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

Ban, Yoshiyuki; Greenberg, David A.; Concepcion, Erlinda; Skrabanek, Lucy; Villanueva, Ronald; Tomer, Yaron

doi:10.1073/pnas.2434175100

Cited by 174 publications

(157 citation statements)

References 71 publications

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“…25 The AITD genes include genes involved in immune regulation such as HLA-DR 62,63 CTLA-4, 64-66 and PTPN22, 67,68 and thyroid specific genes, including thyroglobulin. 69 It is likely some of these genes also contribute to the genetic susceptibility to IIT. However, of these AITD susceptibility genes only the HLA genes have been tested as susceptibility genes for IIT.…”

Section: Genetic Factorsmentioning

confidence: 99%

The clinical and physiological spectrum of interferon‐alpha induced thyroiditis

et al. 2006

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Interferon-alpha (IFN␣) is a major treatment modality for several malignant and nonmalignant diseases, especially hepatitis C. Prospective studies have shown that up to 15% of patients with hepatitis C receiving IFN␣ develop clinical thyroid disease, and up to 40% were reported to develop thyroid antibodies. Some of these complications may result in discontinuation of interferon therapy. Thus, interferon induced thyroiditis (IIT) is a major clinical problem for patients receiving interferon therapy. IIT can be classified as autoimmune type and non-autoimmune type. I nterferons were discovered in the 1950Јs and were immediately recognized for their ability to render cells resistant to virus infection. 1 Interferons have been classified into two major groups, type I interferons and type II interferons, based on their capacity to bind to common receptor types. Type I interferons bind to a type I interferon receptor and include interferon-␣, interferon-␤, interferon-, and interferon-. 2 Type II interferons bind to a distinct type II receptor and include interferon-␥. 2 In addition to their antiviral properties, interferons have immunomodulatory, antiangiogenic, antiproliferative and antitumor activity, and act as important regulators of growth and differentiation. 3 Interferons work by directly binding to either type I or type II receptors. The cytoplasmic domains of the transmembrane glycoproteins are associated with members of the JAK family of kinases. They activate various signaling pathways, including the JAK-STAT pathway, the Crk-pathway, the IRS signaling pathway, and the MAP kinase pathway, which leads to signal transduction and subsequent activation or repression of specific genes. 3,4 More than twenty interferon-induced proteins have been identified. 5 Interferon-alpha (IFN␣) was the first cytokine to be reproduced by recombinant DNA technology and has emerged as a major therapeutic modality for several malignant and nonmalignant diseases. Among the diseases treated by IFN␣ are melanoma, renal cell carcinoma, hairy cell leukemia, Kaposi's sarcoma, and hepatitis B and C. 5 However, the most common prescription for IFN␣

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Section: Genetic Factorsmentioning

confidence: 99%

The clinical and physiological spectrum of interferon‐alpha induced thyroiditis

et al. 2006

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“…Weaker replicated effects are also likely to be conferred by the interleukin 2 receptor alpha gene (IL2RA), 14 CD40 15,16 and FCRL 4 with lesser ORs of 1.10-1.30. Other loci in Caucasian subjects have been reported although findings are less consistent (thyroglobulin 17,18 ) or require further replication (including PTPN2 and CD226 19 ). To help identify further susceptibility loci, large-scale genome-wide association studies (comprising 4500 000 SNPs) have been conducted and are at last beginning to deliver novel susceptibility loci for a number of common diseases including the autoimmune diseases.…”

Section: Discussionmentioning

confidence: 99%

Follow-up of potential novel Graves' disease susceptibility loci, identified in the UK WTCCC genome-wide nonsynonymous SNP study

et al. 2010

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A recent association scan using a genome-wide set of nonsynonymous coding single-nucleotide polymorphisms (nsSNPs) conducted in four diseases including Graves' disease (GD), identified nine novel possible regions of association with GD. We used a case-control approach in an attempt to replicate association of these nine regions in an independent collection of 1578 British GD patients and 1946 matched Caucasian controls. Although none of these loci showed evidence of association with GD in the independent data set, when combined with the original Wellcome Trust Case-Control Consortium study group, minor differences in allele frequencies (PX10 À3 ) remained in the combined collection of 5924 subjects for four of the nsSNPs, present within HDLBP, TEKT1, JSRP1 and UTX. An additional 29 Tag SNPs were screened within these four gene regions to determine if further associations could be detected. Similarly, minor differences only (P¼0.042-0.002) were detected in two HDLBP and two TEKT1 Tag SNPs in the combined UK GD collection. In conclusion, it is unlikely that the SNPs selected in this replication study have a significant effect on the risk of GD in the United Kingdom. Our study confirms the need for large data sets and stringent analysis criteria when searching for susceptibility loci in common diseases.

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“…Indeed, it is assumed that autoimmune thyroid diseases are caused by the combined effects of multiple susceptibility genes and environmental factors which affect both the thyroid and the systemic immune system. [27][28][29][30] Several susceptibility genes have been identified by whole candidate gene analysis, genome linkage studies genome-wide association studies, and whole genome sequencing techniques. These genes are classified as nonspecific immune-related genes and thyroid-specific genes.…”

Section: Loss Of Self-tolerance To the Thyroid In Humans Role Of Genementioning

confidence: 99%

An overview of the pathogenic mechanisms of autoimmune thyroid disorders

Park¹

2014

KMJ

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<title>Abstract Objectives, recent epidemiologic studies in humans suggest an increased prevalence of thyroiditis associated with the excessive administration of iodine. More than three times of recommended daily intake of iodine was observed among people in North America. These people generally presented higher level of anti-thyroglobulin antibody, anti-thyroperoxidase antibody, serum thyroid-stimulating hormone and exacerbation of lymphocytic infiltration in thyroid, which indicated the overconsumption of iodine could induce hypothyroidism and enhance the autoimmune response. However, the precise mechanism of excessive iodine intake induced autoimmune thyroid disease remains largely unknown.</p><p>Over half a century has elapsed since the 1956 identification of thyroglobulin antibodies and the devising of the first experimental model of autoimmune thyroiditis. Since then an incredible amount of experimental work has led to an ever deeper understanding of the nature of thyroid auto-antigens, the main immune mechanisms responsible for Hashimoto's thyroiditis and graves’ disease, their genetics, and therir environmental risk factor. Yet, in the majority of genetically predisposed people the individual trigger of thyroid autoimmunity remains obscure. Similarly, effective prevention strategies still remain to be established and, hopefully, will be the target of future studies.</p>

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

Cited by 174 publications

References 71 publications

The clinical and physiological spectrum of interferon‐alpha induced thyroiditis

The clinical and physiological spectrum of interferon‐alpha induced thyroiditis

Follow-up of potential novel Graves' disease susceptibility loci, identified in the UK WTCCC genome-wide nonsynonymous SNP study

An overview of the pathogenic mechanisms of autoimmune thyroid disorders

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