Genetic association studies of the FOXP3 gene in Graves’ disease and autoimmune Addison’s disease in the United Kingdom population

Owen, Catherine J.; Eden, James; Jennings, Claire; Wilson, Valerie; Cheetham, Tim; Pearce, Simon H. S.

doi:10.1677/jme.1.02072

Cited by 68 publications

(45 citation statements)

References 58 publications

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“…Mutations in FOXP3 result in the fatal immunodysregulation, polyendocrinopathy, enteropathy, X-linked (IPEX) syndrome. Polymorphisms in FOXP3 have been associated with AITD in Caucasians (especially with Graves' disease developing below the age of 30 years) but not in Japanese (29,30). The location of FOXP3 on the X chromosome might contribute to the female preponderance of AITD.…”

Section: Genetic Factorsmentioning

confidence: 99%

MECHANISMS IN ENDOCRINOLOGY: Autoimmune thyroid disease: old and new players

Effraimidis

Wiersinga

2014

European Journal of Endocrinology

284

196

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The last 10 years have seen some progress in understanding the etiology of autoimmune thyroid disease (AITD). The female preponderance can now be explained -at least in part -by fetal microchimerism and X-chromosome inactivation. The number of identified susceptibility genes for AITD is increasing (among others now including TSHR, TG, HLA, CTLA4, PTPN22, CD40, FCRL3, IL2RA, and FOXP3), but these genes together probably do not explain more than about 10% of the heritability of AITD. As twin studies indicate that genes contribute for 70% of AITD, it follows that there must be many more loci, each of them contributing a little. While the genetic studies have clarified why various autoimmune diseases so often cluster in the same patient, the molecular mechanism of action of these genetic polymorphisms (frequently located in introns) has hardly been explained. Polymorphisms in AITD susceptibility genes may become helpful in clinical practice, e.g. in assessing risk of recurrent Graves' hyperthyroidism (GH) after a course of antithyroid drugs. Moderate alcohol intake decreases the risk on overt GH and overt Hashimoto's hypothyroidism. Current smokers -as well known -are at increased risk for Graves' disease, but -surprisingly -at diminished risk for Hashimoto's thyroiditis. Low selenium and low vitamin D levels might increase the risk of developing AITD, but data are still inconclusive. Current options for preventive interventions in subjects at risk to develop AITD are very limited.

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Section: Genetic Factorsmentioning

confidence: 99%

MECHANISMS IN ENDOCRINOLOGY: Autoimmune thyroid disease: old and new players

Effraimidis

Wiersinga

2014

European Journal of Endocrinology

284

196

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“…The nuclear transcription factor forkhead box protein 3 (FoxP3) has been described to be fundamental in regulating the differentiation and function of T reg cells [4,5]. Indeed, mutations located on the FOXP3 gene have been associated with the onset of several autoimmune diseases, such as immune dysregulation, polyendocrinopathy, enteropathy, X-linked syndrome (IPEX), type 1 diabetes, Grave's disease and systemic lupus erythematosus (SLE) [6][7][8][9][10]. Like other members of the Fox protein family, FoxP3 is characterized by a highly conserved forkhead DNA-binding domain, a leucine zipper-like domain and a zinc finger motif.…”

Section: Regulatory T Cells (T Reg ) Represent a Subset Of Cd4mentioning

confidence: 99%

“…During the active state of the disease the small intestine of CD patients is characterized by a drop in lactate levels, an increased intestinal permeability due to the interaction between gliadin and epithelial cells (6) and high production of butyrate from the microbial flora (7). Furthermore, expanded intraepithelial lymphocytes (IELs) produce a high amount of proinflammatory cytokines such as interferon (IFN)-g and interleukin (IL)-17 (8). The increased intestinal permeability allows gliadin peptides to translocate to the lamina propria of the small intestine, where they are recognized by APC (9).…”

Section: Regulation Of Foxp3 Isoforms In Coeliac Diseasementioning

confidence: 99%

Proinflammatory cytokine interferon-γ and microbiome-derived metabolites dictate epigenetic switch between forkhead box protein 3 isoforms in coeliac disease

Serena

Shu

Camhi

et al. 2017

Clinical and Experimental Immunology

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SummaryCoeliac disease (CD) is an autoimmune enteropathy triggered by gluten and characterized by a strong T helper type 1 (Th1)/Th17 immune response in the small intestine. Regulatory T cells (T reg ) are CD4 1 CD25 11 forkhead box protein 3 ( FoxP3 1 ) cells that regulate the immune response. Conversely to its counterpart, FoxP3 full length (FL), the alternatively spliced isoform FoxP3 D2, cannot properly down-regulate the Th17-driven immune response. As the active state of CD has been associated with impairments in T reg cell function, we aimed at determining whether imbalances between FoxP3 isoforms may be associated with the disease. Intestinal biopsies from patients with active CD showed increased expression of FOXP3 D2 isoform over FL, while both isoforms were expressed similarly in non-coeliac control subjects (HC). Conversely to what we saw in the intestine, peripheral blood mononuclear cells (PBMC) from HC subjects did not show the same balance between isoforms. We therefore hypothesized that the intestinal microenvironment may play a role in modulating alternative splicing. The proinflammatory intestinal microenvironment of active patients has been reported to be enriched in butyrate-producing bacteria, while high concentrations of lactate have been shown to characterize the preclinical stage of the disease. We show that the combination of interferon (IFN)-g and butyrate triggers the balance between FoxP3 isoforms in HC subjects, while the same does not occur in CD patients. Furthermore, we report that lactate increases both isoforms in CD patients. Collectively, these findings highlight the importance of the ratio between FoxP3 isoforms in CD and, for the first time, associate the alternative splicing process mechanistically with microbial-derived metabolites.

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“…Treg are commonly identified by the intracellular expression of forkhead box P3 transcription factor (FOXP3) that controls their development and function [12][13][14][15]. Mutations in human FOXP3 gene cause the IPEX syndrome [16], while its polymorphisms are associated with immune-mediated diseases [17][18][19][20].…”

Section: Introductionmentioning

confidence: 99%

Single nucleotide polymorphisms in the promoter regions of Foxp3 and ICOSLG genes are associated with Alopecia Areata

et al. 2012

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Alopecia areata (AA), an autoimmune disease affecting anagen stage hair follicles, is associated with polymorphisms in immune-related genes and with decreased number of CD4? CD25? T regulatory cells (Treg). Treg function is modulated by the forkhead box protein 3 (FOXP3) transcription factor and by inducible costimulator (ICOS), through interaction with the relative ligand, ICOSLG, whose genes are polymorphic. The aim of the study was to investigate whether specific single nucleotide polymorphisms (SNPs) of the rs2294020 FOXP3 and/ or rs378299 ICOSLG genes may be associated with AA. A case-control study was performed in 120 AA patients and 84 controls. SNPs were analyzed by gene sequencing. FOXP3 and ICOSLG gene expressions were analyzed by real-time PCR. Increased frequencies of the genotype carrying the FOXP3 rs2294020-3675(A) [P = 0.002, OR (95 % CI): 2.55 (1.2-2.7)] or the ICOSLG rs378299-509(C) [P = 0.01, OR (95 % CI): 2.21 (1.1-2.6)] allelic variants were observed in AA patients than in controls. The genotype carrying the combination of the FOXP3 rs2294020-3675(A) and ICOSLG rs378299-509(C) allelic variants with the HLA DQB1*03 allele was more frequently present in AA patients than in controls (P = 0.04). The presence of the FOXP3 rs2294020-3675(A) or the I-COSLG rs378299-509(C) allelic variant was associated with reduced relative gene expression in AA patients. These data suggest that rs2294020 SNP of FOXP3 gene and rs378299 SNP of ICOSLG gene are associated with AA and with a reduced expression of the FOXP3 and ICOSLG genes in alopecia patients.

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Genetic association studies of the FOXP3 gene in Graves’ disease and autoimmune Addison’s disease in the United Kingdom population

Cited by 68 publications

References 58 publications

MECHANISMS IN ENDOCRINOLOGY: Autoimmune thyroid disease: old and new players

MECHANISMS IN ENDOCRINOLOGY: Autoimmune thyroid disease: old and new players

Proinflammatory cytokine interferon-γ and microbiome-derived metabolites dictate epigenetic switch between forkhead box protein 3 isoforms in coeliac disease

Single nucleotide polymorphisms in the promoter regions of Foxp3 and ICOSLG genes are associated with Alopecia Areata

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