The landscape of HLA mediated variation in health and immunity

项目摘要 人类染色体6p21上的人类白细胞抗原(人类白细胞抗原)区域是人类染色体中最重要的医学区域。 人类基因组。100多种传染病、自身免疫性和药物性疾病表型与癌症有关 与人类白细胞抗原的遗传变异有关。然而，尽管对人类白细胞抗原和疾病进行了近半个世纪的研究 尽管如此，关于人类白细胞抗原对人类健康和疾病的全面影响，仍然存在悬而未决的问题。 这些研究的一个主要限制是缺乏足够的样本量来发现和复制，这可以归因于 人类白细胞抗原区域的复杂性使得在非常大的队列中进行关联研究往往是不切实际的。至 迄今为止，几乎所有检测人类健康中人类白细胞抗原变异的大规模研究都依赖于人类白细胞抗原的统计归因 来自SNP(单核苷酸多态)数据的等位基因，而不是这些基因座的直接基因分型。在此，我们建议 利用国家骨髓捐赠者计划收集的预先存在的高质量的人类白细胞抗原基因分型数据，以便 以前所未有的规模研究人类白细胞抗原变异对人类健康和免疫的影响。我们将收集自我报告 超过100,000人的样本的健康史，允许检查基因-表型 与高分辨率基因型别的关联。进一步，我们将研究人类白细胞抗原变异与抗体之间的关系。 100,000多人对人类巨细胞病毒(CMV)的反应。为关联提供上下文 研究中，我们将检查1000多个抗体的抗原靶标与人类白细胞抗原变异的关系 健康的个体。在具体目标1中，我们将建立一个通过国家骨髓捐赠者收集的非常大的数据集 项目(NMDP)，以确定在广泛的表型组中跨多种疾病和表型的潜在的人类白细胞抗原关联 联合研究(Phewas)。Phewas分析的表型信息将从自我报告调查数据中获得 来自NMDP收集的大约130种条件、疾病和特征的人类白细胞抗原基因分型受试者。具体而言 目的2我们将测定健康受试者血清中抗体的抗原特异性，按人类白细胞抗原(Has)进行分层。 基因分型。我们将利用一种可编程的噬菌体展示试验，它由744,000个横跨人体的多肽组成 蛋白质组，代表整个人类多肽组。此外，我们将针对病毒的噬菌体展示进行筛选 (480,000个多肽)用于病毒抗原的特异性，并测试这些抗原与人类白细胞抗原分子的结合。我们将研究 来自1000多名健康捐赠者的血清样本。在具体目标3中，我们将具体解决与以下方面有关的血清状态 人类巨细胞病毒(CMV)在100多万人的样本中。巨细胞病毒在所有人类群体中普遍存在， 感染会对免疫系统产生深远的影响。这一分析将提供第一次大规模的 巨细胞病毒血清状态与人类白细胞抗原变异的关系在人类健康和免疫力的多个要素中，关键 这项研究的特点是为我们的每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的人类白细胞抗原基因分型数据。在这样做的过程中，我们将扩大我们对 这些重要的免疫位点在人类健康的广泛条件下，跨多个祖先反映了 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.