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

某些免疫反应基因的广泛变异是导致几乎所有人类疾病风险变异的宿主遗传决定因素的核心。我们已经研究了高度多态性的KIR和HLA位点，以及其他相关的、较少多态性的位点对几种疾病的遗传影响。我们对这些效应的一般理解的贡献总结在这里。据估计，美国有400万人，全世界有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。绝大多数丙型肝炎病毒感染持续存在，三分之一的持续感染者将发展为慢性肝病，如肝硬化和肝细胞癌。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HCV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差异。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，该多态性与HCV药物治疗的反应密切相关。与T/T基因型个体相比，C/C基因型rs12979860个体对HCV药物治疗的持续病毒学应答（SVR）率大于2倍。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和最显著的遗传效应，并指出了IL28B在病毒清除中的主要和基本作用。IL28B通过JAK-STAT通路触发级联，导致干扰素刺激基因（ISGs）上调，从而产生抗病毒状态。rs12979860 SNP影响IL28B功能和HCV免疫应答的机制尚未阐明。该机制的一个线索可能来自于确定SNP是否影响其他慢性病毒感染的结果，其中干扰素和isg在宿主反应中很重要，如乙型肝炎病毒（HBV）和人类免疫缺陷病毒-1 （HIV）。考虑到HBV和HIV感染的两种结果以及干扰素和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感染的抵抗以及HIV疾病的缓慢进展相关。C/C基因型与HBV恢复（OR为1.20）、HIV感染抵抗（OR为1.04）或HIV疾病进展无关（所有结果P均大于0.05）。这些结果与HCV结果的强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在HCV感染中有益作用的机制，以及它们与HIV和HBV感染中的不同之处。HLA I类位点的变异对HIV-1疾病结果的影响比迄今为止发现的任何其他遗传位点的变异都要大。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。这种对人类的观察似乎也适用于恒河猴。我们进行了统计分析，表明在该动物模型中，特定的MHC I类和II类等位基因与SIV复制控制有关。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。我们之前的研究表明，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，但这种影响的机制尚未明确。通过与来自MGH、MIT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与树突状细胞上表达的抑制受体免疫球蛋白样转录物4 （ILT4）结合的亲和力比B*35-PY分子B*3501更强。il - t4对B*3503的优先识别与体外显著增强的树突状细胞功能障碍以及B*3503感染HIV-1个体的树突状细胞功能损伤相关。这些数据为理解HLA I类与HIV-1疾病进展的关联以及对宿主抗HIV-1免疫的操纵提供了一个新的视角。总的来说，感染HIV-2病毒后患艾滋病的时间比感染HIV-1病毒的时间长，而且许多感染HIV-2病毒的人一生都很健康。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。我们在世界上HIV-2感染率最高的城市之一几内亚比绍的开罗测定了一个相对孤立的人群的HLA I类和KIR基因谱。HLA-B*15等位基因B*1503和B*1510在该群体中出现的频率相对较高。此外，携带B*1503（而不是B*1510）的HIV-2感染者与不携带该等位基因的人相比，具有更高的HIV-2病毒载量和更低的CD4计数，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HLA与HIV-1的最强关联。有趣的是，先前的数据表明，HLA-B*1503与HIV-1进化支b感染的低病毒载量相关，但对进化支C感染的病毒载量没有显著影响。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。总的来说，本研究中最强的关联赋予了对HIV-2结果的易感性，而保护因素相当弱。这一观察结果与在HIV-1疾病中观察到的相反，在HIV-1疾病中，最强的HLA关联赋予保护作用。也许这反映了HIV-2的低致病性和大多数HLA I类同种异体有效控制病毒的能力，而HIV-1的大多数同种异体无法维持病毒限制。我们的研究首次详细分析了HLA和KIR遗传变异对HIV-2感染的抗性/易感性和疾病进展的影响。免疫反应基因的遗传多样性，如HLA和KIR基因座，有望在很大程度上解释暴露个体对病毒感染结果的差异。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，证明了在病毒感染中密切关注这些基因是合理的。

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.