R01AI158861

The landscape of HLA-mediated variation in health and immunity - 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 is the lack of sufficient sample size for discovery and replication, which can be attributed to the complex nature of the HLA region. 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 an 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. Furthermore, 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.

San Francisco Regents Of The University Of California

TO ASSIST PUBLIC AND PRIVATE NONPROFIT INSTITUTIONS AND INDIVIDUALS TO ESTABLISH, EXPAND AND IMPROVE BIOMEDICAL RESEARCH AND RESEARCH TRAINING IN INFECTIOUS DISEASES AND RELATED AREAS, TO CONDUCT DEVELOPMENTAL RESEARCH, TO PRODUCE AND TEST RESEARCH MATERIALS. TO ASSIST PUBLIC, PRIVATE AND COMMERCIAL INSTITUTIONS TO CONDUCT DEVELOPMENTAL RESEARCH, TO PRODUCE AND TEST RESEARCH MATERIALS, TO PROVIDE RESEARCH SERVICES AS REQUIRED BY THE AGENCY FOR PROGRAMS IN INFECTIOUS DISEASES, AND CONTROLLING DISEASE CAUSED BY INFECTIOUS OR PARASITIC AGENTS, ALLERGIC AND IMMUNOLOGIC DISEASES AND RELATED AREAS. PROJECTS RANGE FROM STUDIES OF MICROBIAL PHYSIOLOGY AND ANTIGENIC STRUCTURE TO COLLABORATIVE TRIALS OF EXPERIMENTAL DRUGS AND VACCINES, MECHANISMS OF RESISTANCE TO ANTIBIOTICS AS WELL AS RESEARCH DEALING WITH EPIDEMIOLOGICAL OBSERVATIONS IN HOSPITALIZED PATIENTS OR COMMUNITY POPULATIONS AND PROGRESS IN ALLERGIC AND IMMUNOLOGIC DISEASES. BECAUSE OF THIS DUAL FOCUS, THE PROGRAM ENCOMPASSES BOTH BASIC RESEARCH AND CLINICAL RESEARCH. SMALL BUSINESS INNOVATION RESEARCH (SBIR) PROGRAM EXPANDS AND IMPROVES PRIVATE SECTOR PARTICIPATION IN BIOMEDICAL RESEARCH. THE SBIR PROGRAM INTENDS TO INCREASE AND FACILITATE PRIVATE SECTOR COMMERCIALIZATION OF INNOVATIONS DERIVED FROM FEDERAL RESEARCH AND DEVELOPMENT, TO INCREASE SMALL BUSINESS PARTICIPATION IN FEDERAL RESEARCH AND DEVELOPMENT, AND TO FOSTER AND ENCOURAGE PARTICIPATION OF SOCIALLY AND ECONOMICALLY DISADVANTAGED SMALL BUSINESS CONCERNS AND WOMEN-OWNED SMALL BUSINESS CONCERNS IN TECHNOLOGICAL INNOVATION. THE SMALL BUSINESS TECHNOLOGY TRANSFER (STTR) PROGRAM STIMULATES AND FOSTERS SCIENTIFIC AND TECHNOLOGICAL INNOVATION THROUGH COOPERATIVE RESEARCH AND DEVELOPMENT CARRIED OUT BETWEEN SMALL BUSINESS CONCERNS AND RESEARCH INSTITUTIONS, TO FOSTER TECHNOLOGY TRANSFER BETWEEN SMALL BUSINESS CONCERNS AND RESEARCH INSTITUTIONS, TO INCREASE PRIVATE SECTOR COMMERCIALIZATION OF INNOVATIONS DERIVED FROM FEDERAL RESEARCH AND DEVELOPMENT, AND TO FOSTER AND ENCOURAGE PARTICIPATION OF SOCIALLY AND ECONOMICALLY DISADVANTAGED SMALL BUSINESS CONCERNS AND WOMEN-OWNED SMALL BUSINESS CONCERNS IN TECHNOLOGICAL INNOVATION. RESEARCH CAREER DEVELOPMENT AWARDS SUPPORT THE DEVELOPMENT OF SCIENTISTS DURING THE FORMATIVE STAGES OF THEIR CAREERS. INDIVIDUAL NATIONAL RESEARCH SERVICE AWARDS (NRSAS) ARE MADE DIRECTLY TO APPROVE APPLICANTS FOR RESEARCH TRAINING IN SPECIFIED BIOMEDICAL SHORTAGE AREAS. IN ADDITION, INSTITUTIONAL NATIONAL RESEARCH SERVICE AWARDS ARE MADE TO ENABLE INSTITUTIONS TO SELECT AND MAKE AWARDS TO INDIVIDUALS TO RECEIVE TRAINING UNDER THE AEGIS OF THEIR INSTITUTIONAL PROGRAM.

93.855 - Allergy and Infectious Diseases Research

National Institute of Allergy and Infectious Diseases (NIAID) [HHS - NIH]

San Francisco, California 94143 United States

Single Zip Code

NIH Research Project Grant (Parent R01 Clinical Trial Not Allowed) (PA-20-185)

Amendment Since initial award the total obligations have increased 361% from $750,148 to $3,457,896.