Association of gene expression involving innate immunity and genetic variation in IL28B with antiviral response

Innate immunity plays an important role in host antiviral response to hepatitis C viral(HCV)infection。Recently，single nucleotide polymorphism(SNP)of IL28B and host response to pegylated interferon·(PEG-IFN·)and ribavirin(RBV)were shown to be strongly associated.We aimed to determine the gene expression involving innate immunity in IL28B genotypes and elucidate its relation to response to antiviral treatment.We genotyped IL28B SNPs(Rs8099917 And Rs12979860)in88chronic hepatitis C patients treated with PEG-IFN·-2b/RBV and quantified expressions of viral sensors(RIG-I，MDA5，and LGP2)，adaptor molecule(IPS-1)，related ubiquitin E3-ligase(RNF125)，modulators(ISG15 And USP18)，and IL28(IFN·).Both IL28B SNPs were 100%identical；54patients possessed rs8099917TT/rs12979860CC(IL28B Major Patients)and 34possessed rs8099917TG/rs12979860CT(IL28B Minor Patients)。Hepatic expressions of viral sensors and modulators in IL28B minor patients were significantly up-regulated compared with that in IL28B major patients(~3.3fold，p&lt；0.001)。However，expression of IPS-1was significantly lower in IL28B minor patients(1.2fold，p=0.028)。Hepatic expressions of viral sensors and modulators were significantly higher in non-virological responders(NVR)than that in others despite stratification by IL28B genotype(~2.6fold，p&lt；0.001)。Multivariate and ROC analyses indicated that higher RIG-I and ISG15expressions and RIG-I/IPS-1expression ratio were independent factors for NVR。Conclusion：Gene expression involving innate immunity is strongly associated with IL28B genotype and response to PEG-IFN·/RBV.Both IL28B minor allele and higher RIG-land ISG15expressions and RIG-I/IPS-1ratio are independent factors for NVR。

Innate immunity plays an important role in host antiviral response to hepatitis C viral (HCV) infection. Recently, single nucleotide polymorphism (SNP) of IL28B and host response to pegylated interferon・(PEG-IFN・)and ribavirin (RBV) were shown to be strongly associated. We aimed to determine the gene expression involving innate immunity in IL28B genotypes and elucidate its relation to response to antiviral treatment. We genotyped IL28B SNPs (rs8099917 and rs12979860) in 88 chronic hepatitis C patients treated with PEG-IFN・-2b/RBV and quantified expressions of viral sensors (RIG-I, MDA5, and LGP2), adaptor molecule (IPS-1), related ubiquitin E3-ligase (RNF125), modulators (ISG15 and USP18), and IL28 (IFN・). Both IL28B SNPs were 100% identical ; 54 patients possessed rs8099917 TT/rs12979860 CC (IL28B major patients) and 34 possessed rs8099917 TG/rs12979860 CT (IL28B minor patients). Hepatic expressions of viral sensors and modulators in IL28B minor patients were significantly up-regulated compared with that in IL28B major patients (~3.3 fold, p<0.001). However, expression of IPS-1 was significantly lower in IL28B minor patients (1.2 fold, p=0.028). Hepatic expressions of viral sensors and modulators were significantly higher in non-virological responders (NVR) than that in others despite stratification by IL28B genotype (~2. 6 fold, p<0.001). Multivariate and ROC analyses indicated that higher RIG-I and ISG15 expressions and RIG-I/IPS-1 expression ratio were independent factors for NVR. Conclusion : Gene expression involving innate immunity is strongly associated with IL28B genotype and response to PEG-IFN・/RBV. Both IL28B minor allele and higher RIG-land ISG15 expressions and RIG-I/IPS-1 ratio are independent factors for NVR.