(taken from the application) In the past 2 years we have conducted a multi-phase set of studies aimed at mapping the susceptibility loci for autoimmune thyroid disease (AITD). These studies are supported by a K08 award given to the applicant (DK 02498-03). The applicant is proposing to expand these studies, and for that purpose he is applying for an R03 award to run concurrently with his K08 award during the last 2 years of the K08 award (PAR-98-087). In the first phase we have assembled a dataset of 56 multiplex families (354 individuals) and screened them for 14 candidate genes and 5 chromosomal regions which may be linked with AITD. Using this approach, we have identified 5 new loci which showed evidence of linkage with AITD. We are now ready to move to the next phase of the study which is the confirmation of the already identified loci in an independent dataset of families.
The specific aims of this proposed study are: 1) To assemble a confirmatory dataset of 50 AITD families, similar to the current dataset; 2) To confirm the loci identified using the first dataset by linkage studies on the confirmatory dataset; 3) To analyze additional candidate genes on both datasets. The confirmation of linkage to some or all of these loci will then enable us to continue to the next phase of the project which is identifying the genes. We have the capability to enroll in a relatively short period of time a confirmatory set of families. We have designed a protocol for family identification and enrollment. We have created a repository for storage of blood and DNA samples from study subjects, and we have developed a database to store all the information and analyze it. Microsatellite marker analysis will be performed using two ABI-310 automated sequencers. The requested R03 supplement to our K08 award will be used solely for salary support for a research nurse coordinator that will speed up enrolling the confirmatory dataset. Once the new dataset is assembled, we will be able to test the loci we have identified and confirm or reject them. In addition the combined dataset of more than 100 families will enable us to perform association studies using TDT analysis. The TDT association analysis will be used to fine map the AITD susceptibility loci. These analyses will begin to map the genes contributing to the expression of AITD, and hopefully will allow better understanding of the mechanisms initiating these diseases. Thus, treatment modalities could be designed based on the mechanisms initiating the diseases.
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