Genetic Polymorphisms Analysis Of Genes In IL6 Signaling Pathway In HCV-infected Persons From Yunnan Province

Hepatitis C virus(HCV)was one of the main causes of serious liver diseases.Recently,due to large population and lack of effective screening and treatment,the numbers of HCV-infected persons increased in China.Yunnan province was located in Southwest China and adjacent to the "Golden Triangle" region,so the persons with HCV infection were much more than that of other provinces.So it was more important to prevent and treat HCV-infected persons in Yunnan,Although the studies of HCV infected and pathogenic mechanisms were much more,the complete causes were not clearly understood.However,with the rapid development and application of genomic analysis,it was widely proved that host genetic factors participated in virus infection,self-clearance,and treatment.So to study the genes in IL6 signaling pathway could help us further understand HCV infected and pathogenic mechanisms.In this study,we analyzed genotypes and alleles of genetic polymorphisms in genes of IL6 signaling pathway in HCV-infected persons and matched general controls from Yunnan Province,and then the association between genotypes of these genetic variations and biochemical characteristics was studied.The results identified the association between genetic variations of genes in IL6 signaling pathway and HCV-infection and/or biochemical characteristics of HCV-infected persons.At the same time,we identified that HCV-infection could changed the expression level of these proteins in IL6 signaling pathway in cell assay.Firstly,we collected 394 HCV infected persons and 395 ethnic and gender matched controls to genotype 26 single nucleotide polymorphisms(SNPs)(including tagSNPs and SNPs in functional regions)of 6 genes(STAT3t HNF4a,HNF1α,IL6,IL6R and MRP2)in IL6 signaling pathway.The results showed that HCV infection in Yunnan is associated with genetic variations of genes in IL6 signaling pathway.The frequency of genotype GG of SNP rs3212172 in the HNF4a gene(P=0.029)and genotype AA of SNP rs4075015(P=0.03)and genotype CC of SNP rs7553796(P=1.504×10-7)in the IL6R gene were significantly higher than that in controls.Genotypes of these three SNPs might play risk factors in HCV-infection.The frequency of genotype AT of SNP rs4075015(P=0.007)and genotype AA of SNP rs7553796(P=0.001)in the IL6R gene were statistically lower in HCV-infected persons than that of controls,so the persons with these two genotypes might be protected from HCV-infection.In addition,we grouped the HCV-infected persons by genotypes of SNPs,then analyzed whether there were association between the biochemical characteristics and genetic variations of HCV-infected persons.Analysis results confirmed that the GGT level were significantly higher in HCV-infected persons with genotype GT of SNP rs1169309 in the HNF1α gene(P=0.0415)and genotype AG of rs1053023 in the STAT3 gene(P=0.0125)than that of persons with genotype TT of SNP rs 1169309 and genotype AA of rs1053023,respectively.ALB level in HCV-infected persons with genotype CC expression of SNP rs2069840,genotype AA of SNP rs2069852,genotype TT of SNP rs1524107 in the IL6 gene and genotype AA of SNP rs 1885301,genotype GG of SNP rs2804402,genotype AA and AG of SNP rs717620 were significantly higher than that of persons with genotype CG&GG of SNP rs2069840(P=0.014),genotype AG(P=0.0151)and GG(P=0.0059)of SNP rs2069852,genotype CT of SNP rs1524107(P=0.0061),genotype AG(P=0.0043)and genotype GG(P=0.0145)of SNP rs1885301,genotype AA(P=0.0151)and AG(P=0.0039)of SNP rs2804402,and genotype GG of SNP rs717620(AA v.s.GG,P=0.0469;AG v.s.GG,P=0.0231).ALB level in HCV-infected persons with genotype AG of SNP rs1885301 and genotype AG of SNP rs12826 in the MRP2 gene was higher than that of persons with genotype GG of SNP rs1885301(P=0.0333)and genotype GG of SNP rs12826(P=0.0431).We detected mRNA and protein expressing level of these six genes in IL6 signaling pathway in HCV infected Huh7.5.1 cell lines.The expression level of mRNA and proteins in these genes seemed coincident:expression level of HNF4a increased in 24 hours and decreased in 48 hours and 72 hours after HCV-infection;expression level of IL6,HNF1α and STAT3 continued to increase with time after HCV-infection;but expression level of IL6R declined with time after HCV-infection.All these results showed that HCV-infection could change the expression level of six proteins in IL6 signaling pathway.Taken together,the genetic variations of six genes in IL6 signaling pathway were associated with HCV-infection and/or biochemical characteristics of HCV-infected persons.At same time,HCV-infection could change the expression of these genes.These results meant genes in IL6 signaling pathway could influence HCV-infection in both genetic and functional aspects.This study provided theoritical basis on prevention,new drugs research,and individualized therapy for HCV-infected persons in Yunnan.