The applicant proposes to continue studies begun in the laboratory of the sponsor in the last year. The studies proposed in this application are aimed at mapping the genes causing autoimmune thyroid diseases (AITD). AITD are among the commonest human autoimmune disorders, affecting up to 5% of the general population. Little is known concerning the genes causing AITD. However, epidemiological evidence for a genetic predisposition to AITD is abundant (e.g., the concordance rate in monozygotic twins is 75%).
The specific aims of this proposed study are: 1) to collect clinical and serological data and obtain blood for genetic marker typing from AITD families, 2) to prove a genetic susceptibility to AITD, by linkage and association studies, using candidate genes, and chromosomal regions of interest (14q, 6p21), and 3) to confirm the preliminary evidence for linkage between AITD and the marker D14S81, and to localize the gene more precisely. In preliminary studies we have examined possible linkage of AITD to 7 candidate genes using microsatellite marker polymorphisms: 1) HLA (marker TNFa), 2) TSH receptor [TSHR] (markers D14S120-D14S293 flanking the TSHR gene), 3) thyroid peroxidase (TPO) (marker TPO[+]), 4) thyroglobulin (Tg) (marker MYC), 5) IgH (marker IgH@), 6) IDDM-4 (marker FGF3), and 7) IDDM-5 (marker ESR). One hundred and seven subjects from 19 families were studied (14 with GD, and 32 with HT). The results showed negative LOD scores for the Tg, IgH, IDDM-4 and -5 markers and low positive LOD scores for TPO (LOD score=0.42, theta=0.1), and for TNFa (LOD score=0.33, theta=0.1). Positive LOD scores were found for TSHR markers in a geographically logical sequence, the highest being for D14S81 (LOD score= 1.043, theta=0.20). Thus our preliminary results demonstrate lack of linkage of AITD to the Tg, IgH, and IDDM-4 and -5 genes, and evidence for possible linkage to the 14q31 gene region, which requires further confirmation. In the proposed study we will gather data from 100 families over 5 years. We will study at least 19 candidate genes including HLA, TSHR, TPO, Tg, IgH, TcRa, TcRb, IL-2, IFNg, and IDDM-3, -4 and -5, as well as 2 chromosomal regions of interest, 14q, and 6p21. AITD patients will be identified in our clinics in the New York area, as well as in other clinics, and recruited with their families to the study. We will obtain blood samples from the recruited family members, extract DNA from the blood and analyze it for microsatellite polymorphisms. We will then analyze for linkage between these polymorphisms and the expression of AITD in its various forms in the families. The identification of a genetic marker for AITD will allow a better understanding and classification of the diseases. Thus rational treatments could be offered based on the mechanisms initiating the diseases.
