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Multiple SNPs in intron 41 of thyroglobulin gene are associated with autoimmune thyroid disease in the Japanese population.

ABSTRACT: BACKGROUND: The etiology of the autoimmune thyroid diseases (AITDs), Graves' disease (GD) and Hashimoto's thyroiditis (HT), is largely unknown. However, genetic susceptibility is believed to play a major role. Two whole genome scans from Japan and from the US identified a locus on chromosome 8q24 that showed evidence for linkage with AITD and HT. Recent studies have demonstrated an association between thyroglobulin (Tg) polymorphisms and AITD in Caucasians, suggesting that Tg is a susceptibility gene on 8q24. OBJECTIVES: The objective of the study was to refine Tg association with AITD, by analyzing a panel of 25 SNPs across an extended 260 kb region of the Tg. METHODS: We studied 458 Japanese AITD patients (287 GD and 171 HT patients) and 221 matched Japanese control subjects in association studies. Case-control association studies were performed using 25 Tg single nucleotide polymorphisms (SNPs) chosen from a database of the Single Nucleotide Polymorphism Database (dbSNP). Haplotype analysis was undertaken using the computer program SNPAlyze version 7.0. PRINCIPAL FINDINGS AND CONCLUSIONS: In total, 5 SNPs revealed association with GD (P<0.05), with the strongest SNP associations at rs2256366 (P?=?0.002) and rs2687836 (P?=?0.0077), both located in intron 41 of the Tg gene. Because of the strong LD between these two strongest associated variants, we performed the haplotype analysis, and identified a major protective haplotype for GD (P?=?0.001). These results suggested that the Tg gene is involved in susceptibility for GD and AITD in the Japanese.

SUBMITTER: Ban Y

PROVIDER: S-EPMC3360768 | biostudies-literature | 2012

REPOSITORIES: biostudies-literature

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Multiple SNPs in intron 41 of thyroglobulin gene are associated with autoimmune thyroid disease in the Japanese population.

Ban Yoshiyuki Y Tozaki Teruaki T Taniyama Matsuo M Skrabanek Luce L Nakano Yasuko Y Ban Yoshio Y Hirano Tsutomu T

PloS one 20120525 5

<h4>Background</h4>The etiology of the autoimmune thyroid diseases (AITDs), Graves' disease (GD) and Hashimoto's thyroiditis (HT), is largely unknown. However, genetic susceptibility is believed to play a major role. Two whole genome scans from Japan and from the US identified a locus on chromosome 8q24 that showed evidence for linkage with AITD and HT. Recent studies have demonstrated an association between thyroglobulin (Tg) polymorphisms and AITD in Caucasians, suggesting that Tg is a suscept ...[more]

PMID: 22662162

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Project description:BACKGROUND:Our studies over recent years have focused on some new ideas concerning the pathogenesis for the orbital reaction that characterizes Graves' ophthalmopathy namely, that there are antigens expressed by thyroid tissue and orbital tissue where they are targeted by autoantibodies and/or sensitized T cells, leading to orbital inflammation. While this has been well studied for the thyroid stimulating hormone-receptor, the possible role of another major thyroid antigen, Thyroglobulin (TG), has been largely ignored. METHODS:We identified novel variant 1623 A/G single nucleotide polymorphism (SNP) (rs180195) in the promoter of TG gene associated with autoimmune thyroid disorders. We genotyped the TG SNPs rs2069566, rs2076739, rs121912646, rs121912647, rs121912648, rs121912649, rs121912650, rs137854433, rs137854434, and rs180195 by MassARRAY SNP analysis using iPLEX technology in a cohort of 529 patients with thyroid autoimmunity with and without ophthalmopathy, and controls. RESULTS:We showed that variant 1623 A/G SNP (rs180195) in the promoter of TG gene is a marker for thyroid autoimmunity, but not for ophthalmopathy. We showed that there was a significant difference in the distribution of the major allele (G) vs minor allele (A) in patients with Hashimoto's thyroiditis (HT). In HT the wild-type (GG) genotype was less common. We showed that the genotypes homozygous AA and heterozygous GA rs180195 SNP in the promoter of TG gene were more closely associated with thyroid autoimmunity than the wild-type (GG) polymorphism, and are thus, markers of autoimmunity. CONCLUSION:rs180195 SNP was previously identified by Stefan et al independently of us, who showed that this TG SNP predisposed to autoimmune thyroid diseases. However, this is the first study to explore the association between TG SNPs and HT. Our findings support the notion that the thyroid and orbital disorders are not part of the same disease, ie, "Graves' disease" or "Hashimoto's disease", but separate autoimmune disorders.

Dataset Information

Multiple SNPs in intron 41 of thyroglobulin gene are associated with autoimmune thyroid disease in the Japanese population.

Publications

Multiple SNPs in intron 41 of thyroglobulin gene are associated with autoimmune thyroid disease in the Japanese population.

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