UMLS:C0011854 - FACTA Search

Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Target Concepts:

Query: UMLS:C0011854 (type 1 diabetes)
20,749 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

There is growing evidence that genetic variation plays an important role in the determination of individual susceptibility to complex disease traits. In contrast to coding sequence polymorphisms, where the consequences of non-synonymous variation may be resolved at the level of the protein phenotype, defining specific functional regulatory polymorphisms has proved problematic. This has arisen for a number of reasons, including difficulties with fine mapping due to linkage disequilibrium, together with a paucity of experimental tools to resolve the effects of non-coding sequence variation on gene expression. Recent studies have shown that variation in gene expression is heritable and can be mapped as a quantitative trait. Allele-specific effects on gene expression appear relatively common, typically of modest magnitude and context specific. The role of regulatory polymorphisms in determining susceptibility to a number of complex disease traits is discussed, including variation at the VNTR of INS, encoding insulin, in type 1 diabetes and polymorphism of CTLA4, encoding cytotoxic T lymphocyte antigen, in autoimmune disease. Examples where regulatory polymorphisms have been found to play a role in mongenic traits such as factor VII deficiency are discussed, and contrasted with those polymorphisms associated with ischaemic heart disease at the same gene locus. Molecular mechanisms operating in an allele-specific manner at the level of transcription are illustrated, with examples including the role of Duffy binding protein in malaria. The difficulty of resolving specific functional regulatory variants arising from linkage disequilibrium is demonstrated using a number of examples including polymorphism of CCR5, encoding CC chemokine receptor 5, and HIV-1 infection. The importance of understanding haplotypic structure to the design and interpretation of functional assays of putative regulatory variation is highlighted, together with discussion of the strategic use of experimental tools to resolve regulatory polymorphisms at a transcriptional level. A number of examples are discussed including work on the TNF locus which demonstrate biological and experimental context specificity. Regulatory variation may also operate at other levels of control of gene expression and the modulation of splicing at PTPRC, encoding protein tyrosine phosphatase receptor-type C, and of translational efficiency at F12, encoding factor XII, are discussed.
...
PMID:Regulatory polymorphisms underlying complex disease traits. 1559 5

The cytotoxic T lymphocyte antigen 4 (CTLA4) acts as a potent negative regulator of T-cell response, and has been suggested as a pivotal candidate gene for autoimmune disorders such as Graves' disease, type 1 diabetes and autoimmune hypothyroidism, among others. Several single-nucleotide polymorphisms (SNPs) have been proposed as the susceptibility variants, or to be in strong linkage disequilibrium (LD) with the variant. Nevertheless, contradictory results have been found, which may be due to lack of knowledge of the genetic structure of CTLA4 and its geographic variation. We have typed 17 SNPs throughout the CTLA4 gene region in order to analyze the haplotype diversity and LD structure in a worldwide population set (1262 individuals from 44 populations) to understand the variation pattern of the region. Allele and haplotype frequency differentiation between populations is consistent with genomewide averages and points to a lack of strong population-specific selection pressures. LD is high and its pattern is not significantly different within or between continents. However, haplotype composition is significantly different between geographical groups. A continent-specific set of haplotype tagging SNPs has been designed to be used for future association studies. These are portable among populations, although their efficiency might vary depending on the population haplotype spectrum.
...
PMID:Haplotype tagging efficiency in worldwide populations in CTLA4 gene. 1603 71

Autoimmune diseases such as Graves' disease and type 1 diabetes have been linked with +49A/G and CT60 single nucleotide polymorphisms (SNPs) in the 3' UTR of the cytotoxic T-lymphocyte antigen-4 (CTLA-4) gene. Both these SNPs are functionally relevant and linked with T-lymphocyte activation. Hypoparathyroidism is seen in 70% of patients with autoimmune polyendocrinopathy candidiasis ectodermal dystrophy syndrome (APECED). Although calcium sensing receptor autoantibodies (CaSRAb) and generalized activation of T lymphocytes are reported among patients with sporadic idiopathic hypoparathyroidism (SIH), CTLA-4 gene SNPs and APECED-related autoimmune regulator (AIRE) gene mutations have not been assessed in them. We studied lead CTLA-4 gene SNPs and APECED-related AIRE gene mutations in 73 patients with SIH and 114 healthy subjects. The CTLA-4 gene SNPs +49A/G in exon 1, CT60A/G in 3' UTR and -318C/T in the promoter region were genotyped by polymerase chain reaction-restriction fragment-length polymorphism (PCR-RFLP) using BstEII, NcoI and MseI endonucleases, respectively. The APECED-related AIRE gene mutations, which is R257X (Finn-major) in exon 6, 4-bp insertion and 13-bp deletion in exon 8, and Iranian Jews population 'Y85C' mutation in exon 2, were studied by PCR-RFLP (Taq-I), PCR and nucleotide sequencing, respectively. CaSRAb were studied by immunoblotting. The frequencies of CTLA-4 A/A(49), A/G(49) and G/G(49) genotypes in the patients (47.9%, 38.4% and 13.7%) and controls (45.6%, 39.5% and 14.9%, respectively) and the frequencies of CT60 A/A, A/G, and G/G genotypes in the patient (42.4%, 37.0% and 20.6%) and the control (38.6%, 40.4% and 21.0%, respectively) groups were not significantly different. The frequencies of various haplotypes including genetic loci +49A/G and CT60 and frequencies of G alleles at these positions were comparable between patient and the control groups and its presence did not correlate with clinical and biochemical indices of the disease. None of the patients had APECED-related AIRE gene mutations. Lack of significant difference in the pattern of CTLA-4 A/G(49) and/or CT60A/G genotypes and absence of common APECED syndrome-related AIRE gene mutations among patients and controls suggest that these sites do not play a role in the development of the SIH.
...
PMID:Polymorphisms at +49A/G and CT60 sites in the 3' UTR of the CTLA-4 gene and APECED-related AIRE gene mutations analysis in sporadic idiopathic hypoparathyroidism. 1631 5

The major susceptibility locus for type 1 diabetes mellitus (T1D) maps to the human lymphocyte antigen (HLA) class II region in the major histocompatibility complex on chromosome 6p21. In southern European populations, like the Basques, the greatest risk to T1D is associated with DR3 homo- and heterozygosity and is comparable to that of DR3/DR4, the highest risk genotype in northern European populations. Celiac disease (CD) is another DR3-associated autoimmune disorder showing certain overlap with T1D that has been explained by the involvement of common genetic determinants, a situation more frequent in DR3-rich populations, like the Basques. As both T1D- and CD-associated HLA alleles are part of conserved extended haplotypes (CEH), we compared DR3-homozygous T1D and CD patients to determine whether CEHs were equally distributed between both disorders or there was a differential contribution of different haplotypes. We observed a very pronounced distribution bias (P<10(-5)) of the two major DR3 CEHs, with DR3-B18 predominating in T1D and DR3-B8 in CD. Additionally, high-density single nucleotide polymorphism (SNP) analysis of the complete CEH [A*30-B*18-MICA*4-F1C30-DRB1*0301-DQB1*0201-DPB1*0202] revealed extraordinary conservation throughout the 4.9 Mbp analyzed supporting the existence of additional diabetogenic variants (other than HLA-DRB1*0301-DQB1*0201), conserved within the DR3-B18 CEH (but not in other DR3 haplotypes) that could explain its enhanced diabetogenicity.
...
PMID:Conserved extended haplotypes discriminate HLA-DR3-homozygous Basque patients with type 1 diabetes mellitus and celiac disease. 1692 49

Patients with type 1 diabetes are treated with daily injections of human insulin, an autoantigen expressed in thymus. Natural CD4(+)CD25(high) regulatory T-cells are derived from thymus, and accordingly human insulin-specific regulatory T-cells should exist. We had a chance to study peripheral blood mononuclear cells (PBMCs) from children with type 1 diabetes both before and after starting insulin treatment, and thus we could analyze the effects of insulin treatment on regulatory T-cells in children with type 1 diabetes. PBMCs were stimulated for 72 h with bovine/human insulin. The mRNA expression of regulatory T-cell markers (transforming growth factor-beta, Foxp3, cytotoxic T-lymphocyte antigen-4 [CTLA-4], and inducible co-stimulator [ICOS]) or cytokines (gamma-interferon [IFN-gamma], interleukin [IL]-5, IL-4) was measured by quantitative RT-PCR. The secretion of IFN-gamma, IL-2, IL-4, IL-5, and IL-10 was also studied. The expression of Foxp3, CTLA-4, and ICOS mRNAs in PBMCs stimulated with bovine or human insulin was higher in patients on insulin treatment than in patients studied before starting insulin treatment. The insulin-induced Foxp3 protein expression in CD4(+)CD25(high) cells was detectable in flow cytometry. No differences were seen in cytokine activation between the patient groups. Insulin stimulation in vitro induced increased expression of regulatory T-cell markers, Foxp3, CTLA-4, and ICOS only in patients treated with insulin, suggesting that treatment with human insulin activates insulin-specific regulatory T-cells in children with newly diagnosed type 1 diabetes. This effect of the exogenous autoantigen could explain the difficulties to detect in vitro T-cell proliferation responses to insulin in newly diagnosed patients. Furthermore, autoantigen treatment-induced activation of regulatory T-cells may contribute to the clinical remission of the disease.
...
PMID:Insulin treatment in patients with type 1 diabetes induces upregulation of regulatory T-cell markers in peripheral blood mononuclear cells stimulated with insulin in vitro. 1713 Apr 91

Progress has been made in investigating the genetic factors involved in type 1 diabetes (T1D) development for the past few years. While Linkage disequilibrium (LD) mapping has been useful for both the confirmation and fine-mapping of susceptibility intervals, as well as identification of etiological mutations, identification of specific disease genes has been a challenge and limited to known candidate genes. The overall risk for T1D from the HLA DR and DQ molecules (IDDM1) is determined by combinations of polymorphic alleles. Functional studies indicate that the susceptible and protective HLA-DR and -DQ bind and present non-overlapping peptides. Although consistent linkage evidence was reported for the susceptibility intervals IDDM2, IDDM5 and IDDM12, evidence for most other intervals varies in different data sets. The variable number of tandem repeats at the 5' end of the insulin gene (IDDM2) regulates insulin expression in the thymus. Studies on IDDM5 have led to the discovery of a novel polymorphism 163 A-->G (M55V) in SUMO4 gene, which was found to be associated with T1D patients with Asian origin. Functionally SUMO4 conjugates to IkBalpha and negatively regulates NFkB transcriptional pathway. The M55V substitution reduces the sumoylation activity of the V55 variant, which resulted in higher NFkB dependent transcriptional activity. The polymorphisms of the cytotoxic T lymphocyte antigen 4 gene (CTLA4, IDDM12) encoding a regulatory molecule in the immune system associate with T1D and autoimmune thyroid diseases (ATD). The 3' untranslated region of this gene determines the level of soluble CTLA-4. Genetic mapping of variants conferring a small disease risk can identify pathways in complex disorders, as evidenced by quantitative alterations of candidate genes contributing to autoimmune tissue destruction. Moreover, the identification of two transcription factors that, when mutated, are responsible for severe autoimmune disease is leading to a better understanding of T cell tolerance. Both AIRE and Foxp3, identified initially via their association with genetically manipulated mice, are involved in tolerance induction in humans. Although mutations in these genes may cause rare but serious diseases, it is likely that other transcription factors will contribute to the genetic load that predisposes certain individuals to disease.
...
PMID:Functional evaluation of the type 1 diabetes (T1D) susceptibility candidate genes. 1744 64

Type 1 Diabetes Mellitus is a complex and polygenic disease due to gene-environment interactions. The role of genetic background of diabetes has been extensively investigated. However, final conclusions have not yet been reached. Family and twin studies have shown that genetic factors are important contributors to the genetic risk of the disease. Although more than 18 diabetes-predisposing genes have been reported to date, only the major histocompatibility complex (HLA) region on chromosome 6p21 (IDDM1) and the insulin gene on chromosome 11p15 (IDDM 2) have been conclusively associated with susceptibility to type 1 diabetes. However, it has been shown recently that cytotoxic lymphocyte antigen 4 (CTLA4) on chromosome 2q33 (IDDM12) and LYP/PTPN22 on chromosome 1p13 also contribute to the genetic risk of T1DM. The article reviews the recent advances in this field. By identifying new loci or reanalyzing the known ones and with the help of more powerful studies, it is possible in the future to be able to shed more light on the complex field of the genetics of type 1 diabetes and to further understand the pathophysiology of the disease, which will allow us eventually to treat or prevent it.
...
PMID:Genetics of type 1 diabetes mellitus. 1755 74

Cytotoxic T lymphocyte antigen 4 (CTLA4) is a potent inhibitory co-stimulatory molecule believed to be involved in type 1 diabetes and other autoimmune diseases. An association has been reported of both mRNA expression and serum levels of the soluble splice variant of CTLA4 (sCTLA4) with type 1 diabetes. Furthermore, recombinant fusion proteins CTLA4Ig and LEA29Y have been proposed as therapies for type 1 diabetes. We studied the role of (s)CTLA4 in islet autoimmunity. Binding capacity of the proteins to antigen-presenting cells was determined by flow cytometry in competition and binding assays. Functionality of sCTLA4 as well as the therapeutic inhibitory fusion proteins CTLA4Ig and LEA29Y was measured in a dose-response lymphocyte stimulation test, using a panel of diabetes-associated T cell clones reactive to islet autoantigens. As controls, mixed lymphocyte reactions (MLR) were performed to assess functionality of these proteins in a primary alloreactive setting. All three CTLA4 molecules were able to bind to antigen-presenting cells and inhibit the expression of CD80/CD86. sCTLA4 was able to suppress proliferation of different committed autoreactive T cell clones in a dose-dependent manner, whereas CTLA4Ig and LEA29Y were not. Conversely, CTLA4Ig and LEA29Y, rather than sCTLA4, were able to suppress naive alloreactive proliferation in a MLR. Our results indicate a differential role for sCTLA4, CTLA4Ig and LEA29Y proteins in memory versus primary immune responses with implications for efficacy in intervention therapy.
...
PMID:Differential inhibition of autoreactive memory- and alloreactive naive T cell responses by soluble cytotoxic T lymphocyte antigen 4 (sCTLA4), CTLA4Ig and LEA29Y. 1792 73

Autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED) is a rare autosomal recessive disorder typically presenting with chronic mucocutaneous candidiasis, hypoparathyroidism, and adrenal failure variably accompanied by other symptoms. APECED is caused by a mutation in the autoimmune regulator gene (AIRE). Today over 60 different mutations are known world-wide, most of them localized in exons 2, 8, and 10. We report here a German girl with rheumatoid factor positive arthritis, chronic mucocutaneous candidiasis, autoimmune hepatitis, chronic diarrhea, vitiligo, hypothyroidism, hypoparathyroidism, and adrenal failure who is homozygous for a novel mutation at the end of exon 3 of the AIRE gene (c.462G>A), within the conserved splice donor sequence. This mutation probably introduces a frameshift after amino acid 154 (p.Pro154fs) by skipping exon 4. In addition, we analyzed five other family members out of three generations for the AIRE gene mutation and for polymorphisms in the cytotoxic T lymphocyte antigen 4 (CTLA4) gene region and lymphoid protein tyrosine phosphatase (PTPN22) gene, which are associated with the occurrence of sporadic autoimmune Addison's disease, type 1 diabetes mellitus, and generalized vitiligo.
...
PMID:Novel homozygous AIRE mutation in a German patient with severe APECED. 1920 22

We studied the association of cytotoxic T lymphocyte antigen-4 gene (CTLA4) polymorphisms with the development of type 1 diabetes (T1D) in Korean children and adolescents. A total of 176 Korean subjects (92 females and 84 males) with childhood-onset T1D were studied. The A/G polymorphism at position 49 in CTLA4 exon 1 and the C/T polymorphism at position -318 in the CTLA4 promoter were analyzed by PCR-RFLP methods. The genotype and allele frequencies of the CTLA4 polymorphisms in the T1D patients were not different from those in the controls. These polymorphisms were not associated with the clinical characteristics or the development of autoimmune thyroid disease in the T1D patients. The frequency of the A allele was significantly higher in the patients that did not have two out of the three susceptible HLA-DRB1 alleles, which were DRB1*0301, *0405 and *09012, compared to the controls (P<0.05). These results suggest that CTLA4 polymorphisms do not directly confer any susceptibility to T1D. However, a CTLA4-mediated susceptibility effect on the development of T1D might be significant in children and adolescents that do not have susceptible HLA class II alleles.
...
PMID:Association of cytotoxic T lymphocyte antigen-4 gene polymorphisms and HLA class II alleles with the development of type 1 diabetes in Korean children and adolescents. 1994 52

<< Previous 1 2 3 Next >>