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 ... - 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.