| Chronic hepatitis C(CHC) remains a major health burden that affects about 130-150 million people worldwide. As a main cause of cirrhosis and hepatocellular carcinoma, it leads to 350,000 to 500,000 deaths each year. HCV causes both transient and persistent infection,and approximately 70–80% of HCV infection becomes chronic. Treatment of chronic hepatitis C(CHC) has evolved with advances in antivirals, and peg-interferon-alpha/ribavirin(peg-IFN-α/RBV) therapy remains a standard regimen in many countries due to limited access to direct acting antivirals(DAAs). A sustained viral response(SVR) is a desirable end point of antiviral treatment, which may slow down or reverse the progression of fibrosis,prevent hepatitis C-related complications and improve survival. Apart from viral factors(viral load, viral co-infections, HCV genotype) and host factors(older age, male gender, ethnicity,insulin resistance, cirrhosis, and IL28 B rs12979860 CC genotype), peg-IFN-α/RBV therapy is often poorly tolerated and interrupted because of RBV-induced hemolytic anemia and IFN-induced thrombocytopenia. Therefore, we can adjust and develop the best treatment regimen before antiviral therapy by using several biomarker candidates to evaluate and predict clinical manifestatuions, such as liver fibrosis and treatment induced side effects, and antiviral outcomes.Those genetic factors involved in our research were: solute carriers(SLCs), Kruppel-like factor(KLF12), cannabinoid receptor 2(CNR2), and vitamin D related gene polymorphisms.Previous studies reported that some of SLC genes could encode a main protein involved in cell uptake of RBV and were associated with liver diseases, and KLF12 may affects the βchain of hemoglobin thus leads to hemolytic anemia. Vitamin D deficiency is known to be associated with the outcomes of IFN-α2b/RBV therapy, as well as with the presence of severeliver fibrosis, in CHC patients. Vitamin D related gene polymorphisms are metabolically active in the vitamin D pathway and are reported to have predictive effects on liver fibrosis and treatment responses. CNR2 gene encodes the cannabinoid 2 receptor, which has hepatoprotective properties in alcoholic and nonalcoholic fatty liver diseases. A variant that substitutes glutamine(Q) 63 with arginine(R) in CNR2 rs35761398 compromises the function of the CB2 receptor. Researchers found that this polymorphism was associated with hepatic inflammation in CHC and chronic hepatitis B patients, no available data about impacts on antiviral treatment responses.Thus our whole study can be divided into three parts due to different influential mechanism and affect area of these single nucleotide polymorphisms(SNPs).1. Antiviral treatment response and treatment-induced cytopenia correlate with SLCs and KLF12 genotypes in CHC patients:This part was mainly focused on possible correlations of SLC4A11 rs3810560, SLC16A9rs12356193, SLC29A1 rs760370 and KLF12 rs9543524 polymorphisms with viral clearance(spontaneous and treatment-induced) and adverse effects in CHC patients.We genotyped the SNPs by a matrix-assisted laser desorption ionization time of flight mass spectrometry(MALDI-TOF-MS) method in 525 northern Chinese CHC patients, 137 patients with spontaneous clearance(SHC), and 207 healthy controls(HCs). Cross-sectional study was carried out in all 869 individuals for differences of genotype distributions among three groups. 357 CHC patients received standard dual therapy of subcutaneous injection of recombinant IFN-α2b(5 MU, 3 times/week) and oral RBV(800 mg/day for < 60 kg body weight, 1000 mg/day for 60–75 kg, and 1200 mg/day for > 75 kg) for 48 weeks and then were followed up for 24 weeks. Patients with treatment adherence > 80% were included in the curative effect analysis. And 175 patients were chosen for analysis of drug-induced cytopenia. Blood tests were collected at baseline and 2, 4, 12, 24, 36, 48, and 72 weeks after therapy for hematologic tests, biochemical assays and viral markers. Fibro Scan examinations were performed to evaluate stage of liver fibrosis. All raw P values by Pearson Chi-square tests of SNPs were corrected by the Bonferroni method before multivariate logistic regression analyses.Results of this part are as follows:A higher rate of sustained viral response(SVR) was detected in patients with SLC4A11rs3810560 CC variant versus TT/TC variant(76.9% vs. 59.2%; OR, 2.42; 95% CI, 1.06–5.56,P = 0.037 after adjustment), but there was no significant difference among different HCV genotypes. RBV-induced anemia was independently correlated with SLC29A1 rs760370 AA genotype(OR, 2.90; 95% CI, 1.29–6.54, P = 0.010), and the severity of IFN-induced thrombocytopenia was related to GG genotype(OR, 4.98; 95% CI, 1.27–19.61; P = 0.021);the detected effects held true for HCV-2a patients, but weakened in HCV-1b patients. A reactive increase in platelet count was closely associated with KLF12 rs9543524 TT variant(OR, 4.44; 95% CI, 1.45–13.70; P = 0.009).2. Roles of vitamin D related gene polymorphisms on treatment outcomes and liver fibrosis:This part aimed to assess whether GC rs7041 and rs222020, CYP2R1 rs10741657,DHCR7 rs12785878 polymorphisms are associated with liver fibrosis and outcomes of combined therapy in CHC patients.Here 522 CHC patients(354 CHC patients who received antiviral therapy were selected in the curative effect analysis and 321 in analysis of hepatic fibrosis), 137 SHC individuals,and 210 HCs were included. Cross-sectional study was carried out in all 869 individuals for differences of genotype distributions among three groups. Statistical analysis methods were as mentioned previously.Results of this part are as follows:Patients with GC rs222020 TC genotype had higher end of treatment viral response rates compared to those with genotype TT or CC(86.2% vs. 72.1% vs. 64.5%, P = 0.004). After adjustment, GC rs222020 TC genotype was found to predict ETVR independently(TC vs. TT,OR, 2.94; 95% CI, 1.43–5.88, P = 0.003; TC vs. TT/CC, OR, 3.13; 95% CI, 1.56–6.25, P =0.001), as were baseline HCV viral load, neutrophil counts, and baseline Fibro Scan score.Similar phenomenon occurred in 160 HCV-1b patients(TC vs. TT, OR, 5.26; 95% CI,1.85–14.29, P = 0.002; TC vs. CC, OR, 33.33; 95% CI, 3.70–500, P = 0.002; TC vs. TT/CC,OR, 5.88; 95% CI, 2.17–16.67, P < 0.001 after adjusted). Furthermore, patients with GCrs222020 TC genotype were more likely to have moderately severe fibrosis(≥ 7.3 k Pa)(OR,2.05; 95% CI, 1.14–3.69; P = 0.016 in all genotype group; OR, 3.54; 95% CI, 1.48–8.46, P =0.004 in the HCV 1b group).3. Impact of CB2-63 varaints on therapeutic response and hepatic fibrosis:We aimed to investigate the involvement of CNR2 rs35761398(CB2-63) variants in the course of CHC and patient responses to antiviral therapy.Genotyping of CB2-63 was performed in 359 northern Chinese CHC patients who received 48 weeks of antiviral therapy(cohort study on variation trends of clinical indicators during therapy and treatment outcomes), and 212 of them underwent Fibro Scan examination at baseline and at the end of treatment.Results of this part are as follows:Patients with the QQ genotype had a higher frequency of rapid viral response(RVR)(OR, 2.42; 95% CI, 1.13–5.18, P = 0.023 in all genotype group; OR, 4.41; 95% CI,1.02–18.87, P = 0.047 in HCV-2a group), and they also persistently showed higher platelet counts and triglyceride levels than the other genotypes during the investigation period(P <0.05). On the other hand, patients with the QQ/QR genotype had a lower frequency of moderately severe fibrosis(F2, ≥7.3 k Pa) at the end of treatment(OR, 5.94; 95% CI,1.61–21.85, P = 0.007 in all genotype group; OR, 3.97; 95% CI, 1.71–9.24, P = 0.001 in the HCV 1b group).Together, conclusions of our study were:(1) Those gene polymorphisms in our syudy showed no correlation with spontaneous clearence and HCV infection.(2) SLC4A11 rs3810560 polymorphism independently affected the SVR rates in CHC patients, whereas SLC29A1 rs760370 and KLF12 rs9543524 SNPs correlated with treatment-induced adverse events.(3) Our results supported the potential contribution of the GC rs222020 TC genotype to successful treatment outcomes, as well as the genotype’s value, in predicting the degree of liver fibrosis.(4) The CB2-63 genotype appeared to impact the RVR to antiviral therapy as well as theplatelet count and the extent of liver fibrosis in the recombined IFN-α2b/RBV-treated CHC patients. |
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