Insulin dependent diabetes mellitus (IDDM) is a chronic autoimmune disease with a strong genetic component. The main component of genetic predisposition maps to the HLA region. The overall goal of this project is to identify the loci and the specific alleles within the HLA region that contribute to IDDM susceptibility. Although the genetic epidemiology of IDDM is complex, recently, molecular approaches based on polymerase chain reaction (PCR) amplification have shown that specific alleles at the Class II loci (in particular at DQB1 ,DQA1, and DRB1) appear to confer susceptibility and resistance. Sequence comparisons of susceptible, neutral, and protective alleles have implicated specific polymorphic residues of the class II molecules as functionally important; however, it is clear that IDDM risk cannot be predicted based on the presence or absence of individual amino acid residues. The determination of HLA class II haplotype frequencies among patients and controls in different ethnic groups has shown that the pattern of disease associations for IDDM can differ in different populations. Detailed molecular typing of the HLA region will help clarify these differences. We propose to carry out PGR/oligonucleotide probe typing for all polymorphic class II loci, using the non-radioactive methods previously developed, on a large number of IDDM families from different ethnic groups, including Mexican-Americans and African-Americans. The use of families allows the unambiguous determination of haplotypes as well as the application of theoretical approaches to determine modes of inheritance and heterogeneity effects. We will also apply HLA class (A,B, and C) PCR/oligonucleotide typing methods (currently under development) as well as PCR methods for typing other potentially relevant polymorphic genes (eg the transporter loci) within the HLA region. Since previous results have suggested that specific combinations of class II alleles can contribute to disease susceptibility, the data will be analyzed with respect to gene interactions. Sequencing of PCR products will allow us to determine the extent of allelic diversity at the HLA region loci and sequence comparisons to identify potentially important residues will be carried out. The analysis of non-HLA region genes in the same families will be explored by our collaborators, allowing us to examine the interactions of HLA and non-HLA genes in IDDM susceptibility. This project should identify the loci and alleles within the HLA region that contribute to IDDM susceptibility and help define the risk for predisposed individuals.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK046626-03
Application #
2145883
Study Section
Diabetes, Endocrinology and Metabolic Diseases B Subcommittee (DDK)
Project Start
1993-09-01
Project End
1996-03-31
Budget Start
1995-09-10
Budget End
1996-03-31
Support Year
3
Fiscal Year
1995
Total Cost
Indirect Cost
Name
Roche Molecular Systems, Inc.
Department
Type
DUNS #
City
Alameda
State
CA
Country
United States
Zip Code
94501
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
Valdes, Ana M; Erlich, Henry A; Noble, Janelle A (2005) Human leukocyte antigen class I B and C loci contribute to Type 1 Diabetes (T1D) susceptibility and age at T1D onset. Hum Immunol 66:301-13
Valdes, A M; Wapelhorst, B; Concannon, P et al. (2005) Extended DR3-D6S273-HLA-B haplotypes are associated with increased susceptibility to type 1 diabetes in US Caucasians. Tissue Antigens 65:115-9
Noble, Janelle A; White, Amy M; Lazzeroni, Laura C et al. (2003) A polymorphism in the TCF7 gene, C883A, is associated with type 1 diabetes. Diabetes 52:1579-82
Single, Richard M; Meyer, Diogo; Hollenbach, Jill A et al. (2002) Haplotype frequency estimation in patient populations: the effect of departures from Hardy-Weinberg proportions and collapsing over a locus in the HLA region. Genet Epidemiol 22:186-95
Noble, Janelle A; Valdes, Ana M; Bugawan, Teodorica L et al. (2002) The HLA class I A locus affects susceptibility to type 1 diabetes. Hum Immunol 63:657-64
Park, Y S; She, J X; Noble, J A et al. (2001) Transracial evidence for the influence of the homologous HLA DR-DQ haplotype on transmission of HLA DR4 haplotypes to diabetic children. Tissue Antigens 57:185-91
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
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
Redondo, M J; Kawasaki, E; Mulgrew, C L et al. (2000) DR- and DQ-associated protection from type 1A diabetes: comparison of DRB1*1401 and DQA1*0102-DQB1*0602*. J Clin Endocrinol Metab 85:3793-7

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