A functional polymorphism in the promoter/enhancer region of the FOXP3/Scurfin gene associated with type 1 diabetes

Bassuny, Wafaa M.; Ihara, Kenji; Sasaki, Yuka; Kuromaru, Ryuichi; Kohno, Hitoshi; Matsuura, Nobuo; Hara, Toshiro

doi:10.1007/s00251-003-0559-8

Cited by 133 publications

(123 citation statements)

References 42 publications

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“…These results are in contrast with those of Bassuny et al (12), who studied a Japanese sample set of 199 patients and 289 control subjects and reported a weak disease association of the (GT)15 allele of the microsatellite marker located between exon Ϫ1 and exon 1 of FOXP3 (and named J17 in our study). In our sample set, this marker did not show any evidence of association with type 1 diabetes (Tables 1 and 2).…”

contrasting

confidence: 56%

No Association Between Variation of the FOXP3 Gene and Common Type 1 Diabetes in the Sardinian Population

et al. 2004

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Mutations of the forkhead/winged helix transcription factor FOXP3 gene on chromosome Xp11.23 cause a rare recessive monogenic disorder called IPEX (immune dysregulation, polyendocrinopathy, including type 1 diabetes, enteropathy, and X-linked syndrome). FOXP3 is necessary for the differentiation of a key immune suppressive subset of T-cells, the CD4؉CD25؉ regulatory T-cells. Previously, we reported a significant malefemale bias in the common, multifactorial form of type 1 diabetes in Sardinia and evidence of linkage of chromosome Xp11 to the disease. These findings indicate that FOXP3 is a prime functional and positional candidate locus for the common form of type 1 diabetes. In the present study, we initially scanned 82 kb of the FOXP3 region for common polymorphisms, including sequencing all of the coding and functionally relevant portions of the gene in 64 Sardinian individuals. Then the most informative polymorphisms in 418 type 1 diabetic families and in 268 male case and 326 male control subjects were sequentially genotyped and tested for disease association. There is no evidence that variants in the FOXP3 regions analyzed are associated with type 1 diabetes and account for the male-female bias observed in Sardinia. Our data indicate that allelic variation in or near the coding regions of the FOXP3 gene does not have a major role in the inherited susceptibility to the common form of type 1 diabetes. Diabetes 53: [1911][1912][1913][1914] 2004 I t is believed that most cases of type 1 diabetes result from an autoimmune, T-cell-dependent destruction of the insulin-producing pancreatic ␤-cells and subsequent irreversible insulin deficiency. Autoimmune diabetes is more commonly inherited as a common multifactorial trait but can also occur in two rare monogenic disorders, APECED (autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy) and IPEX, both of which are characterized by a severe autoimmune pathology of several organs and tissues. The FOXP3 gene and the mouse orthologue Foxp3 are members of a gene family that encode transcription factors possessing a winged helix or forkhead box ("fox") DNA-binding domain. It has been recently shown that Foxp3 represents a key regulator of the development and function of a subset of CD4 regulatory T-cells, which express the interleukin-2 receptor CD25, and are central in the regulation of both the adaptive and innate immune system (1-4). The elucidation of the molecular bases of these rare Mendelian disorders has provided insights into the etiology of autoimmunity in humans and in mice (2,3,5-9). It is possible that common DNA polymorphisms of FOXP3 also influence susceptibility to the common, multifactorial form of type 1 diabetes. This hypothesis was strengthened by the observation that in common type 1 diabetes in Sardinia there is a strong male bias in disease incidence, and evidence of linkage of disease to the same region of chromosome X that encodes FOXP3 (10,11) has been observed. Furthermore, we have excluded the involvement of a Y-chromosome gene as ...

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confidence: 56%

No Association Between Variation of the FOXP3 Gene and Common Type 1 Diabetes in the Sardinian Population

et al. 2004

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“…In this context, polymorphisms in the promoter region of genes coding for molecules strictly linked to the function of Treg may alter gene expression impacting on Treg activity [27]. Indeed, polymorphisms in the FOXP3 promoter gene sequence appear to confer a significant susceptibility to type 1 diabetes in the Japanese population [28] or to be associated with an increased risk of psoriasis in a Chinese population [29]. Our observation that the rs2294020 SNP in the promoter region of the FOXP3 gene is associated with AA is in line with the above considerations.…”

Section: Discussionmentioning

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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“…Several studies have indicated that genetic defects in FOXP3 may lead to its altered levels and functionality and, indeed, autoimmune disorders have been related to various deleterious mutations in FOXP3 [34][35][36][37][38]. With respect to vitiligo, polymorphisms of FOXP3 have been associated with predispostion to the development of the disease (Table 2) [39-41].…”

Section: Forkhead Box P3mentioning

confidence: 99%

Regulatory T cells in vitiligo: Implications for pathogenesis and therapeutics

Dwivedi

Kemp

Laddha

et al. 2015

Autoimmunity Reviews

111

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Vitiligo is a hypomelanotic autoimmune skin disease arising from a breakdown in immunological self-tolerance, which leads to aberrant immune responses against melanocytes.Regulatory T cells (Tregs) are crucial to the development of self-tolerance and so are major foci in the study of autoimmune pathogenesis of vitiligo. This review will summarise recent findings concerning the role of Tregs in the pathogenesis of vitiligo. In addition, as antigen-specific Tregs are a potential route for the reinstatement of immune tolerance, new strategies that expand or induce de novo generation of Tregs and which are currently being investigated as therapies for other autoimmune diseases, will be discussed. These approaches will highlight the opportunities for Treg cell-based therapeutics in vitiligo.4

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A functional polymorphism in the promoter/enhancer region of the FOXP3/Scurfin gene associated with type 1 diabetes

Cited by 133 publications

References 42 publications

No Association Between Variation of the FOXP3 Gene and Common Type 1 Diabetes in the Sardinian Population

No Association Between Variation of the FOXP3 Gene and Common Type 1 Diabetes in the Sardinian Population

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

Regulatory T cells in vitiligo: Implications for pathogenesis and therapeutics

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