Association of the TGrI29 microsatellite in thyroglobulin gene with autoimmune thyroiditis in a Argentinian population: a case–control study

Varela, Viviana; Rizzo, Leonardo; Domené, Sabina; Bruno, Oscar D.; Tellechea, Mariana Lorena; Rivolta, Carina M.; Targovnik, Héctor M.

doi:10.1007/s12020-010-9398-1

Cited by 7 publications

(2 citation statements)

References 41 publications

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“…Moreover, TG has emerged as the only thyroid-specific gene that confers susceptibility to both GD and HT (11). Following these findings, association studies have identified several polymorphisms in the TG locus that were associated with AITD in various ethnic populations (11)(12)(13)(14)(15). Moreover, we performed a comprehensive sequence analysis of the entire TG coding region (48 exons) and identified a single-nucleotide polymorphism (SNP) cluster in exons 10 -12 as well as an SNP in exon 33 that were significantly associated with AITD in North American Caucasians (11).…”

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confidence: 99%

Novel Variant of Thyroglobulin Promoter Triggers Thyroid Autoimmunity through an Epigenetic Interferon α-modulated Mechanism

Stefan

Jacobson

Huber

et al. 2011

Journal of Biological Chemistry

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Autoimmune thyroid diseases (AITD) arise from complex interactions between genetic, epigenetic, and environmental factors. Whole genome linkage scans and association studies have established thyroglobulin (TG) as a major AITD susceptibility gene. However, the causative TG variants and the pathogenic mechanisms are unknown. Here, we describe a genetic/ epigenetic mechanism by which a newly identified TG promoter single-nucleotide polymorphism (SNP) variant predisposes to AITD. Sequencing analyses followed by case control and familybased association studies identified an SNP (؊1623A3 G) that was associated with AITD in the Caucasian population (p ‫؍‬ 0.006). We show that the nucleotide substitution introduced by SNP (؊1623A/G) modified a binding site for interferon regulatory factor-1 (IRF-1), a major interferon-induced transcription factor. Using chromatin immunoprecipitation, we demonstrated that IRF-1 binds to the 5 TG promoter motif, and the transcription factor binding correlates with active chromatin structure and is marked by enrichment of mono-methylated Lys-4 residue of histone H3, a signature of active transcriptional enhancers. Using reporter mutations and siRNA approaches, we demonstrate that the disease-associated allele (G) conferred increased TG promoter activity through IRF-1 binding. Finally, treatment of thyroid cells with interferon ␣, a known trigger of AITD, increased TG promoter activity only when it interacted with the disease-associated variant through IRF-1 binding. These results reveal a new mechanism of interaction between environmental (IFN␣) and genetic (TG) factors to trigger AITD.Autoimmune thyroid diseases (AITD), 4 including Graves disease (GD) and Hashimoto thyroiditis (HT), are characterized by infiltration of the thyroid by T and B cells that react with local antigens leading to immune destruction of the thyroid in HT and production of thyroid-stimulating hormone receptor (TSHR) antibodies in GD. These result in the clinical manifestations of hypothyroidism in HT and hyperthyroidism in GD (1, 2). There is solid evidence that interactions between susceptibility genes and environmental triggers activate the sequence of cellular and humoral immune responses to thyroid antigens that cause AITD (1, 3, 4). Several environmental factors, including exposure to excess iodine, selenium deficiency, various infectious diseases, certain drugs, and pollutants have been associated with AITD (5, 6). Among these factors, interferon ␣ (INF␣), a therapeutic agent widely used for the treatment of chronic hepatitis C infection, has recently emerged as a major factor that triggers AITD (7,8).To date, several gene loci have been associated with AITD, including immune genes (HLA-DR, CTLA-4, CD40, FOXP3, and CD25) and thyroid-specific genes (TSHR and TG). Whole genome linkage screens, performed by our group (9) and others (10), have shown that the thyroglobulin (TG) locus on chromosome 8q24 is strongly linked with AITD. Moreover, TG has emerged as the only thyroid-specific gene that confers susceptibili...

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confidence: 99%

Novel Variant of Thyroglobulin Promoter Triggers Thyroid Autoimmunity through an Epigenetic Interferon α-modulated Mechanism

Stefan

Jacobson

Huber

et al. 2011

Journal of Biological Chemistry

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“…These genes encode the main thyroid autoantigens in the course of autoimmune thyroid diseases (AITD). The Tg gene was shown to be associated with a predisposition to AIT in various populations [ 20 , 21 , 22 , 23 , 24 , 25 , 26 , 27 ]. It is postulated that some Tg SNPs modify protein structure and, thus, change the immunogenicity of the molecule [ 20 ].…”

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confidence: 99%

Is There a Link between Thyroid Peroxidase Gene Promoter Polymorphisms and Autoimmune Thyroiditis in the Polish Population?

Lacka,

Maciejewski,

Jarecki

et al. 2024

IJMS

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(1) Autoimmune thyroiditis (AIT) is the most common cause of primary hypothyroidism and one of the most frequent organ-specific autoimmune diseases. Its pathogenesis is polygenic and still requires further research. The aim of the study was to assess, for the first time in the Caucasian population, the role of selected TPO gene promoter polymorphisms (rs2071399 G/A, rs2071400C/T, rs2071402 A/G, and rs2071403 A/G) in the development of AIT. A total of 237 patients diagnosed with AIT and 130 healthy controls were genotyped for four TPO gene polymorphisms, and the results were statistically analyzed to check for the role of these polymorphisms. There were no significant differences in the genotype and allele frequencies of the studied TPO gene promoter polymorphisms between patients and controls (p > 0.05). The haplotype distribution (rs2071400–rs2071402–rs2071403) between the two studied groups was similar for the most common variants (CGA, CAG, TGG). Only a rare haplotype (CGG) occurred more frequently among patients compared to controls (p = 0.04). The studied TPO gene promoter polymorphisms did not show an association with susceptibility to AIT in the Caucasian Polish population, contrary to the results in Japanese patients.

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Diagnostic value of antithyroid peroxidase antibody for incidental autoimmune thyroiditis based on histopathologic results

et al. 2012

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Detection of antithyroid peroxidase antibody (TPOAb) is widely used in the diagnosis of autoimmune thyroiditis (AIT), but no research has evaluated the diagnostic accuracy of TPOAb detection using histopathologic reference standards. To fill this research gap, this study assessed the diagnostic accuracy of detection of TPOAb and that of other serological markers in asymptomatic patients who had been diagnosed with AIT by histopathologic analysis after thyroid surgery. After review of patient records, 598 patients who had undergone thyroid nodule surgery were enrolled for examination for thyroid parenchyma by a pathologist and classification into no co-existing lymphocytic thyroiditis, Hashimoto thyroiditis, or non-Hashimoto type of lymphocytic thyroiditis (NHLT). The correlation between patient serological data and thyroid parenchyma pathology was analyzed. Statistically significant differences (P < 0.05) were found between co-existing lymphocytic thyroiditis and no co-existing lymphocytic thyroiditis groups regarding thyroid-stimulating hormone (TSH) and TPOAb levels. And, TPOAb titer was significantly associated with the degree of inflammation. An abnormal TPOAb titer was found in 86 of the 598 patients (14.4 %) and the specificity of TPOAb detection for AIT diagnosis was found to be 96.9 %. The prevalence of Hashimoto thyroiditis and NHLT in the 560 papillary thyroid cancer (PTC) patients was found to be 7.9 and 17.9 %, respectively. The results indicate that TPOAb titer is associated with the degree of thyroid inflammation and that detection of TPOAb is a very specific means of diagnosing AIT. The results also indicate that the incidence of AIT and PTC coexistence is relatively high.

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Association of the TGrI29 microsatellite in thyroglobulin gene with autoimmune thyroiditis in a Argentinian population: a case–control study

Cited by 7 publications

References 41 publications

Novel Variant of Thyroglobulin Promoter Triggers Thyroid Autoimmunity through an Epigenetic Interferon α-modulated Mechanism

Novel Variant of Thyroglobulin Promoter Triggers Thyroid Autoimmunity through an Epigenetic Interferon α-modulated Mechanism

Is There a Link between Thyroid Peroxidase Gene Promoter Polymorphisms and Autoimmune Thyroiditis in the Polish Population?

Diagnostic value of antithyroid peroxidase antibody for incidental autoimmune thyroiditis based on histopathologic results

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