Association of a Rare Thyroglobulin Gene Microsatellite Variant with Autoimmune Thyroid Disease

Collins, Joanne; Heward, J. M.; Carr‐Smith, Jackie; Daykin, J.; Franklyn, Jayne A.; Gough, Stephen

doi:10.1210/jc.2003-030093

Cited by 68 publications

(59 citation statements)

References 36 publications

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“…Moreover, association studies showed a significant association of Tgms2 with AITD (23; P ϭ 0.004). These results have been replicated recently in a U.K. dataset (25). As in our study, the U.K. study also showed a significant association between Tgms2 and AITD (P Ͻ 0.001).…”

supporting

confidence: 91%

Amino acid substitutions in the thyroglobulin gene are associated with susceptibility to human and murine autoimmune thyroid disease

Ban

Greenberg

Concepcion

et al. 2003

Proc. Natl. Acad. Sci. U.S.A.

173

131

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The 8q24 locus, which contains the thyroglobulin (Tg) gene, was previously shown to be strongly linked with autoimmune thyroid disease (AITD). We 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 < 0.01). Haplotype analysis demonstrated that the combination of these two SNP groups was more significantly associated with AITD (P < 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. We then sequenced exons 10,12, and 33 of the mouse Tg gene in 19 strains of mice. Fifty percent of the strains susceptible to thyroiditis had a unique SNP haplotype at exons 10 and 12, whereas none of the mouse strains that were resistant to thyroiditis had this SNP haplotype (P ‫؍‬ 0.01). We concluded that Tg is a susceptibility gene for AITD, both in humans in and in mice. A combination of at least two Tg SNPs conferred susceptibility to human AITD. Moreover, the exon 33 SNP showed evidence for interaction with HLA-DR3 in conferring susceptibility to Graves' disease.Graves' disease ͉ Hashimoto's disease ͉ thyroiditis T he autoimmune thyroid diseases (AITDs), including Graves' disease (GD) and Hashimoto's thyroiditis (HT), are among the most common human autoimmune diseases with recent data showing a prevalence of clinical AITD of up to 1% in the U.S. population (1, 2). The hallmark of GD is the production of thyroid-stimulating hormone receptor (TSHR)-stimulating antibodies causing hyperthyroidism, whereas HT is characterized by the apoptosis of thyrocytes, leading to hypothyroidism (reviewed in refs. 3 and 4). However, despite their contrasting clinical presentations, GD and HT share many features in common, mainly, infiltration of the thyroid by T cells and production of antithyroid autoantibodies [antithyroglobulin and anti-thyroid peroxidase (TPO) antibodies] (3-5). AITDs are complex diseases, which are caused by an interaction between susceptibility genes (6-8) and nongenetic factors, such as infection (9-12). This paradigm is based on solid epidemiologic evidence demonstrating a genetic predisposition to AITDs, including: (i) familial clustering (13); (ii) a sibling risk ratio ( s ) of Ͼ10 (7, 14); (iii) a high concordance rate in monozygotic twins when compared with dizygotic twins (15-18); and (iv) the presence of thyroid autoantibodies, which are markers of subclinical AITD, in up to 50% of siblings of patients with AITD (19,20).We have previously performed a whole-genome scan in a dataset of 102 multiplex, multigenerational AITD families (540 individuals; refs. 21-23). Three loci on chromosomes 6p, 8q, and 10q showed evidence for linkage with the entire AITD dataset giving maximum multipoint heterogeneity logarithm of odds (lod) scores of 2.0, 3.5, and 4.1, respectively. The 8q24 locus was also reported to be linked with AITD in a dat...

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supporting

confidence: 91%

Amino acid substitutions in the thyroglobulin gene are associated with susceptibility to human and murine autoimmune thyroid disease

Ban

Greenberg

Concepcion

et al. 2003

Proc. Natl. Acad. Sci. U.S.A.

173

131

View full text Add to dashboard Cite

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“…Indeed, this mechanism has been shown to play a major role in the etiology of Type 1 diabetes [56]. Thyroglobulin (Tg) gene is the first thyroid-autoantigen gene to be shown to confer susceptibility for AITD [57][58][59]. Similar to results reported in Caucasian population, a significant association between the 330bp/352bp genotype of Tgms2 and HT was found in a large cohort of Japanese AITD patients [55].…”

Section: Serum Igg4 and Its Thyroid Originsupporting

confidence: 57%

IgG4-related disease of the thyroid glands [Review]

Kakudo

Taniguchi

et al. 2012

Endocr J

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Abstract. Recent reports on Hashimoto's thyroiditis (HT) with increased numbers of IgG4-positive plasma cells suggest that this type of HT may have a close relationship to IgG4-related disease (IgG4-RD). This unique subgroup of HT is termed as IgG4 thyroiditis and reveals distinct clinical, serological, and sonographic features from the non-IgG4 thyroiditis group. On the basis of immunostaining for IgG4, HT was divided into an IgG4 thyroiditis group and a non-IgG4 thyroiditis group. Clinically, IgG4 thyroiditis was associated with younger age group, lower female-male ratio, higher levels of thyroid autoantibodies, diffuse low echogenicity, more rapid progress requiring surgical treatment and more subclinical hypothyroidism. Serum IgG4 concentrations elevated in IgG4 thyroiditis and decreased significantly after a thyroidectomy. Histopathologically, IgG4 thyroiditis showed a higher grade of stromal fibrosis, lymphoplasmacytic infiltration, and follicular cell degeneration than non-IgG4 thyroiditis. IgG4 thyroiditis may represent IgG4-RD of thyroid gland, because it shares common histopathological characteristics with IgG4-RD in other organs. The identification of IgG4-RD of the thyroid gland opens new insights not only for patient's treatment with HT but also for the development of new therapeutic approaches for this rapidly progressive destructive subtype of HT. This article mainly focuses on reviewing the unique histopathological, clinical, and serological features of IgG4 thyroiditis group of HT. The etiology and genetic changes of HT are also discussed.

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“…4 Indeed, additional putative GD susceptibility genes have been recently identified, including CTLA-4, [31][32][33][34] CD40, 35,36 and thyroglobulin. [37][38][39] Patients and methods…”

Section: Discussionmentioning

confidence: 99%

Arginine at position 74 of the HLA-DR β1 chain is associated with Graves' disease

et al. 2004

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Graves' disease (GD) is associated with HLA-DR3 (DRB1*03) in Caucasians, but the exact amino-acid sequence in the DR b1 chain conferring susceptibility to GD is unknown. Therefore, the aim of our study was to identify the critical sequence among the HLA-DRB1 amino-acid residues occupying the peptide-binding pocket, which conferred susceptibility to GD. We sequenced the HLA-DRB1 locus in 208 Caucasian GD patients and 149 Caucasian controls. Sequence analysis showed an increased frequency of DR b-Arg-74 in GD patients compared to controls (41.8 and 13.4%, respectively; P ¼ 2.3 Â 10 À8 , OR ¼ 4.6). Moreover, subset analyses showed that DR b-Arg-74 was also significantly more frequent in the HLA-DR3 negative GD patients than in controls (7.6 vs 0.8%, P ¼ 0.02, OR ¼ 10.5), suggesting that the association with DR b-Arg-74 is independent of the association with HLA-DR3. Structural modeling studies demonstrated that the change at position 74 from the neutral amino acids Ala or Gln to the positively charged amino-acid Arg significantly modifies the three-dimensional structure of the DR peptide-binding pocket. Our results suggested that structural heterogeneity of the DR b-chain peptidebinding pocket P4 at residue 74 predispose some at risk individuals to GD.

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Association of a Rare Thyroglobulin Gene Microsatellite Variant with Autoimmune Thyroid Disease

Cited by 68 publications

References 36 publications

Amino acid substitutions in the thyroglobulin gene are associated with susceptibility to human and murine autoimmune thyroid disease

Amino acid substitutions in the thyroglobulin gene are associated with susceptibility to human and murine autoimmune thyroid disease

IgG4-related disease of the thyroid glands [Review]

Arginine at position 74 of the HLA-DR β1 chain is associated with Graves' disease

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