Autoimmune Thyroid Disease, Susceptibility To, 3


A number sign (#) is used with this entry because a combination of single-nucleotide polymorphisms (SNPs) of the thyroglobulin gene (TG; 188450) has been associated with susceptibility to autoimmune thyroid disease showing linkage to 8q24. Variation in the ZFAT1 gene (610931) has also been identified as contributing to susceptibility to AITD in the 8q24 region.

The autoimmune thyroid disorders, or AITDs, comprise 2 related disorders, Graves disease (275000) and Hashimoto thyroiditis (140300). See 608173.


Tomer et al. (1999) performed a whole-genome scan in 56 families that revealed 7 major AITD loci and additional minor loci, among them one on chromosome 8q24 containing the thyroglobulin gene (TG; 188450).

Sakai et al. (2001) undertook a genomewide analysis of 123 Japanese sib pairs affected with AITD. At 19 regions on 14 chromosomes, the multipoint maximum lod score was greater than 1. Chromosome 8q23-q24 yielded suggestive evidence for linkage to Hashimoto thyroiditis, with a maximum lod score of 3.77 at marker D8S272.

Tomer et al. (2002) analyzed the TG region in detail using an expanded dataset of 102 families. Linkage analysis showed strong evidence for linkage at the TG gene locus, with a multipoint lod score (MLS) of 3.5 between markers D8S514 and D8S284. Tomer et al. (2002) identified a microsatellite inside TG intron 27, designated Tgms2, that showed strong evidence for linkage to AITD (MLS, 2.9), further suggesting that the TG gene is linked to AITD. Tomer et al. (2002) stated that TG was the first thyroid-specific gene to be found linked and associated with AITD. They noted that Sakai et al. (2001) identified a susceptibility locus for Hashimoto thyroiditis on chromosome 8q24 very close to the locus identified by them, and stated that the study of Sakai et al. (2001) suggested that the TG gene may predispose to AITD across populations of different ethnic backgrounds.

Tomer et al. (2003) performed a whole-genome linkage study in an expanded data set of 102 multiplex families with AITD (540 individuals), using 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). At the 8q locus the maximum 2-point lod score was 2.9 for marker D8S284 assuming autosomal recessive inheritance and penetrance of 30%.

Molecular Genetics

Association with Variation in the TG Gene

Ban et al. (2003) sequenced all 48 exons of the TG gene and identified 14 single-nucleotide polymorphisms (SNPs). Case-control association studies demonstrated that an exon 10-12 SNP cluster and an exon 33 SNP were significantly associated with AITD (p less than 0.01); see 188450.0008-188450.0010. Haplotype analysis demonstrated that the combination of these 2 SNP groups was more significantly associated with AITD (p less than 0.001). Gene-gene interaction studies provided evidence for an interaction between HLA-DR3 and the exon 33 SNP, giving an odds ratio of 6.1 for Graves disease. The finding of a unique SNP haplotype at exons 10 and 12 of the mouse Tg gene led Ban et al. (2003) to conclude that TG is a susceptibility gene for AITD in both humans and mice.

In a study of 1,214 Caucasian patients in the United Kingdom with AITD (960 with Graves disease and 254 with autoimmune hypothyroidism) examining the same SNPs in the TG gene as those studied by Ban et al. (2003), Collins et al. (2004) found no evidence for association of these DNA variants with AITD. Collins et al. (2004) stated that their study was the largest case-control association study to that time, and concluded that while they could not exclude the TG region as harboring a susceptibility locus for AITD, the SNPs in exons 10, 12, and 33 do not have a causal role for AITD in the United Kingdom.

Collins et al. (2003) performed a case-control association study on patients with AITD and controls using the associated markers D8S284 and Tgms2 identified by Tomer et al. (2002). No differences in allele frequencies were observed between AITD cases and controls for D8S284. Compared with the 3 common alleles (frequencies greater than 10%), the rare alleles of Tgms2 were increased (chi square = 10.6; P = 0.001). This group included the 336-bp allele (increased in cases vs controls: chi square = 24.97; P less than 0.001), which had been reported to be associated with AITD. The rarity of this allele in the United Kingdom, however, precluded analysis in their family dataset. The authors concluded that although these findings may represent a random event, in view of previous reports of linkage and association of this gene region to AITD, they may be an example of a rare causal variant of a complex disease.

Association with Variation in the ZFAT1 Gene

In an association analysis using 112 Japanese probands from AITD families studied by Sakai et al. (2001), Shirasawa et al. (2004) identified an association between the ZFAT1 gene (610931) and AITD linked to chromosome 8q24. Independent association analysis in 515 affected individuals and 526 controls confirmed the association. A functional SNP in intron 9 of the ZFAT1 gene, Ex9b-SNP10 (610931.0001), was associated with increased risk for AITD. Shirasawa et al. (2004) noted that association of the TG gene with AITD was found in Caucasians. They did not find this association in their study, and suggested that this finding may be due to differences in ethnic background between Caucasians and Japanese.