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IFNL4 and IFNL3 associated polymorphisms strongly influence the spontaneous IFN-alpha receptor-1 expression in HCV-infected patients.

Bordi L, Caglioti C, Garbuglia AR, Lapa D, Castilletti C, Taibi C, Capobianchi MR, Lalle E - PLoS ONE (2015)

Bottom Line: Single-nucleotide polymorphism in IFNL3 gene (rs12979860) predicts spontaneous and therapy-induced HCV clearance.Recently, a dinucleotide polymorphism, ss469415590 (TT or ΔG), has been discovered in the region upstream IFNL3 gene, which is in high linkage disequilibrium with rs12979860. ss469415590[ΔG] is a frameshift variant that creates a novel gene, designed IFNL4, encoding the interferon-lambda 4 protein (IFNL4).The aim of the present study was to extend the analysis of IFNAR-1 mRNA levels to the ss469415590 variants.

View Article: PubMed Central - PubMed

Affiliation: Laboratory of Virology, National Institute for Infectious Diseases "L. Spallanzani," Rome, Italy.

ABSTRACT
Single-nucleotide polymorphism in IFNL3 gene (rs12979860) predicts spontaneous and therapy-induced HCV clearance. In a previous study from our group PBMC from patients with favourable rs12979860 genotype showed higher levels of IFNAR-1 mRNA. Recently, a dinucleotide polymorphism, ss469415590 (TT or ΔG), has been discovered in the region upstream IFNL3 gene, which is in high linkage disequilibrium with rs12979860. ss469415590[ΔG] is a frameshift variant that creates a novel gene, designed IFNL4, encoding the interferon-lambda 4 protein (IFNL4). The aim of the present study was to extend the analysis of IFNAR-1 mRNA levels to the ss469415590 variants. Our results highlight that the difference of IFNAR-1 mRNA levels between favourable and unfavourable genotype combinations, at both rs12979860 and ss469415590 loci, is stronger than that observed for single polymorphisms at each locus. These findings suggest may represent the biological basis for the observed association between IFNL3 CC and IFNL4 TT/TT genotypes and favourable outcome of either natural HCV infection (clearance vs chronic evolution) or IFN-based therapy.

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Levels of IFNAR-1 mRNA in PBMC from the HCV-infected naïve subjects after 3h of exposure to 103 IU/ml IFN-alpha2b in vitro, according to their IFNL3 and IFNL4 genotype combinations.Group 1: IFNL3 CC and IFNL4 TT/TT (IFNL3 favourable, IFNL4 favourable) n = 6; Group 2: IFNL3 CT or TT and IFNL4 TT/TT (IFNL3 unfavourable and IFNL4 favourable) n = 11; Group 3: IFNL3 CT or TT and IFNL4 TT/ΔG or ΔG/ΔG (IFNL3 and IFNL4 unfavourable) n = 11. The results are expressed as ratio to beta-actin, after subtraction of values from unexposed cultures (median, IQR).
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pone.0117397.g003: Levels of IFNAR-1 mRNA in PBMC from the HCV-infected naïve subjects after 3h of exposure to 103 IU/ml IFN-alpha2b in vitro, according to their IFNL3 and IFNL4 genotype combinations.Group 1: IFNL3 CC and IFNL4 TT/TT (IFNL3 favourable, IFNL4 favourable) n = 6; Group 2: IFNL3 CT or TT and IFNL4 TT/TT (IFNL3 unfavourable and IFNL4 favourable) n = 11; Group 3: IFNL3 CT or TT and IFNL4 TT/ΔG or ΔG/ΔG (IFNL3 and IFNL4 unfavourable) n = 11. The results are expressed as ratio to beta-actin, after subtraction of values from unexposed cultures (median, IQR).

Mentions: To explore whether the differences in the levels of IFNAR-1 mRNA could lead to an increased response to exogenously administered IFN-alpha, PBMC from patients with the various genotype combinations were exposed to IFN-alpha and the induction of mRNA for IP10, as biomarker of IFN activity, was measured. The results, shown in Fig. 2 Panel B, indicate a gradient of IFN response among the groups in term of IP10 mRNA induction, that paralleled the levels of IFNAR-1 expressed before IFN-alpha treatment (Fig. 2 Panel A). In particular, the difference between Group 1 and Group 3 was highly significant [median: 37.28 (IQR: 33.53–38.37) vs 16.06 (IQR: 9.979–29.27); p = 0.0193]. IFNAR-1 mRNA levels were not significantly modified by IFN-alpha treatment (Fig. 3), reflecting the differences among groups observed at baseline.


IFNL4 and IFNL3 associated polymorphisms strongly influence the spontaneous IFN-alpha receptor-1 expression in HCV-infected patients.

Bordi L, Caglioti C, Garbuglia AR, Lapa D, Castilletti C, Taibi C, Capobianchi MR, Lalle E - PLoS ONE (2015)

Levels of IFNAR-1 mRNA in PBMC from the HCV-infected naïve subjects after 3h of exposure to 103 IU/ml IFN-alpha2b in vitro, according to their IFNL3 and IFNL4 genotype combinations.Group 1: IFNL3 CC and IFNL4 TT/TT (IFNL3 favourable, IFNL4 favourable) n = 6; Group 2: IFNL3 CT or TT and IFNL4 TT/TT (IFNL3 unfavourable and IFNL4 favourable) n = 11; Group 3: IFNL3 CT or TT and IFNL4 TT/ΔG or ΔG/ΔG (IFNL3 and IFNL4 unfavourable) n = 11. The results are expressed as ratio to beta-actin, after subtraction of values from unexposed cultures (median, IQR).
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4326132&req=5

pone.0117397.g003: Levels of IFNAR-1 mRNA in PBMC from the HCV-infected naïve subjects after 3h of exposure to 103 IU/ml IFN-alpha2b in vitro, according to their IFNL3 and IFNL4 genotype combinations.Group 1: IFNL3 CC and IFNL4 TT/TT (IFNL3 favourable, IFNL4 favourable) n = 6; Group 2: IFNL3 CT or TT and IFNL4 TT/TT (IFNL3 unfavourable and IFNL4 favourable) n = 11; Group 3: IFNL3 CT or TT and IFNL4 TT/ΔG or ΔG/ΔG (IFNL3 and IFNL4 unfavourable) n = 11. The results are expressed as ratio to beta-actin, after subtraction of values from unexposed cultures (median, IQR).
Mentions: To explore whether the differences in the levels of IFNAR-1 mRNA could lead to an increased response to exogenously administered IFN-alpha, PBMC from patients with the various genotype combinations were exposed to IFN-alpha and the induction of mRNA for IP10, as biomarker of IFN activity, was measured. The results, shown in Fig. 2 Panel B, indicate a gradient of IFN response among the groups in term of IP10 mRNA induction, that paralleled the levels of IFNAR-1 expressed before IFN-alpha treatment (Fig. 2 Panel A). In particular, the difference between Group 1 and Group 3 was highly significant [median: 37.28 (IQR: 33.53–38.37) vs 16.06 (IQR: 9.979–29.27); p = 0.0193]. IFNAR-1 mRNA levels were not significantly modified by IFN-alpha treatment (Fig. 3), reflecting the differences among groups observed at baseline.

Bottom Line: Single-nucleotide polymorphism in IFNL3 gene (rs12979860) predicts spontaneous and therapy-induced HCV clearance.Recently, a dinucleotide polymorphism, ss469415590 (TT or ΔG), has been discovered in the region upstream IFNL3 gene, which is in high linkage disequilibrium with rs12979860. ss469415590[ΔG] is a frameshift variant that creates a novel gene, designed IFNL4, encoding the interferon-lambda 4 protein (IFNL4).The aim of the present study was to extend the analysis of IFNAR-1 mRNA levels to the ss469415590 variants.

View Article: PubMed Central - PubMed

Affiliation: Laboratory of Virology, National Institute for Infectious Diseases "L. Spallanzani," Rome, Italy.

ABSTRACT
Single-nucleotide polymorphism in IFNL3 gene (rs12979860) predicts spontaneous and therapy-induced HCV clearance. In a previous study from our group PBMC from patients with favourable rs12979860 genotype showed higher levels of IFNAR-1 mRNA. Recently, a dinucleotide polymorphism, ss469415590 (TT or ΔG), has been discovered in the region upstream IFNL3 gene, which is in high linkage disequilibrium with rs12979860. ss469415590[ΔG] is a frameshift variant that creates a novel gene, designed IFNL4, encoding the interferon-lambda 4 protein (IFNL4). The aim of the present study was to extend the analysis of IFNAR-1 mRNA levels to the ss469415590 variants. Our results highlight that the difference of IFNAR-1 mRNA levels between favourable and unfavourable genotype combinations, at both rs12979860 and ss469415590 loci, is stronger than that observed for single polymorphisms at each locus. These findings suggest may represent the biological basis for the observed association between IFNL3 CC and IFNL4 TT/TT genotypes and favourable outcome of either natural HCV infection (clearance vs chronic evolution) or IFN-based therapy.

Show MeSH
Related in: MedlinePlus