Mutation screening of interferon-gamma (IFNgamma) as a candidate gene for asthma

Hayden, Catherine M.; Pereira, Emma; Rye, P. J.; Lj, Palmer; Gibson, Neil; Palenque, Miguel; Hagel, Isabel; Lynch, Neil R.; Goldblatt, Jack; Lesouëf, Peter

doi:10.1111/j.1365-2222.1997.tb02985.x

Cited by 11 publications

(14 citation statements)

References 22 publications

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“…The human IFN-␥ gene on chromosome 12q24.1 spans Ϸ5.4 kb and contains four exons that encode a 146-aa protein. Like other cytokines, the IFN-␥ coding region is invariant, with no reported polymorphisms (8). Several polymorphisms within the IFN-␥ noncoding regions, such as ϩ874A/T, CA repeat microsatellite, and Ϫ179T/G, have been implicated in several autoimmune and chronic inflammatory conditions (9,10).…”

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confidence: 99%

A functional SNP of interferon-γ gene is important for interferon-α-induced and spontaneous recovery from hepatitis C virus infection

Huang

Yang

Borg

et al. 2007

Proc. Natl. Acad. Sci. U.S.A.

106

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Cytokine polymorphisms are associated with disease outcome and interferon (IFN) treatment response in hepatitis C virus (HCV) infection. We genotyped eight SNPs spanning the entire IFN-γ gene in two cohorts and assessed the association between those polymorphisms and treatment response or spontaneous viral clearance. The first cohort was composed of 284 chronically HCV-infected patients who had received IFN-α-based therapy and the second was 251 i.v. drug users who had either spontaneously cleared HCV or become chronically infected. A SNP variant located in the proximal IFN-γ promoter region next to the binding motif of heat shock transcription factor (HSF), −764G, was significantly associated with sustained virological response [ P = 0.04, odds ratio (OR) = 3.51 (confidence interval 1.0–12.5)]. The association was independently significant in multiple logistic regression ( P = 0.04) along with race, viral titer, and genotype. This variant was also significantly associated with spontaneous recovery [ P = 0.04, OR = 3.51 (1.0–12.5)] in the second cohort. Functional analyses show that the G allele confers a two- to three-fold higher promoter activity and stronger binding affinity to HSF1 than the C allele. Our study suggests that the IFN-γ promoter SNP −764G/C is functionally important in determining viral clearance and treatment response in HCV-infected patients and may be used as a genetic marker to predict sustained virological response in HCV-infected patients.

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confidence: 99%

A functional SNP of interferon-γ gene is important for interferon-α-induced and spontaneous recovery from hepatitis C virus infection

Huang

Yang

Borg

et al. 2007

Proc. Natl. Acad. Sci. U.S.A.

106

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“…106,107 No polymorphism of the IFN-g gene has been associated with asthma. 108 Administration of exogenous IFN-g prevents the airway eosinophilia and hyper-responsiveness following allergen exposure in mice. 109,110 Liposome-mediated gene transfer of IFN-g to the pulmonary epithelium in sensitised mice before secondary antigen exposure also inhibited the pulmonary allergic response.…”

Section: Role In Allergy and Asthmamentioning

confidence: 99%

Anti‐inflammatory cytokines in asthma and allergy: interleukin‐10, interleukin‐12, interferon‐γ

Chung

2001

Mediators of Inflammation

170

113

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Interleukin-10 (IL-10) is a cytokine derived from CD4+ T-helper type 2 (T(H2)) cells identified as a suppressor of cytokines from T-helper type 1(T(H1)) cells. Interleukin-12 (IL-12) is produced by B cells, macrophages and dendritic cells, and primarily regulates T(H1) cell differentiation, while suppressing the expansion of T(H2) cell clones. Interferon-gamma (IFN-gamma) is a product of T(H1) cells and exerts inhibitory effects on T(H2) cell differentiation. These cytokines have been implicated in the pathogenesis of asthma and allergies. In this context, IL-12 and IFN-gamma production in asthma have been found to be decreased, and this may reduce their capacity to inhibit IgE synthesis and allergic inflammation. IL-10 is a potent inhibitor of monocyte/macrophage function, suppressing the production of many pro-inflammatory cytokines. A relative underproduction of IL-10 from alveolar macrophages of atopic asthmatics has been reported. Therapeutic modulation of T(H1)/T(H2) imbalance in asthma and allergy by mycobacterial vaccine, specific immunotherapy and cytoline-guanosine dinucleotide motif may lead to increases in IL-12 and IFN-gamma production. Stimulation of IL-10 production by antigen-specific T-cells during immunotherapy may lead to anergy through inhibition of CD28-costimulatory molecule signalling by IL-10s anti-inflammatory effect on basophils, mast cells and eosinophils.

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“…5 Also, it is normalization of IFNg-mediated responses and not reduction in Th2 cytokines that reverses the asthma features. 6 Like most of the cytokines, IFNg gene coding region has been found to be invariant; 7 however, some polymorphisms such as (CA)n repeat in intron 1, þ 874A/T (which is found to be in absolute linkage disequilibrium (LD) with CA (16) repeat) 8 and À179T/G have been identified in the non-coding region of this gene and shown to be associated with pathological features of asthma, 9 diabetes, 10 tuberculosis 11 and several other chronic inflammatory and autoimmune disorders. The (CA)n repeat modulates IFNg levels in vitro 12 and has been shown to be associated with many Th1/Th2-mediated disorders.…”

Section: Introductionmentioning

confidence: 99%

A single nucleotide polymorphism (A → G) in intron 3 of IFNγ gene is associated with asthma

Kumar

Ghosh

2008

Genes Immun

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Interferon-gamma (IFNgamma) is located on chromosome 12, and a number of studies have detected very strong linkage signals around this gene and asthma. The aim of this study was to analyze the association of a (CA)n repeat in intron 1 and six single nucleotide polymorphisms (((rs2069705, T/C) (promoter)), ((rs1861494, A/G), (rs1861493, T/C), (rs2069718, C/T) (intron 3)), ((rs2069727, A/G) and (rs2069728, G/A) (3' untranslated region))) spanning the whole gene with asthma. We report here the association of rs1861494 A/G with atopic asthma in a case-control cohort (n=189 and n=270 cases and controls, respectively) (P=0.0006), which was replicated (P=0.006) in a family study (n=137) as well. Allele G was found to be negatively associated (odds ratio=0.50, 95% confidence interval, P=0.0006). A five-locus haplotype also showed significant association with asthma in the case-control (P=0.002) and the family studies (P=0.0004). In our three-locus sliding window haplotypic analysis, we found the (CA)n repeat, rs1861494 A/G and rs2069718 C/T to be of high priority (P=0.0003). Using electrophoretic mobility shift assay, we provide evidence that the alleles of rs1861494 A/G have differential affinity to bind to putative nuclear factor(s). In conclusion, we report for the first time association of rs1861494 A/G polymorphism with asthma, which may regulate the IFNgamma levels and, hence, modulate asthma pathogenesis.

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Mutation screening of interferon-gamma (IFNgamma) as a candidate gene for asthma

Cited by 11 publications

References 22 publications

A functional SNP of interferon-γ gene is important for interferon-α-induced and spontaneous recovery from hepatitis C virus infection

A functional SNP of interferon-γ gene is important for interferon-α-induced and spontaneous recovery from hepatitis C virus infection

Anti‐inflammatory cytokines in asthma and allergy: interleukin‐10, interleukin‐12, interferon‐γ

A single nucleotide polymorphism (A → G) in intron 3 of IFNγ gene is associated with asthma

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