The long-term goal of this proposal is to increase knowledge of the genetic basis of susceptibility to insulin-dependent diabetes mellitus (IDDM) by 1) refining understanding of the well-known association with HLA, and 2) investigating the role of other genes that may confer susceptibility or help maintain diabetes susceptibility genes in the population.
The specific aims i nclude three related studies. First, in order to shift to the most basic level of genetic information, nucleotide sequences will be obtained for highly variable regions of HLA-DR and DQ beta chains. Variant nucleotide sequences associated with HLA-DR3, DR (and rarely DR2) will be identified, and the frequency of these variants, which define subtypes of the DR specificities, will be determined in a large number of patients and controls. The subtypes that occur most frequently in HLA haplotypes will be tested for association with IDDM. Second, restriction fragment polymorphisms will be detected with probes for the beta chain of the T-cell receptor. These will be used to determine 1) whether germ-line variation in the T-cell receptor is associated with IDDM, separately or in interaction with HLA, and 2) whether susceptibility to IDDM is linked to genes for the T-cell receptor. Third, cloned genes for the mouse t-complex will be used to identify homologous human sequences and determine whether they are linked to HLA, associated with particular HLA specificities, and associated with IDDM. Fourth, the final organization and publication of the international IDDM - Genetic Analysis Workshop will be carried out. Techniques of molecular genetics will be used to achieve these aims. The DNA sequencing will be made possible by using the """"""""polymerase chain reaction"""""""" to amplify nucleotide sequences of interest. The genes for the T-cell receptor and human homologues of the t-complex will be studied using cloned fragments and Southern blotting to identify closely linked restriction fragment polymorphisms. Methods of family and population genetic analysis will be used to assess the results statistically.

National Institute of Health (NIH)
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Research Project (R01)
Project #
Application #
Study Section
Allergy and Immunology Study Section (ALY)
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
University of Pennsylvania
Schools of Medicine
United States
Zip Code
Monos, D S; Kamoun, M; Udalova, I A et al. (1995) Genetic polymorphism of the human tumor necrosis factor region in insulin-dependent diabetes mellitus. Linkage disequilibrium of TNFab microsatellite alleles with HLA haplotypes. Hum Immunol 44:70-9
McGinnis, R E; Spielman, R S (1994) Linkage disequilibrium in the insulin gene region: size variation at the 5' flanking polymorphism and bimodality among ""class I"" alleles. Am J Hum Genet 55:526-32
Spielman, R S; McGinnis, R E; Ewens, W J (1993) Transmission test for linkage disequilibrium: the insulin gene region and insulin-dependent diabetes mellitus (IDDM). Am J Hum Genet 52:506-16
Blanche, H; Wright, L G; Vergnaud, G et al. (1992) Genetic mapping of three human homologues of murine t-complex genes localizes TCP10 to 6q27, 15 cM distal to TCP1 and PLG. Genomics 12:826-8
Thornton, P S; Sumner, A E; Ruchelli, E D et al. (1991) Familial and sporadic hyperinsulinism: histopathologic findings and segregation analysis support a single autosomal recessive disorder. J Pediatr 119:721-4
Gogolin, K J; Wright, L G; Kolaga, V J et al. (1991) RFLPs detected with the human TCP10 gene, a homologue of a mouse t-complex gene. Nucleic Acids Res 19:4313
Concannon, P; Wright, J A; Wright, L G et al. (1990) T-cell receptor genes and insulin-dependent diabetes mellitus (IDDM): no evidence for linkage from affected sib pairs. Am J Hum Genet 47:45-52
(1989) Genetic analysis of complex traits: insulin-dependent diabetes mellitus and affective disorders. Proceedings of a workshop. Chantilly, France, September 2-5, 1987. Genet Epidemiol 6:1-310
Gogolin, K J; Spielman, R S (1989) HLA DR4-DQw3.1 and 3.2 haplotypes among insulin-dependent diabetics and their unaffected sibs in the GAW5 data. Genet Epidemiol 6:113-6
Cox, N J; Spielman, R S (1989) The insulin gene and susceptibility to IDDM. Genet Epidemiol 6:65-9

Showing the most recent 10 out of 13 publications