Association Of Chemokine CC Subfamily Gene Polymorphisms With HCV Spontaneous Clearance And Treatment Response

Section 1 Genetic variants in chemokine CC subfamily gene influence HCV spontaneous clearance[Background] The chemokine CC subfamily gene polymorphisms may be associated with spontaneous clearance of HCV infection.This study aims to explore the relationship between chemokine CCR1,CCR5,CCL3,CCL4,CCL5,CCL8 and CCL15 gene polymorphisms and hepatitis C virus(HCV)spontaneous clearance and provide a scientific basis for the control of HCV infection.[Methods] A total of 1592 subjects were recruited from hemodialysis patient,injecting drug users and paid blood donors into this case-control study,596 were spontaneous clearance patients and 996 were persistent infection patients.Taqman-MGB probe technique was used to genotype CCR1 rs3733096,rs13096371,CCR5 rs746492,rs1800874,CCL3 rs1130371,rs1063340,CCL4 rs1049807,CCL5 rs3817656,CCL8 rs113376 and CCL15 rs854625 polymorphisms to evaluate their association with spontaneous clearance of HCV infection.[Results] Patients carrying the mutant CCR1 rs3733096-G allele(dominant model: adjusted OR = 2.29,95% CI = 1.49-3.53,P <0.001);additive model: adjusted OR = 2.21,95% CI = 1.50-3.25,P <0.001)and carrying the mutant CCL5 rs3817656-C allele(dominant model: adjusted OR = 1.37,95% CI = 1.10-1.70,P = 0.005;additive model: adjusted OR = 1.33,95% CI = 1.12-1.58,P = 0.001)were more likely to become persistent infection.The Cochran-Armitage trend test for the combined effect analysis of unfavorable CCR1 rs3733096-G and CCL5 rs3817656-C alleles with HCV spontaneous clearance showed an increased risk of persistent infection when carrying more unfavorable alleles(OR = 1.34,95% CI = 1.07-1.69;OR = 1.93,95% CI = 1.31-2.84;OR = 8.89,95% CI = 2.09-37.93),trend test P <0.001.Stepwise regression analysis showed that rs3733096,rs3817656,age,and aspartate transaminase(AST)were independent factors of HCV persistent infection.The area under the receiver-operating characteristic(ROC)of these 4 variables was 0.6823.Quantitative trait locus analysis(e QTL)showed that the mutation of CCL5 rs3817656 was significantly associated with the decreased expression of CCL5 in whole blood(P = P = 5.9×10-4).[Conclusion] CCR1 rs3733096-G and CCL5 rs3817656-C alleles are risk factors for spontaneous clearance of HCV infection.Rs3733096,rs3817656,age and AST are independent risk factors for persistent HCV infection.CCL5 rs3817656 may affect the transcriptional regulation of CCL5 gene.Section 2 Genetic variants in chemokine CC subfamily gene influence HCV treatment response[Background] Chemokines are involved in the important process of immune response,and their genetic polymorphisms may be related to the treatment response of interferon in patients with chronic hepatitis C(CHC).This study aims to explore the relationship between the chemokines CCR1,CCR5,CCL3,CCL4,CCL5,CCL8 and CCL15 gene polymorphisms and treatment response of CHC patients,and to provide basis for the clinical treatment of HCV infection.[Methods] This study enrolled 360 CHC patients who completed 48 weeks of treatment and were followed up for 24 weeks.Information of HCV viral load and correlate parameters were collected at baseline,treatment week 4,12,24,48,and 24 weeks after treatment.Taqman-MGB probe technique was used to genotype the 10 SNPs of CCR1 rs3733096,rs13096371,CCR5 rs746492,rs1800874,CCL3 rs1130371,rs1063340,CCL4 rs1049807,CCL5 rs3817656,CCL8 rs113376 and CCL15 rs854625 to assess their relationship with treatment response of HCV infection.[Results] CCL3 rs1063340,CCL4 rs1049807 polymorphisms were associated with sustained virological response(SVR).Patients carrying CCL3 rs1063340-C allele(dominant model: adjusted OR = 0.56,95% CI = 0.35-0.90,P = 0.016)and CCL4 rs1049807-G allele(dominant model: adjusted OR = 0.60,95% CI = 0.38-0.96,P = 0.033)were less likely to obtain SVR.The Cochran-Armitages trend test for the combined effect analysis of unfavorable CCL3 rs1063340-GT/TT and CCL4 rs1049807-AG/GG genotypes showed an increased risk of treatment failure when carrying more unfavorable genotypes,trend test P = 0.038.Patients carrying rs1063340-GT/TT and rs1049807-AG/GG genotypes had lower virus-negative rates than those carrying wild genotypes.The results of e QTL showed that the mutation genotype of rs1049807 was significantly correlated with the up-regulation of CCL4 both in whole blood(P = 3.5 × 10-8)and in liver tissue(P = 0.036).[Conclusion] CCL3 rs1063340-C and CCL4 rs1049807-G alleles are risk factors for SVR in patients with CHC treated with pegylated interferon(PEG-IFN)combined with ribavirin(RBV).CCL4 rs1049807 may affect the transcriptional regulation of CCL4 gene.