The 4.7Mbp HLA region contains numerous immune-system genes, notably those involved in detecting the presence of infection, malignancy and transplanted tissue and providing ligands that interact with lymphocyte receptors to trigger human innate and adaptive immune responses. Some of these genes are extraordinarily polymorphic, subject to balancing selection and associated with resistance/susceptibility to a wide range of infectious, autoimmune and allergic diseases, as well as being major arbiters of transplant rejection, graft-versus- disease following hematopoietic stem cell transplantation, and pregnancy syndromes. Despite the wide-ranging importance of the HLA region, and its dominance in the genetic associations with many human diseases, no concerted effort to systematically study the variation in HLA haplotype sequences has been undertaken. We propose to do this by developing a method that will allow characterization of hundreds of haplotypes in an accurate and cost-effective manner. Recent advances in immunology, have shown that killer-cell immunoglobulin-like receptors, which are primate-specific and reach their utmost complexity in the human species, are natural killer (NK) cell receptors for HLA class I, interactions that are formative in human innate immune defense and reproduction. That both HLA class I and KIR are highly polymorphic, but segregate on different chromosomes, is an extraordinary situation, because almost all individuals express receptors for ligands that they lack and vice versa. KIR polymorphism is increasingly being associated with disease, and in combination with HLA class I can yield stronger associations than either ligand or receptor alone. Because of these functional and genetic interactions, we will also sequence KIR haplotypes (130-250Kbp) from the same individuals whose HLA haplotypes are sequenced. The proposed research will cover the ethnic diversity of the human population, and will examine two types of disease that are associated with HLA/KIR factors. Central to this project is development of new methods that will advance biological understanding of HLA and KIR diversity to much higher level, and will also be applicable to clinical HLA and KIR typing as diagnostics for disease and improving the choice of donors for therapeutic transplantation.

Public Health Relevance

(provided by applicant): The human leukocyte antigen (HLA) complex and the killer cell immunoglobulin-like receptor (KIR) gene family are functionally interacting genomic regions associated with a wide range of human infectious and autoimmune diseases, as well as reproductive success and the outcome of therapeutic transplantation. In this project we will precisely define HLA and KIR genetic variation within the human population. This information will enable the identification of disease-causing genes and their mechanism of action.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project--Cooperative Agreements (U01)
Project #
1U01AI090905-01
Application #
7992673
Study Section
Special Emphasis Panel (ZAI1-MFH-I (M3))
Program Officer
Rice, Jeffrey S
Project Start
2010-07-06
Project End
2015-06-30
Budget Start
2010-07-06
Budget End
2011-06-30
Support Year
1
Fiscal Year
2010
Total Cost
$559,000
Indirect Cost
Name
Stanford University
Department
Biology
Type
Schools of Medicine
DUNS #
009214214
City
Stanford
State
CA
Country
United States
Zip Code
94305
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Huhn, Oisín; Chazara, Olympe; Ivarsson, Martin A et al. (2018) High-Resolution Genetic and Phenotypic Analysis of KIR2DL1 Alleles and Their Association with Pre-Eclampsia. J Immunol 201:2593-2601
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Robinson, James; Guethlein, Lisbeth A; Cereb, Nezih et al. (2017) Distinguishing functional polymorphism from random variation in the sequences of >10,000 HLA-A, -B and -C alleles. PLoS Genet 13:e1006862
Norman, Paul J; Norberg, Steven J; Guethlein, Lisbeth A et al. (2017) Sequences of 95 human MHC haplotypes reveal extreme coding variation in genes other than highly polymorphic HLA class I and II. Genome Res 27:813-823
Béziat, Vivien; Hilton, Hugo G; Norman, Paul J et al. (2017) Deciphering the killer-cell immunoglobulin-like receptor system at super-resolution for natural killer and T-cell biology. Immunology 150:248-264
Norman, Paul J; Hollenbach, Jill A; Nemat-Gorgani, Neda et al. (2016) Defining KIR and HLA Class I Genotypes at Highest Resolution via High-Throughput Sequencing. Am J Hum Genet 99:375-91
Alicata, Claudia; Pende, Daniela; Meazza, Raffaella et al. (2016) Hematopoietic stem cell transplantation: Improving alloreactive Bw4 donor selection by genotyping codon 86 of KIR3DL1/S1. Eur J Immunol 46:1511-7
Alicata, C; Bottino, C; Guethlein, L A et al. (2016) Description of the novel KIR2DL4*035 allele identified using high-throughput sequencing. HLA 87:191-3
Eagen, Kyle P; Hartl, Tom A; Kornberg, Roger D (2015) Stable Chromosome Condensation Revealed by Chromosome Conformation Capture. Cell 163:934-46

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