Association of autoimmune thyroid disease with microsatellite markers for the thyrotropin receptor gene and CTLA-4 in Japanese patients

In a previous study we identified a microsatellite marker near the thyrotro pin receptor (TSHR) gene. Studies with this marker, TSHR-CA, revealed a sig nificant association between autoimmune thyroid disease (AITD) in Japanese patients and one specific allele (allele 1; 180 base pair [bp]) of the micr osatellite sequence. In addition, weak evidence for association of AITD wit h two alleles of the CTLA-4 gene was observed. In the present study, TSHR-C A has been mapped to approximately 600 kb of the TSHR gene using radiation hybrid mapping. TSHR-CA and another TSHR microsatellite marker, TSHR-AT, wh ich is located in intron 2 of TSHR gene, were genotyped in a set of 349 unr elated Japanese AITD patients and 218 Japanese controls. The TSHR-AT marker showed association in this Japanese AITD population with a significant inc rease in allele 5 (294 bp; p < 0.05) and a significant decrease in allele 7 (298 bp; p < 0.05). The association of allele 5 of TSHR-AT was also signif icant in hypothyroid patients (thyrotopin-binding inhibitory immunoglobulin -positive [TBII+], P < 0.01; thyrotropin binding inhibitory immunoglobulin- negative [TBII-], p < 0.05). The association of allele 7 of TSHR-AT were al so significant for the hypothyroid TBII+ patients (p < 0.05). The CTLA-4 ge ne was also genotyped in this expanded set of Japanese AITD patients and co ntrols. Association between AITD susceptibility and allele 2 (102 bp; p < 0 .01) and allele 4 (106 bp; p < 0.01) were observed. These associations were also observed with GD patients (allele 2, p<0.01; allele 4, p < 0.01). Ass ociations with TSHR-CA were observed for Hashimoto's thyroiditis (HT) patie nts with respect to alleles 3 (179 bp; p < 0.05) and 5 (175 bp; p < 0.05) a nd with hypothyroid TBII- patients for allele 4 (177 bp; p < 0.05). The pre sence of specific alleles of TSHR-CA, TSHR-AT, and CTLA-4 contribute signif icant increase in risk of development of AITD. These results confirm and ex pand on our previous study suggesting that alleles of the TSHR and CTLA-4 g enes, or genes near them contribute to AITD susceptibility and set the stag e for future studies of interactions between these genes and AITD.