Single nucleotide polymorphism at exon 7 splice acceptor site of OAS1 gene determines response of hepatitis C virus patients to interferon therapy

Awady, Mostafa K El; Anany, Mohamed A.; Esmat, Gamal; Zayed, Naglaa; Tabll, Ashraf A.; Helmy, Amr; Zayady, Abdel Rahman El; Abdalla, Mohga S; Sharada, Hayat M.; Raziky, Maissa El; El-Akel, Wafaa; Abdalla, Shadia; Din, Noha G Bader El

doi:10.1111/j.1440-1746.2010.06605.x

Cited by 45 publications

(29 citation statements)

References 48 publications

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“…The Neandertal-introgressed allele encodes a protein variant (p46) that is associated with higher enzymatic activity [36]. The adaptive potential of this variant is supported by the observation that this variant (or other variants in strong LD with it) was shown to be associated with: (1) reduced infection and replication rates of West Nile virus ([38], but see [39]); (2) improved resistance to hepatitis C virus (HCV) infection [40, 41]; and (3) variable symptomology of tick-borne encephalitis (TBE) virus-induced disease (homozygous individuals for the Neandertal haplotype show the most severe symptoms of TBE). Strikingly, West Nile, hepatitis C, and TBE are all members of the Flaviviridae family, suggesting that Flaviviruses might have been the main drivers of selection in OAS1 .…”

Section: Discussionmentioning

confidence: 99%

Adaptively introgressed Neandertal haplotype at the OAS locus functionally impacts innate immune responses in humans

et al. 2016

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BackgroundThe 2’-5’ oligoadenylate synthetase (OAS) locus encodes for three OAS enzymes (OAS1-3) involved in innate immune response. This region harbors high amounts of Neandertal ancestry in non-African populations; yet, strong evidence of positive selection in the OAS region is still lacking.ResultsHere we used a broad array of selection tests in concert with neutral coalescent simulations to demonstrate a signal of adaptive introgression at the OAS locus. Furthermore, we characterized the functional consequences of the Neandertal haplotype in the transcriptional regulation of OAS genes at baseline and infected conditions. We found that cells from people with the Neandertal-like haplotype express lower levels of OAS3 upon infection, as well as distinct isoforms of OAS1 and OAS2.ConclusionsWe present evidence that a Neandertal haplotype at the OAS locus was subjected to positive selection in the human population. This haplotype is significantly associated with functional consequences at the level of transcriptional regulation of innate immune responses. Notably, we suggest that the Neandertal-introgressed haplotype likely reintroduced an ancestral splice variant of OAS1 encoding a more active protein, suggesting that adaptive introgression occurred as a means to resurrect adaptive variation that had been lost outside Africa.Electronic supplementary materialThe online version of this article (doi:10.1186/s13059-016-1098-6) contains supplementary material, which is available to authorized users.

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Section: Discussionmentioning

confidence: 99%

Adaptively introgressed Neandertal haplotype at the OAS locus functionally impacts innate immune responses in humans

et al. 2016

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“…The G allele is known to be associated with higher enzyme activity, whereas the more common A allele is associated with lower enzyme activity [26]. It is particularly noteworthy that patients with the homozygous GG genotype demonstrated a higher response to interferon therapy against HCV infection, whereas the AA genotype was associated with non-response to interferon and higher degrees of liver fibrosis [27]. We found by genomic sequence analysis that Huh7 cell line possesses the AA genotype and confirmed by RT-PCR the expression of the splicing variants coding for p42, p48 and p52, respectively, but no expression of p46 transcript (Supplementary data Fig.…”

Section: The Antiviral Activity Of Oas1 P46 Against Hcvmentioning

confidence: 99%

The ribonuclease l‐dependent antiviral roles of human 2′,5′‐oligoadenylate synthetase family members against hepatitis C virus

et al. 2012

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a b s t r a c tThe latent ribonuclease RNase L and the interferon-inducible 2 0 ,5 0 -oligoadenylate synthetase (OAS) have been implicated in the antiviral response against hepatitis C virus (HCV). However, the specific roles of these enzymes against HCV have not been fully elucidated. In this study, a scarce endogenous expression and RNA degrading activity of RNase L in human hepatoma Huh7 cells enabled us to demonstrate the antiviral activity of RNase L against HCV replication through the transient expression of the enzyme. The antiviral potential of specific members of the OAS family was further examined through overexpression and RNA interference approaches. Our data suggested that among the members of the OAS family, OAS1 p46 and OAS3 p100 mediate the RNase L-dependent antiviral activity against HCV.

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“…Consistent with the important role of OAS proteins in viral infection, it was shown that polymorphisms in the OAS genes are associated with increased susceptibility to HCV infection[18] and IFN treatment outcomes[17,19,20]. However, the molecular basis for this association is not well understood.…”

Section: Discussionmentioning

confidence: 99%

Impact of IL28B and OAS gene family polymorphisms on interferon treatment response in Caucasian children chronically infected with hepatitis B virus

Domagalski¹,

Pawłowska²,

Zaleśna³

et al. 2016

WJG

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AIMTo investigate the impact of IL28B and OAS gene polymorphisms on interferon treatment responses in children with chronic hepatitis B.METHODSWe enrolled 52 children (between the ages of 4 and 18) with hepatitis B e antigen-negative chronic hepatitis B (CHB), who were treated with pegylated interferon alfa for 48 wk. Single nucleotide polymorphisms in the OAS1 (rs1131476), OAS2 (rs1293747), OAS3 (rs2072136), OASL (rs10849829) and IL28B (rs12979860, rs12980275 and rs8099917) genes were studied to examine their associations with responses to IFN treatment in paediatric patients. We adopted two criteria for the therapeutic response, achieving an hepatitis B virus (HBV) DNA level < 2000 IU/mL and normalization of ALT activity (< 40 IU/L). To perform the analyses, we compared the patients in terms of achieving a partial response (PR) and a complete response (CR) upon measurement at the 24-wk post-treatment follow-up.RESULTSThe PR and CR rates were 80.8% and 42.3%, respectively. Factors such as age, gender and liver histology had no impact on the type of response (partial or complete). A statistically significant relationship between higher baseline HBV DNA and ALT activity levels and lower rates of PR and CR was shown (P < 0.05). The allele association analysis revealed that only the IL-28B rs12979860 (C vs T) and IL28B rs12980275 (A vs G) markers significantly affected the achievement of PR (P = 0.021, OR = 3.3, 95%CI: 1.2-9.2 and P = 0.014, OR = 3.7, 95%CI: 1.3-10.1, respectively). However, in the genotype analysis, only IL-28B rs12980275 was significantly associated with PR (AA vs AG-GG, P = 0.014, OR = 10.9, 95%CI: 1.3-93.9). The association analysis for CR showed that the TT genotype of IL28B rs12979860 was present only in the no-CR group (P = 0.033) and the AA genotype of OASL rs10849829 was significantly more frequent in the no-CR group (P = 0.044, OR = 0.26, 95%CI: 0.07-0.88). The haplotype analysis revealed significant associations between PR and CR and OAS haplotype (P = 0.0002 and P = 0.001, respectively), but no association with IL28B haplotype was observed.CONCLUSIONIL28B and OAS polymorphisms are associated with different clinical outcomes in CHB children treated with interferon.

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Single nucleotide polymorphism at exon 7 splice acceptor site of OAS1 gene determines response of hepatitis C virus patients to interferon therapy

Cited by 45 publications

References 48 publications

Adaptively introgressed Neandertal haplotype at the OAS locus functionally impacts innate immune responses in humans

Adaptively introgressed Neandertal haplotype at the OAS locus functionally impacts innate immune responses in humans

The ribonuclease l‐dependent antiviral roles of human 2′,5′‐oligoadenylate synthetase family members against hepatitis C virus

Impact of IL28B and OAS gene family polymorphisms on interferon treatment response in Caucasian children chronically infected with hepatitis B virus

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