The Genetics of Disease Progression and Treatment Response in Hepatitis C

丙型肝炎疾病进展和治疗反应的遗传学

• 批准号: 7734200
• 负责人: T. Jake Liang
• 金额: $ 46.61万
• 依托单位: NATIONAL INSTITUTE OF DIABETES AND DIGESTIVE AND KIDNEY DISEASES
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/7734200
• 关键词: Affect; Affinity; African American; Age; Alcohol consumption; Alleles; Antiviral Response; Binding; Binding Sites; Biological Assay; Candidate Disease Gene; Characteristics; Chronic; Chronic Hepatitis C; Clinical; Data; Disease Outcome; Disease Progression; Electrophoretic Mobility Shift Assay; Exhibits; Fibrosis; Frequencies; Gender; Genes; Genetic; Genetic Markers; Genetic Polymorphism; Genetic Variation; Genotype; Haplotypes; Hepatitis C; Hepatitis C virus; Hereditary Disease; IFNAR1 gene; IRF1 gene; Infection; Interferon Type II; Interferon-alpha; Interferons; Interleukin-10; Lead; Link; Liver Cirrhosis; Liver Fibrosis; Liver diseases; Logistic Regressions; Methods; Modeling; Myxovirus; Nuclear; Patients; Pattern; Persons; Play; Population; Positioning Attribute; Primary carcinoma of the liver cells; Promoter Regions; Race; Recovery; Resistance; Ribavirin; Role; STAT1 gene; STAT2 gene; Single Nucleotide Polymorphism; Statistically Significant; Structure; Transforming Growth Factors; Validation; Variant; Viral; Virus; base; caucasian American; cohort; day; eIF-2 Kinase; genetic variant; intravenous drug user; peginterferon alfa-2a; promoter; response; treatment duration

Previously we performed a comprehensive analysis of interferon (IFN)-gamma gene polymorphisms for association with IFN-alfa induced and spontaneous recovery from hepatitis C virus (HCV) infection. We genotyped eight single nucleotide polymorphisms (SNPs) spanning the entire IFN-gamma gene in two cohorts and assessed the association between those polymorphisms and treatment response or spontaneous viral clearance. The first cohort was composed of 284 chronic HCV-infected patients who had received IFN-alfa based therapy and the second was 251 intravenous drug users who had either spontaneously cleared HCV or become chronically infected. A SNP variant located in the proximal IFN-gamma promoter region, -764G, was significantly associated with sustained virological response (SVR) P0.01, OR2.7 (1.3-5.6). The association was independently significant in multiple logistic regression (P 0.04) along with race, viral titer and genotype. This variant was also significantly associated with spontaneous recovery P0.04, OR3.51(1.0-12.5) in the second cohort. In the promoter assay, the -764G IFN-gamma promoter variant had a two- to three-fold higher activity than the common -764C. Electrophoretic mobility shift assay demonstrated that this SNP is located in a specific binding site of a yet-unidentified nuclear factor and the binding affinity was significantly higher with the G than the C allele. Our study suggests that the SNP at position -764 of the IFN-gamma promoter is functionally important in determining viral clearance and treatment response and may be used as a genetic marker to predict SVR in HCV-infected patients. Other candidate genes, including myxovirus resistance-1 (Mx1), protein kinase (PKR), transforming growth factor-?1 (TGFb), interleukin-10 (IL10) and interferon-? (IFNG), were evaluated for associations with liver fibrosis in 374 treatment-naive patients with genotype-1 chronic hepatitis C virus (HCV) infection (194 Caucasian Americans (CAs) and 180 African Americans (AAs)), using a genetic haplotype approach. Among the 14 haplotypes that occurred with a frequency ?10% in the cohort overall, the Mx1-(-123C)-(+6886A)-(+19820G(379V))-(+38645T) (abbreviated Mx1-CAGT), and PKR-(+110T)-(+7949G)-(+13846A)-(+22937T)-(+40342T) (abbreviated PKR-TGATT) haplotypes were independently associated with less severe hepatic fibrosis (Ishak ? 3 vs <3). These associations persisted after adjustment for potential confounders such as alcohol use, gender, age (which is strongly correlated with the estimated duration of HCV infection (Spearmans correlation coefficient (rs)=0.6)), and race (for Mx1-CAGT: OR=0.33; 95%C.I.: 0.16-0.68; p=0.0027; and for PKR-TGATT: OR=0.56; 95%C.I.:0.32-0.98; p=0.0405). Population structure was evaluated using the structured association method using data from 161 ancestry-informative markers and did not affect our findings. We utilized an independent cohort of 34 AA and 160 CA to validate our findings. We did not observe similar associations for these haplotypes and fibrosis in the validation set, although there were notable differences in the characteristics of both patients groups. In summary, we did not observe replicated associations for haplotypes in Mx1 and PKR and fibrosis in patients with genotype-1 chronic hepatitis C. 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 days 1, 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.

此前，我们对干扰素 (IFN)-γ 基因多态性进行了全面分析，分析其与 IFN-α 诱导的丙型肝炎病毒 (HCV) 感染自发恢复的关系。我们对两个队列中跨越整个 IFN-gamma 基因的 8 个单核苷酸多态性 (SNP) 进行了基因分型，并评估了这些多态性与治疗反应或自发病毒清除之间的关联。第一个队列由 284 名接受过 IFN-α 治疗的慢性 HCV 感染患者组成，第二个队列由 251 名静脉注射吸毒者组成，他们要么自发清除 HCV，要么成为慢性感染。位于近端 IFN-gamma 启动子区域 -764G 的 SNP 变异与持续病毒学应答 (SVR) P0.01、OR2.7 (1.3-5.6) 显着相关。该关联在多元逻辑回归中与种族、病毒滴度和基因型独立显着（P < 0.04）。该变异也与第二队列中的自发恢复 P0.04、OR3.51(1.0-12.5) 显着相关。在启动子测定中，-764G IFN-γ启动子变体的活性比常见的-764C高两到三倍。电泳迁移率变动分析表明，该 SNP 位于尚未鉴定的核因子的特异性结合位点，并且与 G 等位基因的结合亲和力明显高于与 C 等位基因的结合亲和力。我们的研究表明，IFN-gamma 启动子 -764 位的 SNP 在确定病毒清除和治疗反应方面具有重要的功能，并且可以用作预测 HCV 感染患者的 SVR 的遗传标记。 其他候选基因，包括粘病毒抗性-1 (Mx1)、蛋白激酶(PKR)、转化生长因子-α1 (TGFb)、白细胞介素-10 (IL10) 和干扰素-α (IFNG)，使用遗传单倍型方法对 374 名未经治疗的基因型 1 慢性丙型肝炎病毒 (HCV) 感染患者（194 名白种美国人 (CA) 和 180 名非裔美国人 (AA)）与肝纤维化的关联进行了评估。在整个队列中出现频率为 10% 的 14 个单倍型中，Mx1-(-123C)-(+6886A)-(+19820G(379V))-(+38645T)（缩写为 Mx1-CAGT），以及PKR-(+110T)-(+7949G)-(+13846A)-(+22937T)-(+40342T)（缩写 PKR-TGATT）单倍型与较不严重的肝纤维化独立相关（Ishak ? 3 vs <3）。在对潜在混杂因素进行调整后，这些关联仍然存在，例如饮酒、性别、年龄（与估计的 HCV 感染持续时间密切相关（Spearmans 相关系数 (rs)=0.6））和种族（对于 Mx1-CAGT：OR= 0.33；95%C.I.：0.16-0.68；p=0.0027；对于 PKR-TGATT：OR=0.56； 95%C.I.：0.32-0.98；p=0.0405)。使用来自 161 个祖先信息标记的数据，使用结构化关联方法评估种群结构，并且不会影响我们的研究结果。我们利用由 34 名 AA 和 160 名 CA 组成的独立队列来验证我们的研究结果。尽管两个患者组的特征存在显着差异，但我们在验证集中没有观察到这些单倍型与纤维化的类似关联。总之，我们没有观察到基因 1 型慢性丙型肝炎患者中 Mx1 和 PKR 的单倍型与纤维化的重复关联。 在使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，病毒的早期和快速下降是持续病毒学应答 (SVR) 的重要预测指标。 干扰素刺激基因 (ISG) 在 HCV 抗病毒反应中发挥重要作用。 这项研究探讨了 ISG 变异是否与治疗前 28 天病毒水平下降有关。 使用线性混合模型，在 180 名非裔美国人和 194 名白种人美国基因 1 HCV 感染患者中使用线性混合模型检查了 16 个 ISG 的单核苷酸多态性与病毒下降动态之间的关联，这些患者接受聚乙二醇化干扰素 α-2a 和利巴韦林治疗。 在治疗前以及第 1、2、7、14 和 28 天获得病毒水平。按种族分别进行分析。 在 MX2、OASL、STAT1 和 STAT2 中观察到统计学上显着的多态性 (p<0.05)，但在种族组中观察到不同的下降模式。 在两个种族组中观察到 IFNAR1、IRF1、MX1、OAS3 和 PKR 变异体的病毒水平下降模式相似，但不具有统计学意义。 一些 ISG 的基因变异与 28 天病毒水平下降有关，但病毒水平下降的模式因种族而异。 这些结果表明，某些 ISG 多态性可能在 28 天病毒下降中发挥作用。