: IFN: Interferon, T4: Thyroxin, STAT: Signal Transducer and Activation of Transcription, MAPK: Mitogen–Activated Protein Kinase, MEK: MAPK Kinase, ISRE: Interferon Stimulated Response Element

Mentions: This is the first paper to look at the IL28B profile in this unique but small cohort of HCV patients who develop TD during treatment with combination IFN-α and RBV. This analysis was performed because one of the novel findings in recent genetic and hepatic literature is the discovery of the gene IL28B and its response to treatment in chronic hepatitis C patients (1, 2, 3). It was been shown that patients who harbor the favorable SNPs of these genes experience a favorable outcome with regards to both spontaneous clearance and response to IFN-α therapy (4). The second recent significant observation is that patients who develop TD, predominantly thyroiditis, are much more likely to achieve SVR than those who do not (5). It is therefore logical to determine if treated HCV patients who developed thyroid disease harbor the favorable IL28B variants. This may help to understand and reconcile the high SVR in patients with TD. Firstly, the commonest genotypes are heterozygotes in rs12979860 and rs12980275, CT and AG respectively where as in rs8099917 it is the homozygous TT variant. This is not dissimilar to those without TD and those in the healthy general population, Table 3. As the TT variant is the commonest favorable genotype in the thyroid group at 52.2 %, it may be the major determinant in achieving the final SVR but noting that its own likelihood of SVR is modest at 56 %. Where there is one or more favorable genotype, the development of TD ensures that SVR will be achieved in a mixture of genotypes 1, 2 and 3 although our data is early and the number is small (Table 2, patients 12 to 23). Secondly, 11 patients do not carry any favorable genotypes. Despite this, the majority achieves SVR at 72.7 % (eight out of 11). This suggested that the development of TD during treatment confers an additional advantage for SVR, despite genetic antagonism. Thirdly, a recent meta-analysis (8) reveals that the presence of IL28B (with any specific genotypes) delivered SVR rates of 34.5 % for genotype 1 and 80.9 % for genotype 2/3 respectively which does not appear to confer any response advantage, Figure 1. The etiologies for this encouraging SVR response in the TD cohort remain speculative but some of the potential considerations include the exposure to supra physiological concentration of thyroid hormones, an exaggerated immune response following IFN therapy or simple genetic predisposition. It has been proposed that the IL28B polymorphism is associated with reduced production of IL28B (1, 2), a Type III interferon (also known as interferon-λ3) bearing close relationship to the Type I interferon (α, β and δ) with similar antiviral effects but triggering signal transduction through a heterodimer consisting of IL10R2 and the unique IF-λR1 receptor chains. It is not known if any specific IL28B genotype is associated with a reduction of interferon-λ3 production and thereby may negate or suppress viral replication. Together with IL-28A and IL-29 which code for IFN-λ2 and IFN-λ1 respectively, IL28B forms a cytokine gene cluster on a chromosomal region mapped to 19q13 (9, 10). Expression of the cytokines encoded by these three genes can be induced by RNA virus infection (11). Interferon-λs are vital in the regulation of a number of viruses including herpes simplex virus and HBV. They induce blockade of HCV replication in time- and dose-dependent fashion (12). They also induce levels of IFN-stimulated genes and the antiviral efficacy of IFN-α. Interferon-λs inhibit HepG2 cell lysis after being infected with encephalo myocarditis virus. IL28B has a role in the regulation intrahepatic IFN-stimulated gene expression with consequences both for viral load and treatment response (13). They have also been shown to be virolytic (14, 15). The rs8099917 TT genotype theoretically may result in an enhanced type III IFN-λ response which involve the JAK/STAT pathway and may amplify the immunotherapeutic response. In spite of the extensive and understandable interest in the use of IL28B polymorphisms in predicting the likelihood of achieving SVR, our study found that the value of this parameter was limited in our cohort of patients. This contradicting data is consistent with the concept that, whilst being an important determinant of antiviral activity, the assessment of IL28B polymorphisms displays reduced predictive power in certain important subgroups of HCV patients, such as those in our study with treatment-related thyroiditis. In this specific cohort, out of 19 who had one or more unfavorable genotype, 15 achieved SVR at 78.9 %, those with two or more unfavorable genotype, the SVR is 75.0 % (12/16) whilst those with the complete trio of unaffordability has a SVR of 72.7 % (8/11), Table 2. Conversely the presence of one or more favorable IL28 polymorphisms displayed only 58 % sensitivity and 75 % specificity for the outcome of achieving SVR. One false positive was detected, with the TT genotype in SNP rs8099917 associated with non-SVR. Having more than one favorable allele is 100 % specific for attaining SVR, but regrettably, it results in correct classification of SVR vs. non-SVR in only ~50 % of cases. This result is not surprising because there are many other contributors to the chance of achieving SVR, including immune factors such as natural killer cell receptors, HLA class I and II loci, and polymorphisms for the genes: Chemokine Receptor 5δ32, IFNg-764G, IL10, IL12, Transforming Growth Factor b, and Tumor Necrosis Factor a (16). More importantly, previous studies have indicated the potentiation of IFN activities by thyroxin which may in turn contributes to SVR. These included IFN-α, β and γ and are thought to act via the action of intracellular Mitogen Activated Protein Kinase (MAPK) (17, 18) upon exposure to thyroxin (19). The MAPK then phosphorylates the STAT1a which in turns activate IFN-related gene translation, inducing and leading to the favorable outcome downstream, Figure 2. All 3 types of IFN share an indistinguishable signaling pathway downstream after receptor binding (9). For these specific reasons, it is strongly suggestive that TD confers an advantageous SVR outcome above that of genetic predisposition.


The reduced predictive value of interleukin 28b gene polymorphisms in a cohort of patients with thyroiditis developed during antiviral therapy for chronic hepatitis C: a preliminary study.

Tran HA, Jones TL, Ianna EA, Gibson RA, Reeves GE - Hepat Mon (2012)

The Cellular Mechanism of the Synergy Between Thyroxin and InterferonsAbbreviations: IFN: Interferon, T4: Thyroxin, STAT: Signal Transducer and Activation of Transcription, MAPK: Mitogen–Activated Protein Kinase, MEK: MAPK Kinase, ISRE: Interferon Stimulated Response Element
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC3475014&req=5

fig107: The Cellular Mechanism of the Synergy Between Thyroxin and InterferonsAbbreviations: IFN: Interferon, T4: Thyroxin, STAT: Signal Transducer and Activation of Transcription, MAPK: Mitogen–Activated Protein Kinase, MEK: MAPK Kinase, ISRE: Interferon Stimulated Response Element
Mentions: This is the first paper to look at the IL28B profile in this unique but small cohort of HCV patients who develop TD during treatment with combination IFN-α and RBV. This analysis was performed because one of the novel findings in recent genetic and hepatic literature is the discovery of the gene IL28B and its response to treatment in chronic hepatitis C patients (1, 2, 3). It was been shown that patients who harbor the favorable SNPs of these genes experience a favorable outcome with regards to both spontaneous clearance and response to IFN-α therapy (4). The second recent significant observation is that patients who develop TD, predominantly thyroiditis, are much more likely to achieve SVR than those who do not (5). It is therefore logical to determine if treated HCV patients who developed thyroid disease harbor the favorable IL28B variants. This may help to understand and reconcile the high SVR in patients with TD. Firstly, the commonest genotypes are heterozygotes in rs12979860 and rs12980275, CT and AG respectively where as in rs8099917 it is the homozygous TT variant. This is not dissimilar to those without TD and those in the healthy general population, Table 3. As the TT variant is the commonest favorable genotype in the thyroid group at 52.2 %, it may be the major determinant in achieving the final SVR but noting that its own likelihood of SVR is modest at 56 %. Where there is one or more favorable genotype, the development of TD ensures that SVR will be achieved in a mixture of genotypes 1, 2 and 3 although our data is early and the number is small (Table 2, patients 12 to 23). Secondly, 11 patients do not carry any favorable genotypes. Despite this, the majority achieves SVR at 72.7 % (eight out of 11). This suggested that the development of TD during treatment confers an additional advantage for SVR, despite genetic antagonism. Thirdly, a recent meta-analysis (8) reveals that the presence of IL28B (with any specific genotypes) delivered SVR rates of 34.5 % for genotype 1 and 80.9 % for genotype 2/3 respectively which does not appear to confer any response advantage, Figure 1. The etiologies for this encouraging SVR response in the TD cohort remain speculative but some of the potential considerations include the exposure to supra physiological concentration of thyroid hormones, an exaggerated immune response following IFN therapy or simple genetic predisposition. It has been proposed that the IL28B polymorphism is associated with reduced production of IL28B (1, 2), a Type III interferon (also known as interferon-λ3) bearing close relationship to the Type I interferon (α, β and δ) with similar antiviral effects but triggering signal transduction through a heterodimer consisting of IL10R2 and the unique IF-λR1 receptor chains. It is not known if any specific IL28B genotype is associated with a reduction of interferon-λ3 production and thereby may negate or suppress viral replication. Together with IL-28A and IL-29 which code for IFN-λ2 and IFN-λ1 respectively, IL28B forms a cytokine gene cluster on a chromosomal region mapped to 19q13 (9, 10). Expression of the cytokines encoded by these three genes can be induced by RNA virus infection (11). Interferon-λs are vital in the regulation of a number of viruses including herpes simplex virus and HBV. They induce blockade of HCV replication in time- and dose-dependent fashion (12). They also induce levels of IFN-stimulated genes and the antiviral efficacy of IFN-α. Interferon-λs inhibit HepG2 cell lysis after being infected with encephalo myocarditis virus. IL28B has a role in the regulation intrahepatic IFN-stimulated gene expression with consequences both for viral load and treatment response (13). They have also been shown to be virolytic (14, 15). The rs8099917 TT genotype theoretically may result in an enhanced type III IFN-λ response which involve the JAK/STAT pathway and may amplify the immunotherapeutic response. In spite of the extensive and understandable interest in the use of IL28B polymorphisms in predicting the likelihood of achieving SVR, our study found that the value of this parameter was limited in our cohort of patients. This contradicting data is consistent with the concept that, whilst being an important determinant of antiviral activity, the assessment of IL28B polymorphisms displays reduced predictive power in certain important subgroups of HCV patients, such as those in our study with treatment-related thyroiditis. In this specific cohort, out of 19 who had one or more unfavorable genotype, 15 achieved SVR at 78.9 %, those with two or more unfavorable genotype, the SVR is 75.0 % (12/16) whilst those with the complete trio of unaffordability has a SVR of 72.7 % (8/11), Table 2. Conversely the presence of one or more favorable IL28 polymorphisms displayed only 58 % sensitivity and 75 % specificity for the outcome of achieving SVR. One false positive was detected, with the TT genotype in SNP rs8099917 associated with non-SVR. Having more than one favorable allele is 100 % specific for attaining SVR, but regrettably, it results in correct classification of SVR vs. non-SVR in only ~50 % of cases. This result is not surprising because there are many other contributors to the chance of achieving SVR, including immune factors such as natural killer cell receptors, HLA class I and II loci, and polymorphisms for the genes: Chemokine Receptor 5δ32, IFNg-764G, IL10, IL12, Transforming Growth Factor b, and Tumor Necrosis Factor a (16). More importantly, previous studies have indicated the potentiation of IFN activities by thyroxin which may in turn contributes to SVR. These included IFN-α, β and γ and are thought to act via the action of intracellular Mitogen Activated Protein Kinase (MAPK) (17, 18) upon exposure to thyroxin (19). The MAPK then phosphorylates the STAT1a which in turns activate IFN-related gene translation, inducing and leading to the favorable outcome downstream, Figure 2. All 3 types of IFN share an indistinguishable signaling pathway downstream after receptor binding (9). For these specific reasons, it is strongly suggestive that TD confers an advantageous SVR outcome above that of genetic predisposition.

Bottom Line: Single nucleotide polymorphism in the interleukin28B (IL28B) gene was recently shown to be associated with a significant increase in response to interferon-α and ribavirin treatment in patients with chronic hepatitis C.Similarly, thyroid disease (TD) occurring during treatment confer an improved sustained virologic response (SVR).This suggests that TD in this clinical context may be a critical factor in the achievement of SVR, probably above that of the genetic predisposition.

View Article: PubMed Central - PubMed

Affiliation: Hunter Area Pathology Service, John Hunter Hospital, Newcastle, Australia.

ABSTRACT

Background: Single nucleotide polymorphism in the interleukin28B (IL28B) gene was recently shown to be associated with a significant increase in response to interferon-α and ribavirin treatment in patients with chronic hepatitis C. Similarly, thyroid disease (TD) occurring during treatment confer an improved sustained virologic response (SVR).

Objectives: To determine the role of IL28B genotypes in a cohort of hepatitis C patients who develop TD during treatment and its relationship to SVR.

Patients and methods: IL28B gene profiles including rs12979860, rs12980275 and rs 8099917 and their genotypes were determined in a cohort of 23 hepatitis C patients who developed TD during treatment and their relationship to SVR.

Results: Out of 23 studies cases, 19 has one or more favorable genotypes, of which 15 (78.9%) achieved SVR. Eleven has all three unfavorable genotypes and yet achieved 72.7 % SVR. The presence of more than one favorable genotype only correctly predicts SVR vs. non- SVR in ~50 % of cases, i.e. by chance.

Conclusions: Despite the small number of subjects, the presence of one or more unfavorable IL28B genotype does not portend a poor SVR prognostic outcome. This suggests that TD in this clinical context may be a critical factor in the achievement of SVR, probably above that of the genetic predisposition.

No MeSH data available.


Related in: MedlinePlus