Effects of genetic polymorphism in MHC, KIR, and related loci on human disease

MHC、KIR及相关位点遗传多态性对人类疾病的影响

• 批准号: 8175343
• 负责人: Mary N. Carrington
• 金额: $ 118.54万
• 依托单位: DIVISION OF BASIC SCIENCES - NCI
• 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/8175343
• 关键词: Acquired Immunodeficiency Syndrome; Acute Hepatitis; Affect; Affinity; African; African American; Alleles; Animal Model; Antiviral Agents; Autoimmune Diseases; Binding; Blood; CD4 Lymphocyte Count; Caucasians; Caucasoid Race; Cervical; Chronic; Cirrhosis; Collaborations; Commit; Communicable Diseases; Communities; Cytotoxic T-Lymphocytes; Data; Dendritic Cells; Development; Disease; Disease Outcome; Disease Progression; Effector Cell; Employee Strikes; Epidemiology; European; Fetal Diseases; Frequencies; Functional disorder; Genes; Genetic; Genetic Determinism; Genetic Polymorphism; Genetic Variation; Genetic screening method; Genotype; Goals; Guinea-Bissau; HIV-1; HLA Antigens; Hepatitis B Virus; Hepatitis C; Hepatitis C virus; High Prevalence; Human; Immune Response Genes; Immune response; Immunity; Immunoglobulins; In Vitro; Individual; Infection; Inflammatory Bowel Diseases; Institutes; Integration Host Factors; Interferons; Killer Cells; Laboratories; Leukocytes; Life; Ligands; Link; Liver diseases; Macaca mulatta; Major Histocompatibility Complex; Malignant - descriptor; Malignant Neoplasms; Malignant neoplasm of cervix uteri; Nasopharynx Carcinoma; Natural Killer Cells; Nature; Neoplasms; Non-Hodgkin' s Lymphoma; Nuclear Pore Complex; Other Genetics; Outcome; Pathway interactions; Pharmaceutical Preparations; Population; Pre-Eclampsia; Predisposition; Primary carcinoma of the liver cells; Proteins; Psoriatic Arthritis; Reagent; Receptor Gene; Recovery; Research Personnel; Resistance; Resolution; Rewards; Risk; Role; SIV; Simian B disease; Single Nucleotide Polymorphism; Solid; Testing; Time; Transcript; Universities; Up-Regulation; Variant; Viral; Viral Load result; Virus; Virus Diseases; Wisconsin; Work; base; cohort; functional disability; genetic variant; genome wide association study; human disease; human leukocyte antigen gene; melanoma; novel; receptor; response; therapeutic vaccine; vector

The extensive variation at some of the immune response genes is central amongst the host genetic determinants that contribute to the variability in risk of virtually all human diseases. We have studied the genetic effects of the highly polymorphic KIR and HLA loci, as well as other related, less polymorphic loci on several diseases. Our contributions to the general understanding of these effects are summarized here. An estimated 4 million people in the US and 170 million people worldwide are infected with hepatitis C virus (HCV), which is the most common blood-borne infection in the U.S. The vast majority of HCV infections persist and one-third of those with persistent infection will develop chronic liver diseases such as cirrhosis and hepatocellular cancer. Several epidemiological, viral, and host factors have been shown to be associated with HCV clearance or persistence. Notably, a strong immune response to HCV favors viral clearance suggesting that genetic variation in immune response genes might contribute to the differential ability of individuals to clear the virus. A recent genome-wide association study (GWAS) identified a single nucleotide polymorphism (SNP), rs12979860, 3kb upstream of the IL28B gene, which was strongly associated with response to HCV drug treatment. Individuals with the C/C genotype at rs12979860 had a greater than 2-fold rate of sustained virological response (SVR) to HCV drug treatment compared to individuals with the T/T genotype. In order to determine the effects of this SNP on the natural clearance of HCV, we genotyped an existing HCV cohort, made up of people who spontaneously cleared the virus (388 people) or who had persistent infection (620 people). We found that individuals of both European and African ancestry with the C/C genotype were significantly more likely to spontaneously clear the virus. To date, this is the strongest and most significant genetic effect that has been found to associate with spontaneous resolution of HCV infection and points to a principal and fundamental role for IL28B in viral clearance. IL28B produces an antiviral state by triggering a cascade through the JAK-STAT pathway leading to upregulation of the interferon-stimulated genes (ISGs). The mechanism of how the rs12979860 SNP affects IL28B function and the immune response to HCV has not been elucidated. One clue to the mechanism may come from determining whether the SNP affects the outcome of other chronic viral infections where interferons and ISGs are important in the host response, such as hepatitis B virus (HBV) and human immunodeficiency virus-1 (HIV). Given the dichotomous outcomes in both HBV and HIV infections and the importance of interferons and ISGs in these infections, we next tested whether the rs12979860 SNP associates with recovery from an acute HBV infection, resistance to HIV infection, and slower progression of HIV disease. The C/C genotype was not associated with HBV recovery (OR 1.20), resistance to HIV infection (1.04), or HIV disease progression (P greater than 0.05 for all outcomes). These results are in stark contrast to the strong association with HCV outcomes. Thus, the effects of this SNP cannot be generalized to other chronic viral infections. Further studies are needed to understand the mechanisms underlying the beneficial effect of this SNP in HCV infection and how they differ from that in HIV and HBV infections. Variation at the HLA class I locus has a stronger influence on HIV-1 disease outcome than variation found at any other genetic locus identified to date. In support of this finding, genome-wide association studies (GWAS), for which we provided HLA genotypes, provide overwhelming confirmation of the primary role of the MHC in outcome to HIV infection in both Caucasians and African Americans. This observation in humans appears to be true also for rhesus monkeys. We performed statistical analyses that showed that specific MHC class I and II alleles are associated with control of SIV replication in this animal model. These studies were carried out in collaboration with investigators at Duke University (GWAS) and University of Wisconsin (SIV study). We previously showed that HLA-B*35-Px subtypes were associated with accelerated progression to AIDS as compared to the related B*35-PY alleles, but the mechanism for this effect was not defined. In collaboration with investigators from the Ragon Institute of MGH, MIT and Harvard we showed that the B*35-Px molecule B*3503 binds with greater affinity to immunoglobulin-like transcript 4 (ILT4), an inhibitory receptor that is expressed on dendritic cells, than does the B*35-PY molecule B*3501. The preferential recognition of B*3503 by ILT4 was associated with significantly stronger dendritic cell dysfunction in vitro and a striking functional impairment of dendritic cells in HIV-1 infected individuals with B*3503. The data provide a novel perspective for the understanding of HLA class I associations with HIV-1 disease progression and for the manupulation of host immunity against HIV-1. Overall, the time to AIDS after HIV-2 infection is longer than with HIV-1 and many individuals infected with HIV-2 virus remain healthy throughout their lives. Multiple HLA and KIR gene products have been implicated in the control of HIV-1 but the effect of variation at these loci on HIV-2 disease is unknown. We determined HLA class I and KIR gene profiles of a relatively isolated population in Caio, Guinea-Bissau, with one of the highest prevalence rates of HIV-2 infection in the world. The HLA-B*15 alleles B*1503 and B*1510 were observed at a relatively high frequency in this community compared to neighbouring populations. Furthermore, HIV-2-infected individuals with B*1503 (but not B*1510) had significantly higher HIV-2 viral loads and lower CD4 counts compared to those without this allele, suggesting that this allele might be linked to poor control of viral replication and more rapid disease progression. Notably, none of the strongest HLA associations with HIV-1 were observed in our HIV-2 cohort. Interestingly, previous data indicate that HLA-B*1503 associates with low viral loads in HIV-1 clade B-infection, but has no significant effect on viral load in clade C infection. In general, alleles strongly associated with HIV-1 disease showed no effect in HIV-2 disease. In general, the strongest associations in this study conferred susceptibility to HIV-2 outcomes, while protective factors were quite weak. This observation is contrary to that observed in HIV-1 disease, where the strongest HLA associations confer protection. Perhaps this reflects the less pathogenic nature of HIV-2 and the ability of most HLA class I allotypes to effectively control the virus, as compared to HIV-1, where most allotypes are unable to maintain viral restriction. Our study is the first to provide a detailed analysis of the effects of HLA and KIR genetic variation on resistance/susceptibility to HIV-2 infection and disease progression. Genetic diversity of immune response genes, such as HLA and KIR loci, holds promise for explaining, in large part, the variability in outcome to viral infection amongst exposed individuals. Understanding how this diversity influences the immune response presents new opportunities for development of effective therapeutics and vaccines, justifying close scrutiny of these genes in viral infections.

一些免疫反应基因的广泛变异是宿主遗传决定因素的核心，导致几乎所有人类疾病风险的变异。我们研究了高度多态性的 KIR 和 HLA 基因座以及其他相关的、较少多态性的基因座对多种疾病的遗传效应。我们对这些影响的一般理解所做的贡献总结如下。据估计，美国有 400 万人、全球有 1.7 亿人感染丙型肝炎病毒 (HCV)，这是美国最常见的血源性感染。绝大多数 HCV 感染会持续存在，其中三分之一的持续感染者会发展为肝硬化和肝细胞癌等慢性肝病。一些流行病学、病毒和宿主因素已被证明与 HCV 清除或持续存在相关。值得注意的是，对丙型肝炎病毒的强烈免疫反应有利于病毒清除，这表明免疫反应基因的遗传变异可能导致个体清除病毒的能力不同。最近的一项全基因组关联研究 (GWAS) 发现了 IL28B 基因上游 3kb 的单核苷酸多态性 (SNP) rs12979860，该位点与 HCV 药物治疗的反应密切相关。与具有 T/T 基因型的个体相比，rs12979860 具有 C/C 基因型的个体对 HCV 药物治疗的持续病毒学应答 (SVR) 率高出 2 倍以上。为了确定该 SNP 对 HCV 自然清除的影响，我们对现有的 HCV 队列进行了基因分型，该队列由自发清除病毒的人（388 人）或持续感染的人（620 人）组成。我们发现具有 C/C 基因型的欧洲和非洲血统的个体更有可能自发清除病毒。迄今为止，这是已发现的与 HCV 感染自发消退相关的最强且最显着的遗传效应，并表明 IL28B 在病毒清除中发挥着主要和根本作用。 IL28B 通过 JAK-STAT 通路触发级联反应，导致干扰素刺激基因 (ISG) 上调，从而产生抗病毒状态。 rs12979860 SNP 如何影响 IL28B 功能和 HCV 免疫反应的机制尚未阐明。该机制的一条线索可能来自于确定 SNP 是否会影响其他慢性病毒感染的结果，其中干扰素和 ISG 在宿主反应中发挥重要作用，例如乙型肝炎病毒 (HBV) 和人类免疫缺陷病毒 1 (HIV)。鉴于 HBV 和 HIV 感染的二分结果以及干扰素和 ISG 在这些感染中的重要性，我们接下来测试了 rs12979860 SNP 是否与急性 HBV 感染的恢复、对 HIV 感染的抵抗力以及 HIV 疾病进展的减缓相关。 C/C 基因型与 HBV 恢复 (OR 1.20)、对 HIV 感染的抵抗力 (1.04) 或 HIV 疾病进展无关（所有结果的 P 均大于 0.05）。这些结果与与 HCV 结果的强烈相关性形成鲜明对比。因此，该 SNP 的作用不能推广到其他慢性病毒感染。需要进一步的研究来了解这种 SNP 对 HCV 感染有益作用的机制，以及它们与 HIV 和 HBV 感染有何不同。 HLA I 类基因座的变异对 HIV-1 疾病结果的影响比迄今为止发现的任何其他基因位点的变异都要大。为了支持这一发现，我们提供了 HLA 基因型的全基因组关联研究 (GWAS) 压倒性地证实了 MHC 在白种人和非裔美国人的 HIV 感染结果中的主要作用。这种在人类身上的观察结果似乎也适用于恒河猴。我们进行的统计分析表明，特定的 MHC I 类和 II 类等位基因与该动物模型中 SIV 复制的控制相关。这些研究是与杜克大学 (GWAS) 和威斯康星大学 (SIV 研究) 的研究人员合作进行的。我们之前表明，与相关的 B*35-PY 等位基因相比，HLA-B*35-Px 亚型与艾滋病的加速进展相关，但这种效应的机制尚未确定。通过与 MGH、麻省理工学院和哈佛大学 Ragon 研究所的研究人员合作，我们发现 B*35-Px 分子 B*3503 与免疫球蛋白样转录物 4 (ILT4)（树突状细胞上表达的抑制性受体）的结合力比 B*35-PY 分子 B*3501 更高。 ILT4 对 B*3503 的优先识别与体外显着更强的树突状细胞功能障碍以及 B*3503 感染的 HIV-1 个体中树突状细胞的显着功能损伤相关。这些数据为理解 HLA I 类与 HIV-1 疾病进展的关联以及操纵宿主针对 HIV-1 的免疫力提供了新的视角。总体而言，感染 HIV-2 后患艾滋病的时间比感染 HIV-1 的时间长，并且许多感染 HIV-2 病毒的人一生都保持健康。多个 HLA 和 KIR 基因产物与 HIV-1 的控制有关，但这些位点的变异对 HIV-2 疾病的影响尚不清楚。我们确定了几内亚比绍卡约地区相对孤立人群的 HLA I 类和 KIR 基因谱，该地区是世界上 HIV-2 感染率最高的地区之一。与邻近人群相比，在该群落中观察到 HLA-B*15 等位基因 B*1503 和 B*1510 的频率相对较高。此外，与没有该等位基因的人相比，携带 B*1503（但不是 B*1510）的 HIV-2 感染者的 HIV-2 病毒载量显着较高，而 CD4 计数较低，这表明该等位基因可能与病毒复制控制不良和疾病进展更快有关。值得注意的是，在我们的 HIV-2 队列中没有观察到与 HIV-1 最强的 HLA 关联。有趣的是，之前的数据表明，HLA-B*1503 与 HIV-1 B 分支感染中的低病毒载量相关，但对 C 分支感染中的病毒载量没有显着影响。一般来说，与 HIV-1 疾病密切相关的等位基因对 HIV-2 疾病没有影响。总体而言，本研究中最强的关联性赋予了对 HIV-2 结果的易感性，而保护性因素则相当弱。这一观察结果与 HIV-1 疾病中观察到的结果相反，在 HIV-1 疾病中最强的 HLA 关联可提供保护。也许这反映了与 HIV-1 相比，HIV-2 的致病性较低，并且大多数 HLA I 类同种异型能够有效控制病毒，而 HIV-1 的大多数同种异型无法维持病毒限制。我们的研究首次详细分析了 HLA 和 KIR 遗传变异对 HIV-2 感染的抵抗力/易感性和疾病进展的影响。免疫反应基因（例如 HLA 和 KIR 基因座）的遗传多样性有望在很大程度上解释暴露个体中病毒感染结果的变异性。了解这种多样性如何影响免疫反应为开发有效的治疗方法和疫苗提供了新的机会，证明对病毒感染中的这些基因进行密切审查是合理的。