Genetic variation in IL28B and spontaneous clearance of hepatitis C virus.
Genetic variation in IL28B and spontaneous clearance of hepatitis C virus.
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丙型肝炎病毒 (HCV) 感染是美国最常见的血源性感染，估计美国有 400 万 HCV 感染者，全球有 1.7 亿人感染 HCV。大多数（70%–80%）HCV 感染持续存在，约 30% 持续感染的个体会发展为慢性肝病，包括肝硬化和肝细胞癌。流行病学、病毒和宿主因素与 HCV 清除或持久性的差异有关，研究表明，针对 HCV 的强烈宿主免疫反应有利于病毒清除。因此，参与免疫反应的基因的变异可能有助于清除病毒的能力。在最近的一项全基因组关联研究中，编码 III 型干扰素 IFN-λ3 的 IL28B 基因上游 3kb 的单核苷酸多态性 (rs12979860) 被证明与 HCV 药物治疗反应超过 2 倍的差异密切相关。为了确定自然史背景下 rs12979860 变异对 HCV 感染结果的潜在影响，我们在由自发清除病毒 (N = 388) 或持续感染 (N = 620) 的个体组成的 HCV 队列中对这种变异进行了基因分型。我们表明，C/C 基因型极大地增强了欧洲和非洲血统个体中 HCV 感染的解决率（欧洲：OR = 0.38，p = 10−7；非洲：OR = 0.32，p = 10−4；组合：OR = 0.33，p <10−12）。迄今为止，这是与 HCV 自然清除相关的最强且最显着的遗传效应，这些结果表明 IL28B 在解决 HCV 感染中的主要作用。
Hepatitis C virus (HCV) infection is the most common blood borne infection in the U.S. with estimates of 4 million HCV-infected individuals in the U.S. and 170 million worldwide. The majority (70%–80%) of HCV infections persist and about 30% of individuals with persistent infection develop chronic liver disease, including cirrhosis and hepatocellular carcinoma. Epidemiological, viral, and host factors have been associated with the differences in HCV clearance or persistence and studies have demonstrated that a strong host immune response against HCV favors viral clearance. Thus, variation in genes involved in the immune response may contribute to the ability to clear the virus. In a recent genome-wide association study, a single nucleotide polymorphism (rs12979860) 3kb upstream of the IL28B gene, which encodes the type III interferon IFN-λ3, was shown to associate strongly with more than a 2-fold difference in response to HCV drug treatment. To determine the potential effect of rs12979860 variation on outcome to HCV infection in a natural history setting, we genotyped this variant in HCV cohorts comprised of individuals who spontaneously cleared the virus (N = 388) or had persistent infection (N = 620). We show that the C/C genotype strongly enhances resolution of HCV infection amongst individuals of both European and African ancestry (European: OR = 0.38, p = 10−7; African: OR = 0.32, p = 10−4; combined: OR = 0.33, p <10−12). To date, this is the strongest and most significant genetic effect associated with natural clearance of HCV, and these results implicate a primary role for IL28B in resolution of HCV infection.
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