Insights into immune-related disease born from population genomics

描述（由申请人提供）：4.7Mbp HLA区域包含许多免疫系统基因，特别是参与检测感染、恶性肿瘤和移植组织的存在并提供与淋巴细胞受体相互作用以触发人类先天性和适应性免疫应答的配体的基因。这些基因中的一些是非常多态的，受到平衡选择的影响，并且与对广泛的感染性、自身免疫性和过敏性疾病的抗性/易感性相关，并且是移植排斥、移植物抗- 造血干细胞移植后的疾病和妊娠综合征。尽管HLA区域具有广泛的重要性，并且其在与许多人类的遗传关联中占主导地位， 尽管人类白细胞抗原单倍型序列的变异与疾病的关系密切，但尚未进行系统研究HLA单倍型序列变异的协同努力。我们建议通过开发一种方法来实现这一点，该方法将允许以准确和具有成本效益的方式表征数百种单倍型。免疫学的最新进展已经表明，灵长类特异性的并在人类物种中达到其最大复杂性的嗜酸性细胞免疫球蛋白样受体是HLA I类的自然杀伤（NK）细胞受体，其在人类先天免疫防御和生殖中形成相互作用。HLA I类和KIR都是高度多态性的，但在不同的染色体上分离，这是一种特殊的情况，因为几乎所有的个体都表达他们缺乏的配体的受体，反之亦然。KIR多态性越来越多地与疾病相关，并且与HLA I类结合可以产生比单独的配体或受体更强的关联。由于这些功能和遗传相互作用，我们还将对HLA单倍型测序的同一个体的KIR单倍型（130- 250 Kbp）进行测序。拟议的研究将涵盖人口的种族多样性，并将检查与HLA/KIR因子相关的两种类型的疾病。该项目的核心是开发新的方法，以促进对生物学的理解。 HLA和KIR的多样性更高的水平，也将适用于临床HLA和KIR分型作为疾病的诊断和改善用于治疗性移植的供体的选择。

DESCRIPTION (provided by applicant): The 4.7Mbp HLA region contains numerous immune-system genes, notably those involved in detecting the presence of infection, malignancy and transplanted tissue and providing ligands that interact with lymphocyte receptors to trigger human innate and adaptive immune responses. Some of these genes are extraordinarily polymorphic, subject to balancing selection and associated with resistance/susceptibility to a wide range of infectious, autoimmune and allergic diseases, as well as being major arbiters of transplant rejection, graft-versus- disease following hematopoietic stem cell transplantation, and pregnancy syndromes. Despite the wide-ranging importance of the HLA region, and its dominance in the genetic associations with many human diseases, no concerted effort to systematically study the variation in HLA haplotype sequences has been undertaken. We propose to do this by developing a method that will allow characterization of hundreds of haplotypes in an accurate and cost-effective manner. Recent advances in immunology, have shown that killer-cell immunoglobulin-like receptors, which are primate-specific and reach their utmost complexity in the human species, are natural killer (NK) cell receptors for HLA class I, interactions that are formative in human innate immune defense and reproduction. That both HLA class I and KIR are highly polymorphic, but segregate on different chromosomes, is an extraordinary situation, because almost all individuals express receptors for ligands that they lack and vice versa. KIR polymorphism is increasingly being associated with disease, and in combination with HLA class I can yield stronger associations than either ligand or receptor alone. Because of these functional and genetic interactions, we will also sequence KIR haplotypes (130-250Kbp) from the same individuals whose HLA haplotypes are sequenced. The proposed research will cover the ethnic diversity of the human population, and will examine two types of disease that are associated with HLA/KIR factors. Central to this project is development of new methods that will advance biological understanding of HLA and KIR diversity to much higher level, and will also be applicable to clinical HLA and KIR typing as diagnostics for disease and improving the choice of donors for therapeutic transplantation.