The Genetics of Disease Progression and Treatment Response in Hepatitis C

慢性丙型肝炎病毒（HCV）感染影响全球近1.7亿人。用聚乙二醇化干扰素- α -2a治疗HCV仅能成功根除30%-80%的患者体内的病毒。白细胞介素-6 （IL-6）是一种重要的细胞因子，参与对感染因子的免疫反应，体外研究表明，宿主遗传变异，特别是单倍型，可能影响IL-6的表达。我们研究了IL-6基因单倍型对慢性HCV感染治疗的持续病毒反应（SVR）的贡献。我们观察到IL-6 T-T-G-G-G-G-C-A-G-A单倍型与高加索美国人（CAs）实现SVR的较低风险相关(RR=0.80; 95% ci。： 0.66- 0.98；p = 0.0261)。使用滑动窗口方法，rs1800797-(G)-rs1800796-(G)-rs1800795-(G)单倍型与SVR发生率降低相关（RR=0.79; 95% ci）。: 0.66 - -0.94;p=0.0081), rs1800796-(G)-rs1800795-(G)-rs2069830-(C)单倍型也是如此(RR=0.78; 95%C.I。: 0.66 - -0.94;p=0.0065)。总体而言，校正潜在混杂因素后，rs1800797-(G)-rs1800796-(G)-rs1800795-(G)单倍型与SVR发生率降低独立相关（RR=0.78; 95% ci: 0.62-1.0; p=0.0489）。我们的研究结果进一步说明了IL-6基因调控的复杂性以及单倍型对IL-6表达的潜在重要性。我们的发现为IL-6基因遗传变异的潜在重要性和对HCV治疗的反应提供了额外的支持。

Chronic hepatitis C virus (HCV) infection affects nearly 170 million individuals worldwide. Treatment of HCV with pegylated interferon-alfa-2a is successful in eradicating virus from only 30%-80% of those treated. Interleukin-6 (IL-6) is an important cytokine involved in the immune response to infectious agents and in vitro studies suggest that host genetic variation, particularly haplotypes, may affect IL-6 expression. We examined the contribution of haplotypes in the IL-6 gene on sustained viral response (SVR) to therapy for chronic HCV infection. We observed the IL-6 T-T-G-G-G-G-C-A-G-A haplotype to be associated with a lower risk of achieving SVR among Caucasian Americans (CAs) (RR=0.80; 95%C.I.: 0.66- 0.98; p=0.0261). Using a sliding window approach, the rs1800797-(G)-rs1800796-(G)-rs1800795-(G) haplotype was associated with a reduced chance of SVR (RR=0.79; 95%C.I.: 0.66-0.94; p=0.0081), as was the rs1800796-(G)-rs1800795-(G)-rs2069830-(C) haplotype (RR=0.78; 95%C.I.: 0.66-0.94; p=0.0065) among CAs. Overall, the rs1800797-(G)-rs1800796-(G)-rs1800795-(G) haplotype was independently associated with a reduced chance of SVR (RR=0.78; 95% C.I.: 0.62-1.0; p=0.0489) after adjustment for potential confounding factors. Our findings further illustrate the complexity of IL-6 genetic regulation and the potential importance of haplotypes on IL-6 expression. Our findings provide additional support for the potential importance of genetic variation in the IL-6 gene and the response to HCV therapy. . Early and rapid viral decline during the first 28 days of treatment for chronic hepatitis C virus (HCV) with pegylated interferon and ribavirin therapy is an important predictor of sustained virologic response (SVR). Interferon stimulated genes (ISGs) play an important role in the antiviral response to HCV. This study examines whether ISG variants are associated with viral level decline during the first 28 days of treatment. The association between single nucleotide polymorphisms in 16 ISGs and the dynamics of viral decline was examined in 180 African American and 194 Caucasian American patients with genotype-1 HCV infection treated with pegylated interferon alpha-2a and ribavirin using linear mixed models. Viral levels were obtained prior to treatment and at days1, 2, 7, 14 and 28. Analyses were conducted separately by race. Statistically significant (p<0.05) polymorphisms were observed in MX2, OASL, STAT1 and STAT2, but different patterns of decline were observed in the race groups. Similar viral level decline patterns were observed in both race groups for variants in IFNAR1, IRF1, MX1, OAS3 and PKR, but were not statistically significant. Genetic variants in some ISGs were associated with 28 day viral decline, but patterns of viral level decline differed by race. These results indicate that some ISG polymorphisms may play a role in the 28 day viral decline. Recent genome-wide association studies have shown that genetic polymorphisms in the IL28 gene are highly associated with viral clearance and treatment response. Furthermore variations in the inosine triphosphate pyrophosphatase (ITPA) gene have also been closely linked to ribavirin-induced anemia in other GWAS studies. We are genotyping our patient populations to further explore this genetic linkage and understand the functional relationship of these associations.