The genes of the human leukocyte antigen (HLA) region control a variety Of functions involved in the immune response, and influence susceptibility to over 40 diseases. Our understanding of the structure and function of the HLA genes, their disease associations, and the evolutionary features of this multigene family has benefitted from recent advances in molecular biology, immunology, disease modelling and population genetics. Theoretical studies in the development of models to determine the modes of inheritance of the HLA associated diseases have led to a better understanding of the inheritance patterns in insulin dependent diabetes mellitus, rheumatoid arthritis, multiple sclerosis, ankylosing spondylitis, hemochromatosis, celiac disease, and others. It is now clear that many of the HLA associated diseases involve heterogeneity in their HLA components, as well as non-HLA genetic components.
The specific aims of our research are to study the genetic components in the etiology of the HLA associated diseases, and population genetic features of the HLA system. A variety of methods to test modes of inheritance of diseases using marker allele information, will be developed. Methods appropriate for the analysis of marker systems which are not highly polymorphic, to both detect linkage and determine modes of inheritance, will be investigated. The information content of particular pedigree types for LOD score analysis will be investigated. Two methods using patterns of linkage disequilibrium will be investigated to determine their usefulness in mapping disease predisposing genes. A number of large collaborative data sets of HLA associated diseases will be analyzed. A framework for genetic counselling of HLA associated, and other complex diseases, will be developed. The results of our studies are generally applicable to the mapping and characterization of complex human genetic traits.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
5R01GM056688-21
Application #
2900912
Study Section
Mammalian Genetics Study Section (MGN)
Project Start
1979-04-01
Project End
2001-03-31
Budget Start
1999-04-01
Budget End
2000-03-31
Support Year
21
Fiscal Year
1999
Total Cost
Indirect Cost
Name
University of California Berkeley
Department
Biology
Type
Schools of Arts and Sciences
DUNS #
094878337
City
Berkeley
State
CA
Country
United States
Zip Code
94704
Thomson, G; Valdes, A M; Noble, J A et al. (2007) Relative predispositional effects of HLA class II DRB1-DQB1 haplotypes and genotypes on type 1 diabetes: a meta-analysis. Tissue Antigens 70:110-27
Chen, John J; Mu, Hua; Jiang, Yebin et al. (2002) Clinical usefulness of genetic information for predicting radiographic damage in rheumatoid arthritis. J Rheumatol 29:2068-73
Thomas, D C; Borecki, I B; Thomson, G et al. (2001) Evolution of the simulated data problem. Genet Epidemiol 21 Suppl 1:S325-31
Thomson, G (2001) An overview of the genetic analysis of complex diseases, with reference to type 1 diabetes. Best Pract Res Clin Endocrinol Metab 15:265-77
Valdes, A M; Noble, J A; Genin, E et al. (2001) Modeling of HLA class II susceptibility to Type I diabetes reveals an effect associated with DPB1. Genet Epidemiol 21:212-23
Thomson, G (2001) Significance levels in genome scans. Adv Genet 42:475-86
Noble, J A; Valdes, A M; Thomson, G et al. (2000) The HLA class II locus DPB1 can influence susceptibility to type 1 diabetes. Diabetes 49:121-5
Mu, H; Chen, J J; Jiang, Y et al. (1999) Tumor necrosis factor a microsatellite polymorphism is associated with rheumatoid arthritis severity through an interaction with the HLA-DRB1 shared epitope. Arthritis Rheum 42:438-42
Valdes, A M; Thomson, G; Erlich, H A et al. (1999) Association between type 1 diabetes age of onset and HLA among sibling pairs. Diabetes 48:1658-61
Guedez, Y; Kotby, A; El-Demellawy, M et al. (1999) HLA class II associations with rheumatic heart disease are more evident and consistent among clinically homogeneous patients. Circulation 99:2784-90

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