The long term goal of this proposal is to define a broad set of genetic polymorphisms spanning the human major histocompatibility complex (MHC) that will be useful for identifying MHC disease associations, including those diseases associated with unrelated donor marrow transplants. The MHC, which is comprised of the HLA class I, II, and III regions, is, from a genetic standpoint, one of the most thoroughly perused areas of the human genome. Since its discovery over 30 years ago, dozens of disease associations have been linked genetically to this region through their associations to the highly polymorphic class I and II antigen- presenting genes. More recently, complete sequence analysis of the class I, II and III regions has defined over 220 genes, and more detailed analyses have given preliminary information on an additional 40 new genes within class I. We will utilize the extensive background of genomic data gathered in the prior years of this grant to develop tools and datasets that will allow us to test the hypothesis that genetic factors within the MHC, but outside of the class I and II loci, can effect and better predict the outcome of an unrelated donor transplant. Thus our original theme of studying the polymorphism and transplantation biology of novel HLA genes can be continued in a logical and effective manner towards testing this hypothesis, by accomplishing the following specific aims: 1) To identify and characterize new genes in the HLA class I region. This will be achieved by utilizing existing computational and expressed sequence tagged (EST)-based gene predictions as a starting point for full-length cDNA isolations and characterization. 2) To develop and define a definitive set of SNPs useful as mapping tools in the association with MHC-linked diseases. To complete this we will define and relate SNP frequencies, linkage disequilibrium, recombination frequency, and location relative to existing and new genes from a spectrum of ethnic groups, and 3) To carry out SNP-based analysis of the MHC and the relationship of SNPs to HLA haplotypes found in marrow transplant recipients, thus opening the way to study the potential involvement of SNPs in unrelated marrow transplant outcome.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI049245-03
Application #
6534318
Study Section
Special Emphasis Panel (ZAI1-EWS-I (M1))
Program Officer
Kirkham, Perry M
Project Start
2000-09-15
Project End
2005-05-31
Budget Start
2002-09-01
Budget End
2003-05-31
Support Year
3
Fiscal Year
2002
Total Cost
$393,357
Indirect Cost
Name
Fred Hutchinson Cancer Research Center
Department
Type
DUNS #
075524595
City
Seattle
State
WA
Country
United States
Zip Code
98109
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Pyo, Chul-Woo; Williams, Luke M; Moore, Yuki et al. (2006) HLA-E, HLA-F, and HLA-G polymorphism: genomic sequence defines haplotype structure and variation spanning the nonclassical class I genes. Immunogenetics 58:241-51
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Hsu, Katharine C; Chida, Shohei; Geraghty, Daniel E et al. (2002) The killer cell immunoglobulin-like receptor (KIR) genomic region: gene-order, haplotypes and allelic polymorphism. Immunol Rev 190:40-52