The landscape of HLA mediated variation in health and immunity

项目摘要 人类染色体6p 21上的人类白细胞抗原（HLA）区域是人类白细胞分化的最重要的医学区域。 人类基因组超过100种感染性、自身免疫性和药理学疾病表型与癌症相关 HLA的遗传变异。然而，尽管近半个世纪的研究调查HLA和疾病， 尽管HLA与人类疾病之间存在关联，但关于HLA介导的对人类健康和疾病的影响的完整程度仍然存在悬而未决的问题。 这些研究的一个主要局限性，缺乏足够的样本量来发现和复制，可以归因于 HLA区域的复杂性质使得在非常大的群组中进行关联研究通常是不切实际的。到 迄今为止，几乎所有大规模的研究人类健康的HLA变异依赖于统计估算的HLA 等位基因的SNP（单核苷酸多态性）数据，而不是这些基因座的直接基因分型。在此，我们建议 利用国家骨髓捐献者计划收集的现有高质量HLA基因分型数据， 研究HLA变异对人类健康和免疫力的影响，规模空前。我们将收集自我报告 来自超过100，000人样本的健康史，允许检查基因型-表型 与高分辨率基因型的关联。进一步，我们将研究HLA变异与抗体之间的关系 在超过1，000，000人中对人巨细胞病毒（CMV）有反应。为关联提供上下文 研究，我们将检查HLA变异和抗体的抗原靶点之间的关系，在1000多个 健康的个体。在具体目标1中，我们将建立一个非常大的数据集，通过国家骨髓捐赠者 计划（NMDP）用于在全表型组中识别多种疾病和表型之间的潜在HLA关联 关联研究（PheWAS）。PheWAS分析的表型信息将从自我报告调查数据中获得 用于NMDP收集的HLA基因分型受试者的约130种状况、疾病和特征。在特定 目的2我们将确定从健康受试者血清样本中抗体的抗原特异性，按HLA分层 基因型我们将利用可编程噬菌体展示试验，包括744，000肽平铺在整个人类 蛋白质组，代表整个人类肽组。此外，我们将针对噬菌体展示筛选病毒组 (480，000肽）对病毒抗原的特异性，并测试这些抗原与HLA分子的结合。我们将研究 超过1000名健康献血者的血清样本在具体目标3中，我们将具体讨论以下方面的血清状态： 人类巨细胞病毒（CMV）的样本超过一百万人。CMV在所有人群中普遍存在， 感染会对免疫系统产生深远的影响。这项分析将提供第一次大规模的检查， HLA变异与CMV血清学状态的关系。在人类健康和免疫力的多个要素中， 这项研究的一个特点是为我们的每一个目标预测了非常大的样本量，通过我们的 利用现有的高分辨率HLA基因分型数据。在这样做的时候，我们将扩大我们的理解的影响， 这些重要的免疫基因座在人类健康中的广泛条件下，在多个祖先中反映了人类免疫系统的变化。 美国人口。

Project Summary The Human Leukocyte Antigen (HLA) region on human chromosome 6p21 is the most medically important region of the human genome. More than 100 infectious, autoimmune and pharmacological disease phenotypes and cancers are associated with genetic variation of HLA. Nevertheless, despite nearly a half-century of study investigating HLA and disease association, outstanding questions remain regarding the full extent of HLA mediated impact on human health and disease. A major limitation to these studies, lack of sufficient sample size for discovery and replication, can be attributed to the complex nature of the HLA region such that it is often impractical to undertake association studies in very large cohorts. To date, nearly all large-scale studies examining HLA variation in human health have relied on statistical imputation of HLA alleles from SNP (single nucleotide polymorphism) data, rather than direct genotyping of these loci. Here, we propose to exploit pre-existing, high-quality HLA genotyping data collected by the National Marrow Donor Program in order to examine the impact of HLA variation in human health and immunity at unprecedented scale. We will collect self-reported health histories from a sample of greater than 100,000 individuals, allowing examination of genotype-phenotype associations with high-resolution genotypes. Further, we will examine the relationship between HLA variation and antibody response to human cytomegalovirus (CMV) in more than 1,000,000 individuals. To provide context to the association studies, we will examine the relationship between HLA variation and antigenic targets of antibodies in more than 1000 healthy individuals. In Specific Aim 1 we will build a very large dataset collected through the National Marrow Donor Program (NMDP) to identify potential HLA associations across numerous diseases and phenotypes in a Phenome Wide Association study (PheWAS). Phenotype information for PheWAS analysis will be obtained from self-report survey data for approximately 130 conditions, diseases and traits from subjects with HLA genotyping collected by NMDP. In Specific Aim 2 we will determine the antigen specificity of antibodies in serum samples from healthy subjects, stratified by HLA genotype. We will utilize a programmable phage display assay, comprised of 744,000 peptides tiled across the human proteome, representing the entire human peptidome. Additionally, we will screen against the phage display for the virome (480,000 peptides) for specificity for viral antigens, and test binding of these antigens to HLA molecules. We will examine serum samples from over 1000 healthy donors. In Specific Aim 3, we will specifically address serostatus with respect to human cytomegalovirus (CMV) in a sample of over a million individuals. CMV is ubiquitous in all human populations and infection can have profound effects on the immune system. This analysis will provide the first large-scale examination of the association of HLA variation with CMV serostatus. Across multiple elements of human health and immunity, the key feature of this study is the extraordinarily large sample size projected for each of our aims, made possible through our leveraging of existing high-resolution HLA genotyping data. In doing so, we will extend our understanding of the effect of these important immune loci in human health across a wide range of conditions, across multiple ancestries reflective of the United States population.