Insulin-dependent diabetes mellitus (IDDM) typically is preceded by years of slow beta cell destruction, so it may be preventable with timely intervention. As preventive measures become available, it will be important to focus them on individuals truly at risk. This project is part of an effort to develop means to determine who is genetically susceptible to IDDM. Both HLA genes and unidentified non-HLA genes contribute to the development of IDDM. Since HLA molecules and T-lymphocyte antigen receptors cooperate intimately in cell-mediated immunity, we postulate that the pertinent non-HLA genes may include those for the alpha and/or beta chain of the T-cell receptor (TCR). We will test this hypothesis in a molecular genetic study of families having 2 or more siblings with IDDM. We will use restriction fragment length polymorphisms (RFLPs) to distinguish the two TCR alpha alleles and the two TCR beta alleles of each parent. In the simplest case, one parent is heterozygous and the other homozygous for a given RFLP. These RFLPs will be used to determine if the diabetic siblings inherit the same TCR alleles significantly more often than expected by chance. If so, these genes will be implicated in the determination of IDDM susceptibility.
Specific Aims are to: 1. Identify sufficient TCR alpha polymorphism to follow the inheritance of the 4 allelic alpha-chain complexes (2 from each parent) in each of 25 study families. 2. If necessary, identify TCR beta RFLPs in addition to those already published, to follow the beta-chain gene complexes in these same 25 families. 3. Determine, within families, if affected sibs have inherited the same TCR alpha or beta complex significantly more often than expected by chance. 4. Determine if the degree of sharing of TCR alleles, by affected sibs, is (a) DR-identical versus 1 or 0 DR alleles shared. (b) Sharing or not sharing DR4.
