Abstract
BackgroundThe 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.ObjectivesThe 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.MethodsWe 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 ConclusionsIn 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.
Highlights
Autoimmune thyroid diseases (AITDs), including Graves’ disease (GD) and Hashimoto’s thyroiditis (HT), are among the most common human autoimmune diseases
Principal Findings and Conclusions: In total, 5 single nucleotide polymorphisms (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 Linkage disequilibrium (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 autoimmune thyroid diseases (AITDs) in the Japanese
Summary
Autoimmune thyroid diseases (AITDs), including Graves’ disease (GD) and Hashimoto’s thyroiditis (HT), are among the most common human autoimmune diseases. HT is characterized by apoptosis of thyrocytes leading to hypothyroidism (reviewed by Weetman [4]). Despite their contrasting clinical presentations, GD and HT share many common features, mainly the infiltration of the thyroid by T cells and the production of anti-thyroid autoantibodies (anti-thyroglobulin and anti-thyroid peroxidase antibodies) [3,4,5]. The etiology of the autoimmune thyroid diseases (AITDs), Graves’ disease (GD) and Hashimoto’s thyroiditis (HT), is largely unknown. Recent studies have demonstrated an association between thyroglobulin (Tg) polymorphisms and AITD in Caucasians, suggesting that Tg is a susceptibility gene on 8q24
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