The autoimmune thyroid diseases (AITDs), comprising Graves disease (GD) and Hashimoto thyroiditis (HT), develop as a result of a complex interaction between predisposing genes and environmental triggers. Previously, we identified six loci that showed evidence for linkage with AITD in a data set of 56 multiplex families. The goals of the present study were to replicate/reject the previously identified loci before fine mapping and sequencing the candidate genes in these regions. We performed a whole-genome linkage study in an expanded data set of 102 multiplex families with AITD (540 individuals), through use of 400 microsatellite markers. Seven loci showed evidence for linkage to AITD. Three loci, on chromosomes 6p, 8q, and 10q, showed evidence for linkage with both GD and HT (maximum multipoint heterogeneity LOD scores [HLOD] 2.0, 3.5, and 4.1, respectively). Three loci showed evidence for linkage with GD: on 7q (HLOD 2.3), 14q (HLOD 2.1), and 20q (LOD 3.3, in a subset of the families). One locus on 12q showed evidence of linkage with HT, giving an HLOD of 3.4. Comparison with the results obtained in the original data set showed that the 20q (GD-2) and 12q (HT-2) loci continued to show evidence for linkage in the expanded data set; the 6p and 14q loci were located within the same region as the previously identified 6p and 14q loci (AITD-1 and GD-1, respectively), but the Xq (GD-3) and 13q (HT-1) loci were not replicated in the expanded data set. These results demonstrated that multiple genes may predispose to GD and HT and that some may be common to both diseases and some are unique. The loci that continue to show evidence for linkage in the expanded data set represent serious candidate regions for gene identification.

No abstract

Thyroid microsomal antibodies (anti-M Ab) have been recently proven to be directed to thyroid peroxidase (TPO). Methods to detect anti-TPO antibodies (anti-TPO Ab) employing purified antigen have been developed, but the available information on the clinical usefulness of this technique is still limited to small patient series. In the present investigation anti-TPO Ab were assayed by a newly developed monoclonal antibody-assisted RIA in a large number (n = 715) of subjects, including 119 normal controls and 596 patients with different autoimmune or nonautoimmune thyroid disease: Anti-TPO Ab were detected in 10 of 119 (8.4%; range, 11-210 U/mL) normal controls, 134 of 181 (74%; range, 11-74.000 U/mL) patients with Graves' disease, all but 1 of 144 (99.3%; range, 11-90.000 U/mL) with Hashimoto's thyroiditis (n - 98) or idiopathic myxedema (n = 46), 20 of 180 (11.1%; range, 11-6.700 U/mL) with miscellaneous nonautoimmune thyroid diseases, 16 of 83 (19.2%; range, 11-6.600 U/mL) patients with differentiated thyroid carcinoma, and in none of 8 patients with subacute thyroiditis. The highest anti-TPO Ab concentrations were found in untreated hypothyroid Hashimoto's thyroiditis, but no simple relationship between anti-TPO Ab levels and thyroid function was observed. Anti-TPO Ab significantly decreased in patients with Graves' disease after treatment with methimazole and in those with hypothyroid Hashimoto's thyroiditis or idiopathic myxedema during L-T4 administration. A highly significant positive correlation (r = 0.979; P less than 0.001) was found between anti-M Ab titers by passive hemagglutination (PH; available in 650 sera) and the corresponding average anti-TPO Ab by RIA; discrepant results were almost exclusively limited to sera with negative or low (1:100-1:400) anti-M Ab titers. Analysis of these discrepant data indicated higher autoimmune disease specificity and sensitivity of anti-TPO Ab RIA tests compared to anti-M Ab by PH. Absorption studies showed that interference of anti-Tg Ab was responsible for anti-M Ab-positive tests in occasional anti-TPO Ab-negative/anti-M Ab-positive sera from autoimmune thyroid disease patients. Anti-TPO Ab determination by RIA was unaffected by circulating thyroglobulin concentrations up to more than 10,000 ng/mL. In conclusion, anti-TPO Ab assay by monoclonal antibody-assisted RIA appears to be more sensitive and specific for thyroid autoimmune diseases than anti-M Ab determination by PH. Since the assay is easy to perform and employs only tracer amounts of purified antigen, these characteristics should allow its rapid diffusion to the clinical routine.

Third-generation TRAb assays are suitable in the differential diagnosis of hyperthyroidism. In GD, TRAb should be tested before deciding whether methimazole can be stopped. TRAb should be used in pregnant women with GD to assess the risk of fetal thyrotoxicosis. The use of TRAb in GO requires further studies.