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.

以前，我们对干扰素（IFN）-Gamma基因多态性进行了全面分析，以与IFN-ALFA诱导的IFN-ALFA相关，并自发从丙型肝炎病毒（HCV）感染中自发恢复。我们基因分型跨越了两个队列中的整个IFN-gamma基因，并评估了这些多态性与治疗反应或自发病毒清除率之间的关联。第一个队列由284例接受基于IFN-ALFA治疗的慢性HCV感染患者组成，第二个是251名静脉注射吸毒者，他们自发清除HCV或长期感染了HCV。位于IFN-GAMMA启动子区域-764G的SNP变体与持续的病毒学反应（SVR）P0.01，OR2.7（1.3-5.6）显着相关。该关联在多个逻辑回归（p 0.04）以及种族，病毒滴度和基因型中具有独立性。该变体也与第二个队列中的自发恢复P0.04，OR3.51（1.0-12.5）显着相关。在启动子测定中，-764g IFN-GAMMA启动子变体的活性比常见-764C高两到三倍。电泳迁移率转移分析表明，该SNP位于尚未确定的核因子的特定结合位点，与G相比，结合亲和力明显高于C等位基因。我们的研究表明，IFN-GAMMA启动子的位置-764的SNP在确定病毒清除和治疗反应方面在功能上很重要，并且可以用作预测HCV感染患者SVR的遗传标记。 其他候选基因，包括粘菌病毒抗性-1（MX1），蛋白激酶（PKR），转化生长因子 - ？1（TGFB），白介素-10（IL10）和Interferon-？ （IFNG）在374例未接受基因型1慢性丙型肝炎病毒（HCV）感染的治疗患者中评估了肝纤维化的关联（194名高加索美国人（CAS）和180名非裔美国人（AAS）），使用遗传单型方法。在总体上出现频率为10％的14个单倍型中，MX1 - （-123C） - （+6886a） - （+19820g（379V）） - （+38645t）（+38645t）（缩写MX1-CAGT）和MX1-CAGT）和PKR - （+110T） - （+7949G） - （+13846a） - （+22937T） - （+40342T）（缩写PKR-TGATT）单倍型与较低的肝纤维化独立相关（Ishak？ishak？3 vs <3）。调整了潜在混杂因素，例如饮酒，性别，年龄（与HCV感染的估计持续时间密切相关（Spearmans相关系数（RS）= 0.6））和种族（MX1-CAGT：OR = 0.33; 95％C.I。for. 95％C.I。per.d.0.16-gr = 0.0027; psr; OR = 0.56; 95％C.I。：0.32-0.98;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，并不影响我们的发现。我们利用了34个AA和160 CA的独立队列来验证我们的发现。我们没有在验证集中观察到这些单倍型和纤维化的相似关联，尽管两组的特征存在显着差异。总而言之，我们没有观察到基因型1-1慢性肝炎患者的MX1和PKR和PKR中的单倍型的复制关联。 在治疗的前28天，早期和快速的病毒下降用于慢性丙型肝炎病毒（HCV），使用pe乙酸干扰素和利巴韦林治疗是持续病毒学反应（SVR）的重要预测指标。 干扰素刺激的基因（ISGS）在抗病毒对HCV的反应中起重要作用。 这项研究检查了治疗的前28天，ISG变体是否与病毒水平下降有关。 在180名非裔美国人和194名高加索裔美国人患有基因型-1 HCV感染中，使用线性混合模型在180名非裔美国人患有基因型-1 HCV感染和194例基因型-1 HCV感染的白种裔美国人患者中，检查了16个ISG中的单核苷酸多态性和病毒下降的动力学之间的关联。 在治疗前，在第1、2、7、14和28天获得病毒水平。通过种族分别进行分析。 在MX2，OASL，STAT1和STAT2中观察到具有统计学意义（P <0.05）的多态性，但在种族组中观察到了不同的下降模式。 在IFNAR1，IRF1，MX1，OAS3和PKR中的两个种族组中，在两个种族组中都观察到了类似的病毒水平下降模式，但在统计学上并不显着。 某些ISG中的遗传变异与28天的病毒下降有关，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天的病毒下降中起作用。