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%的治疗患者的病毒。白细胞介素-6（IL-6）是参与对感染因子的免疫应答的重要细胞因子，并且体外研究表明宿主遗传变异，特别是单倍型，可能影响IL-6表达。我们研究了IL-6基因单倍型对慢性HCV感染治疗持续病毒应答（SVR）的影响。我们观察到IL-6 T-T-G-G-G-G-C-A-G-A单倍型与美国白人（CA）中实现SVR的风险较低相关（RR=0.80; 95%C.I.：0.66- 0.98; p=0.0261）。使用滑动窗口方法，rs 1800797-（G）-rs 1800796-（G）-rs 1800795-（G）单倍型与SVR机会降低相关（RR=0.79; 95%C.I.：0.66-0.94; p=0.0081），rs 1800796-（G）-rs 1800795-（G）-rs 2069830-（C）单倍型也是如此（RR=0.78; 95% C.I.：0.66-0.94; p=0.0065）。 总的来说，rs 1800797-（G）-rs 1800796-（G）-rs 1800795-（G）单倍型与SVR机会降低独立相关（RR=0.78; 95% C.I.：0.62-1.0; p=0.0489）。我们的研究结果进一步说明了IL-6基因调控的复杂性和单倍型对IL-6表达的潜在重要性。我们的研究结果为IL-6基因的遗传变异和对HCV治疗的反应的潜在重要性提供了额外的支持。 . 在用聚乙二醇干扰素和利巴韦林治疗慢性丙型肝炎病毒（HCV）的前28天内，早期和快速的病毒下降是持续病毒学应答（SVR）的重要预测因素。 干扰素刺激基因（Interferon stimulated genes，ISGs）在抗HCV应答中起重要作用。 这项研究检查了ISG变体是否与治疗前28天内的病毒水平下降相关。 采用线性混合模型，对180例非裔美国人和194例白人美国人基因型1型HCV感染患者进行了16个ISG单核苷酸多态性与病毒下降动力学之间的相关性研究，这些患者接受聚乙二醇干扰素α-2a和利巴韦林治疗。 在给药前和第1、2、7、14和28天获得病毒水平。 按人种单独进行分析。 在MX2、OASL、STAT 1和STAT 2中观察到统计学显著（p<0.05）多态性，但在种族组中观察到不同的下降模式。 在两个人种组中观察到IFNAR 1、IRF 1、MX 1、OAS 3和PKR变异体的病毒水平下降模式相似，但无统计学显著性。 一些ISG中的遗传变异与28天病毒下降相关，但病毒水平下降的模式因种族而异。 这些结果表明，一些ISG多态性可能在28天病毒下降中起作用。 最近的全基因组关联研究表明，IL 28基因的遗传多态性与病毒清除和治疗反应高度相关。此外，在其他GWAS研究中，肌苷三磷酸焦磷酸酶（ITPA）基因的变异也与利巴韦林诱导的贫血密切相关。我们正在对我们的患者群体进行基因分型，以进一步探索这种遗传连锁，并了解这些关联的功能关系。

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.