The landscape of HLA mediated variation in health and immunity

HLA 介导的健康和免疫力变化

基本信息

批准号：
10182837
负责人：
JILL Allison HOLLENBACH
金额：
$ 75.01万
依托单位：
UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-05-10 至 2026-04-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10182837
关键词：
6p21 Address Alleles Antibodies Antibody Response Antibody Specificity Antigenic Variation Antigens Autoimmune Autoimmune Diseases Binding Bioinformatics Biological Assay Bone Marrow Complex Consent Cytomegalovirus Data Disease Electronic Mail Elements Genes Genetic Genetic Polymorphism Genetic Variation Genotype Goals HLA Antigens Haplotypes Health Histocompatibility Antigens Class II Human Human Characteristics Human Chromosomes Human Genome Immune Immune system Immunity Immunologic Markers Individual Infection Laboratories Link Malignant Neoplasms Maps Marrow Measures Mediating Medical Methods Patient Self-Report Pattern Peptides Phage Display Pharmacology Phenotype Population Proteins Proteome Recording of previous events Registries Resolution Role Sample Size Sampling Serum Single Nucleotide Polymorphism Specificity Structure Surveys System Testing Time United States Variant Viral Viral Antigens Writing antigen binding antigen test cohort disease phenotype genetic association improved large datasets novel phenome prediction algorithm programs recruit seropositive trait virome volunteer web interface

项目摘要

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.

项目概要人类白细胞抗原 (HLA) 区域位于人类染色体 6p21 上，是医学上最重要的区域。人类基因组。超过 100 种传染性、自身免疫性和药理学疾病表型与癌症相关具有HLA遗传变异。尽管如此，尽管对 HLA 和疾病的研究进行了近半个世纪的研究协会，关于 HLA 介导的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进行发现和复制，可归因于 HLA 区域的复杂性使得在非常大的队列中进行关联研究通常是不切实际的。到迄今为止，几乎所有检查人类健康中 HLA 变异的大规模研究都依赖于 HLA 的统计估算等位基因来自 SNP（单核苷酸多态性）数据，而不是直接对这些位点进行基因分型。在此，我们建议利用国家骨髓捐赠计划收集的现有高质量 HLA 基因分型数据以前所未有的规模研究 HLA 变异对人类健康和免疫力的影响。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超过 1,000,000 人对人类巨细胞病毒 (CMV) 产生反应。为协会提供背景信息研究中，我们将检查 1000 多种 HLA 变异与抗体抗原靶标之间的关系健康的个体。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计划 (NMDP) 在表型组范围内识别多种疾病和表型之间潜在的 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针对 NMDP 收集的具有 HLA 基因分型的受试者的约 130 种状况、疾病和性状。具体来说目标 2 我们将确定健康受试者血清样本中抗体的抗原特异性，并按 HLA 分层基因型。我们将利用可编程噬菌体展示测定法，该测定法由 744,000 种肽组成，分布在人类体内蛋白质组，代表整个人类肽组。此外，我们将针对病毒组的噬菌体展示进行筛选（480,000 个肽）用于检测病毒抗原的特异性，并测试这些抗原与 HLA 分子的结合。我们将检查来自 1000 多名健康捐献者的血清样本。在具体目标 3 中，我们将具体解决以下方面的血清状况超过一百万人的样本中存在人类巨细胞病毒（CMV）。 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。该分析将提供首次大规模检验 HLA 变异与 CMV 血清状态的关联。在人类健康和免疫的多个要素中，关键这项研究的特点是为我们的每个目标预测的样本量非常大，这是通过我们的利用现有的高分辨率 HLA 基因分型数据。在此过程中，我们将加深对以下效果的理解：这些在人类健康中的重要免疫位点跨越多种条件，跨越多个祖先，反映了美国人口。