The long-term objective of this five-year plan is to elucidate the etiology and pathogenesis of insulin-dependent diabetes mellitus (IDDM). The proposed investigations are a logical extension of a nationwide Swedish Registry, established in 1983 for incident cases of IDDM patients developing diabetes at 15-34 years of age. The unique resources of the Swedish Registry will be utilized in a case-control study to define genetic, autoimmune and viral antibody markers for the development of IDDM. The controls will be selected based on the Swedish civic registration numbers to identify individuals who are matched for age and sex. Comparisons will be made to a case-control study of 0-14 year old individuals analyzed with the same methods. The primary goal is to determine whether the same genetic and environmental markers known to be associated with IDDM in the 0-14 year age group are also operative in the 15-34 year group. The reasons to further study the 15-34 year olds are two-fold. First, this is an age group where both IDDM and NIDDM is present. It therefore offers an opportunity to study conversion rates from NIDDM to IDDM and the factors that influence these. Second, this age group is particularly suited to test the hypothesis that genetic and antibody markers alone or in combination permit a differential diagnosis of diabetes mellitus at the time of clinical onset. Specifically, we will: 1) investigate the association between IDDM and markers at the HLA-DQ locus and estimate how age and sex modify the relative risks associated with each of these markers; 2) identify a nucleotide sequence that is present in all of the IDDM patients in 4-kb and 12-kb HLA-DQ associated BamH1 fragments cloned from a patient with IDDM; 3) determine if certain levels or combinations of islet cell and other organ-specific autoantibodies alone or in combination with the HLA gene(s) are markers for IDDM and determine the rate of conversion from NIDDM to IDDM, and (4) estimate the strength of association between IDDM and viral antibody titers and determine by means of multiple logistic regression analysis the joint association of viral antibody, autoantibodies, and HLA specificities with IDDM. It will be determined whether a specific virus plays a role of an independent cofactor or whether the HLA specificities mediate a risk of viral infection. These studies will help to define the mechanisms which result in IDDM and to produce insights leading to the possibility of prevention.
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