Polymorphisms in melanoma differentiation‐associated gene 5 are not associated with clearance of hepatitis C virus in a European American population

Vergara, Candelaria; Thio, Chloe L.; Thomas, David L.; Duggal, Priya

doi:10.1002/hep.27954

Cited by 3 publications

(3 citation statements)

References 4 publications

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“…In parallel, the islet cohort was genotyped for the rs3747517 SNP (Supplementary Table S1). The results from this genotyping were in line with the previously published strong linkage disequilibrium with rs19907609163031.…”

Section: Resultssupporting

confidence: 89%

An IFIH1 gene polymorphism associated with risk for autoimmunity regulates canonical antiviral defence pathways in Coxsackievirus infected human pancreatic islets

Domsgen

Lind

Kong

et al. 2016

Sci Rep

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The IFIH1 gene encodes the pattern recognition receptor MDA5. A common polymorphism in IFIH1 (rs1990760, A946T) confers increased risk for autoimmune disease, including type 1-diabetes (T1D). Coxsackievirus infections are linked to T1D and cause beta-cell damage in vitro. Here we demonstrate that the rs1990760 polymorphism regulates the interferon (IFN) signature expressed by human pancreatic islets following Coxsackievirus infection. A strong IFN signature was associated with high expression of IFNλ1 and IFNλ2, linking rs1990760 to the expression of type III IFNs. In the high-responding genotype, IRF-1 expression correlated with that of type III IFN, suggesting a positive-feedback on type III IFN transcription. In summary, our study uncovers an influence of rs1990760 on the canonical effector function of MDA5 in response to an acute infection of primary human parenchymal cells with a clinically relevant virus linked to human T1D. It also highlights a previously unrecognized connection between the rs1990760 polymorphism and the expression level of type III IFNs.

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Section: Resultssupporting

confidence: 89%

An IFIH1 gene polymorphism associated with risk for autoimmunity regulates canonical antiviral defence pathways in Coxsackievirus infected human pancreatic islets

Domsgen

Lind

Kong

et al. 2016

Sci Rep

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“…Further, haplotypes at IFIH1 encoding His at position 843 and Thr at position 946 were reported to correlate with the resolution of hepatitis C virus (HCV) 28 . Notably, we found IFIH1 H843/T946 was very rare in our data, consistent other recent reports 48 , 49 . Thus, at the population level, the impact of the common risk haplotype (IFIH1 T946/R843 ) upon response to viral challenge and autoimmune disease risk is likely to be important; whereas the impact of the rare IFIH1 H843/T946 haplotype would be negligible.…”

Section: Discussionsupporting

confidence: 93%

The A946T variant of the RNA sensor IFIH1 mediates an interferon program that limits viral infection but increases the risk for autoimmunity

Hundhausen²,

et al. 2017

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The single nucleotide polymorphism, rs1990760, in the cytosolic viral sensor, IFIH1, results in an amino-acid change (p.A946T) and is associated with multiple autoimmune diseases. The impact of this polymorphism on both viral-sensing and autoimmune pathogenesis remains poorly understood. Here, we find that human PBMCs and cell lines with the risk variant, IFIH1T946, exhibit heightened, basal and ligand-triggered type I interferon (IFN-I) production. Consistent with these findings, IFIH1T946 knock-in mice display enhanced basal IFN-I expression, survive a lethal viral challenge, and exhibit increased penetrance in autoimmune models including a combinatorial impact with other risk variants. Further, IFIH1T946 mice manifest an embryonic survival defect consistent with enhanced responsiveness to RNA self-ligands. Together, our data support a model wherein autoimmune risk variant-driven, ligand-triggered IFN-I production functions to protect against viral challenge, likely accounting for its selection within human populations, but provides this advantage at the cost of modestly promoting the risk for autoimmunity.

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“…In regard to IFIH1 rs3747517, which was embedded within an activator protein 1 (AP-1) binding site, no significant relation between rs3747517 and SLE susceptibility was observed in patients from Brazil 20 . However, ethnic differences have been seen in the allele distributions of both rs1990760 and rs3747517 in Europeans, Asians and Africans 20 , 24 , 25 .…”

Section: Discussionmentioning

confidence: 99%

Autoimmune disease associated IFIH1 single nucleotide polymorphism related with IL-18 serum levels in Chinese systemic lupus erythematosus patients

Zhang

Liu

Yang

et al. 2018

Sci Rep

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Systemic lupus erythematosus (SLE) has heterogeneous clinical manifestations. IFIH1 (interferon induced with helicase C domain 1) as one of antiviral helicase genes mediating type I interferon production, plays an essential role in the pathogenesis of SLE. The gene variants in IFIH1 could abnormally activate antiviral defenses and increased type I interferon signaling. The present study aimed to validate associations between single nucleotide polymorphisms (SNP) in IFIH1 and the pathogenesis of SLE. In total, rs1990760, rs3747517 and rs10930046 in IFIH1 are genotyped in 400 SLE patients and 659 health controls in Chinese cohort by an improved multiplex ligation detection reaction (iMLDR) technique. Significant associations were observed between alleles of IFIH1 (rs1990760 C > T, P = 0.005, OR = 1.36, 95%CI = 1.10–1.69; rs3747517 T > C, P = 0.004, OR = 1.31, 95%CI = 1.09–1.58, respectively) and SLE susceptibility. IFIH1 rs1990760 TT genotype carriers had lower serum levels of IL-18 (P < 0.001) and granzyme B (P < 0.001) than CC and CT genotype carriers. IFIH1 rs1990760 CT genotype carriers had higher anti-dsDNA–positive than CC and TT genotype carriers. In conclusion, IFIH1 polymorphisms (rs1990760 and rs3747517) were associated with SLE susceptibility and rs1990760 risk T allele related with IL-18 and granzyme B serum levels in SLE patients.

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Polymorphisms in melanoma differentiation‐associated gene 5 are not associated with clearance of hepatitis C virus in a European American population

Cited by 3 publications

References 4 publications

An IFIH1 gene polymorphism associated with risk for autoimmunity regulates canonical antiviral defence pathways in Coxsackievirus infected human pancreatic islets

An IFIH1 gene polymorphism associated with risk for autoimmunity regulates canonical antiviral defence pathways in Coxsackievirus infected human pancreatic islets

The A946T variant of the RNA sensor IFIH1 mediates an interferon program that limits viral infection but increases the risk for autoimmunity

Autoimmune disease associated IFIH1 single nucleotide polymorphism related with IL-18 serum levels in Chinese systemic lupus erythematosus patients

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