The landscape of HLA mediated variation in health and immunity

HLA 介导的健康和免疫力变化

• 批准号: 10609519
• 负责人: JILL Allison HOLLENBACH
• 金额: $ 73.66万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 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/10609519
• 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; Phenotype; Population; Proteins; Proteome; Recording of previous events; Registries; Resolution; Role; Sample Size; Sampling; Serum; Single Nucleotide Polymorphism; Specificity; Surveys; System; Testing; Time; United States; Variant; Viral; Viral Antigens; Writing; antigen binding; cohort; disease phenotype; improved; large datasets; novel; pharmacologic; phenome; prediction algorithm; programs; recruit; seropositive; trait; virome; volunteer; web interface

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.

项目摘要 人类白细胞抗原（HLA）在人类6p21上是医学上最重要的地区 人基因组。超过100多种感染性，自身免疫和药理学疾病表型和癌症是相关的 与HLA的遗传变异。然而，尽管有近半个世纪的研究调查了HLA和疾病 协会，关于HLA介导的对人类健康和疾病的影响的全部范围仍然存在的杰出问题。 这些研究的主要局限性，缺乏足够的发现和复制的样本量，可以归因于 HLA区域的复杂性质，因此在非常大的人群中进行关联研究通常是不切实际的。到 日期，几乎所有研究人类健康中HLA差异的大规模研究都依赖于HLA的统计归因 来自SNP（单核苷酸多态性）数据的等位基因，而不是直接对这些基因座的基因分型。在这里，我们建议 利用国家骨髓供体计划收集的先前存在的高质量HLA基因分型数据 检查HLA变异对人类健康和免疫力的影响，以前所未有的量表。我们将收集自我报告 来自100,000多人样本的健康历史，允许检查基因型 - 表型 与高分辨率基因型的关联。此外，我们将检查HLA变异与抗体之间的关系 对100万人的人类巨细胞病毒（CMV）的反应。为协会提供背景 研究，我们将检查超过1000多个抗体的HLA变异与抗体的抗原靶标之间的关系 健康的个体。在特定目标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）以识别众多疾病和表型的潜在HLA关联 协会研究（Phewas）。 PHEWAS分析的表型信息将从自我报告调查数据中获得 对于大约130个条件，NMDP收集的HLA基因分型受试者的疾病和特征。具体 AIM 2我们将确定健康受试者血清样品中抗体的抗原特异性，由HLA分层 基因型。我们将使用可编程的噬菌体显示测定法，该测定法包括744,000个肽 蛋白质组，代表整个人类肽组。此外，我们将筛选病毒素的噬菌体显示 （480,000肽）针对病毒抗原的特异性，并将这些抗原与HLA分子的结合。我们将检查 来自1000多名健康供体的血清样品。在特定的目标3中，我们将针对血统 超过一百万个个体样本中的人类巨细胞病毒（CMV）。 CMV在所有人口中无处不在， 感染会对免疫系统产生深远的影响。该分析将提供第一次大规模检查 HLA变异与CMV血清的关联。在人类健康和免疫的多个要素中，关键 这项研究的特征是针对我们每个目标投射的非常大的样本量，通过我们的 利用现有的高分辨率HLA基因分型数据。这样，我们将扩展我们对 这些重要的免疫基因座在人类健康中的各种条件中，跨多个祖先反映了 美国人口。

项目成果

Severe delayed hypersensitivity reactions to IL-1 and IL-6 inhibitors link to common HLA-DRB1*15 alleles.

• DOI: 10.1136/annrheumdis-2021-220578
• 发表时间: 2022-03
• 期刊: ANNALS OF THE RHEUMATIC DISEASES
• 影响因子: 27.4
• 作者: Saper, Vivian E.;Ombrello, Michael J.;Tremoulet, Adriana H.;Montero-Martin, Gonzalo;Prahalad, Sampath;Canna, Scott;Shimizu, Chisato;Deutsch, Gail;Tan, Serena Y.;Remmers, Elaine F.;Monos, Dimitri;Hahn, Timothy;Phadke, Omkar K.;Cassidy, Elaine;Ferguson, Ian;Mallajosyula, Vamsee;Xu, Jianpeng;Duque, Jaime S. Rosa;Chua, Gilbert T.;Ghosh, Debopam;Szymanski, Ann Marie;Rubin, Danielle;Burns, Jane C.;Tian, Lu;Fernandez-Vina, Marcelo A.;Mellins, Elizabeth D.;Hollenbach, Jill A.
• 通讯作者: Hollenbach, Jill A.

Analysis of Genomic DNA from Medieval Plague Victims Suggests Long-Term Effect of Yersinia pestis on Human Immunity Genes.

• DOI: 10.1093/molbev/msab147
• 发表时间: 2021-09-27
• 期刊: Molecular biology and evolution
• 影响因子: 10.7
• 作者: Immel A;Key FM;Szolek A;Barquera R;Robinson MK;Harrison GF;Palmer WH;Spyrou MA;Susat J;Krause-Kyora B;Bos KI;Forrest S;Hernández-Zaragoza DI;Sauter J;Solloch U;Schmidt AH;Schuenemann VJ;Reiter E;Kairies MS;Weiß R;Arnold S;Wahl J;Hollenbach JA;Kohlbacher O;Herbig A;Norman PJ;Krause J
• 通讯作者: Krause J