title: Association of autoimmune thyroid disease with microsatellite markers for the thyrotropin receptor gene and CTLA-4 in Japanese patients.
abstract: In a previous study we identified a microsatellite marker near the thyrotropin receptor (TSHR) gene. Studies with this marker, TSHR-CA, revealed a significant association between autoimmune thyroid disease (AITD) in Japanese patients and one specific allele (allele 1; 180 base pair [bp]) of the microsatellite sequence. In addition, weak evidence for association of AITD with two alleles of the CTLA-4 gene was observed. In the present study, TSHR-CA has been mapped to approximately 600 kb of the TSHR gene using radiation hybrid mapping. TSHR-CA and another TSHR microsatellite marker, TSHR-AT, which is located in intron 2 of TSHR gene, were genotyped in a set of 349 unrelated Japanese AITD patients and 218 Japanese controls. The TSHR-AT marker showed association in this Japanese AITD population with a significant increase 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 significant in hypothyroid patients (thyrotropin-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 also significant for the hypothyroid TBII+ patients (p < 0.05). The CTLA-4 gene was also genotyped in this expanded set of Japanese AITD patients and controls. 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). Associations with TSHR-CA were observed for Hashimoto's thyroiditis (HT) patients with respect to alleles 3 (179 bp; p < 0.05) and 5 (175 bp; p < 0.05) and with hypothyroid TBII- patients for allele 4 (177 bp; p < 0.05). The presence of specific alleles of TSHR-CA, TSHR-AT, and CTLA-4 contribute significant increase in risk of development of AITD. These results confirm and expand on our previous study suggesting that alleles of the TSHR and CTLA-4 genes, or genes near them contribute to AITD susceptibility and set the stage for future studies of interactions between these genes and AITD.
authors.affiliation: Department of Medicine and Clinical Science, Kyoto University Graduate School of Medicine, Japan. akataka@kuhp.kyoto-u.ac.jp
authors.forename: T
authors.initials: T
authors.lastname: Akamizu
authors.forename: M M
authors.initials: MM
authors.lastname: Sale
authors.forename: S S
authors.initials: SS
authors.lastname: Rich
authors.forename: H
authors.initials: H
authors.lastname: Hiratani
authors.forename: J Y
authors.initials: JY
authors.lastname: Noh
authors.forename: N
authors.initials: N
authors.lastname: Kanamoto
authors.forename: M
authors.initials: M
authors.lastname: Saijo
authors.forename: Y
authors.initials: Y
authors.lastname: Miyamoto
authors.forename: Y
authors.initials: Y
authors.lastname: Saito
authors.forename: K
authors.initials: K
authors.lastname: Nakao
authors.forename: D W
authors.initials: DW
authors.lastname: Bowden
mesh_terms: D000069594:Abatacept; D000483:Alleles; D015703:Antigens, CD; D000943:Antigens, Differentiation / Q000235:genetics*; D060908:CTLA-4 Antigen; D005192:Family Health; D005260:Female; D020022:Genetic Predisposition to Disease; D006801:Humans; D018796:Immunoconjugates; D007564:Japan; D008297:Male; D018895:Microsatellite Repeats; D011110:Polymorphism, Genetic; D021101:Radiation Hybrid Mapping; D011989:Receptors, Thyrotropin / Q000235:genetics*; D013967:Thyroiditis, Autoimmune / Q000175:diagnosis / Q000235:genetics*
chemical_list: D015703:Antigens, CD; D000943:Antigens, Differentiation; D060908:CTLA-4 Antigen; C556706:CTLA4 protein, human; D018796:Immunoconjugates; D011989:Receptors, Thyrotropin; D000069594:Abatacept