Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0011854 (type 1 diabetes)
 20,749 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Susceptibility to autoimmune insulin-dependent (type 1) diabetes mellitus is determined by a combination of environmental and genetic factors, which include variation in MHC genes on chromosome 6p21 (IDDM1) and the insulin gene on chromosome 11p15 (IDDM2). However, linkage to IDDM1 and IDDM2 cannot explain the clustering of type 1 diabetes in families, and a role for other genes is inferred. In the present report we describe linkage and association of type 1 diabetes to the CTLA-4 gene (cytotoxic T lymphocyte associated-4) on chromosome 2q33 (designated IDDM12). CTLA-4 is a strong candidate gene for T cell-mediated autoimmune disease because it encodes a T cell receptor that mediates T cell apoptosis and is a vital negative regulator of T cell activation. In addition, we provide supporting evidence that CTLA-4 is associated with susceptibility to Graves' disease, another organ-specific autoimmune disease.
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PMID:The CTLA-4 gene region of chromosome 2q33 is linked to, and associated with, type 1 diabetes. Belgian Diabetes Registry. 881 51

Genome-wide scans for linkage of chromosome regions to type 1 diabetes in affected sib pair families have revealed that the major susceptibility locus resides within the major histocompatibility complex (MHC) on chromosome 6p21 (lambda S = 2.4). It is recognized that the MHC contains multiple susceptibility loci (referred to collectively as IDDM1), including the class II antigen receptor genes, which control the major pathological feature of the disease: T-lymphocyte-mediated autoimmune destruction of the insulin-producing pancreatic beta cells. However, the MHC genes, and a second locus, the insulin gene minisatellite on chromosome 11p15 (IDDM2; lambda S = 1.25), cannot account for all of the observed clustering of disease in families (lambda S = 15), and the scans suggested the presence of other susceptibility loci scattered throughout the genome. There are four additional loci for which there is currently sufficient evidence from linkage and association studies to justify fine mapping experiments: IDDM4 (FGF3/11q13), IDDM5 (ESR/6q22), IDDM8 (D6S281/6q27) and IDDM12 (CTLA-4/2q33). IDDM4, 5 and 8 were detected by genome scanning, and IDDM12 by a candidate gene strategy. Seven other named loci are not discounted but remain to be replicated widely. Multiple susceptibility loci were expected as genome-wide scans of the mouse model of type 1 diabetes had shown that although the MHC is the major mouse locus, at least 13 genes unlinked to the MHC are involved in the development of disease. Genome-wide scans using 1000 affected sibpair families will be required to be confident that all genes with effects on familial clustering equivalent to the insulin gene locus (lambda S = 1.25) have been detected. The identification of aetiological determinants requires exclusion of hitchhiking polymorphisms in regions of linkage disequilibrium, as demonstrated for the MHC and the insulin gene loci, and functional studies implicating the disease-associated variant in pathogenesis. Ultimately, targeting of specific candidate mutations in mice by homologous recombination and replacement will be necessary to prove the primary role of any candidate mutation.
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PMID:Panning for gold: genome-wide scanning for linkage in type 1 diabetes. 887 50

The autoimmune thyroid diseases (AITD), encompassing Graves' disease (GD) and Hashimoto's thyroiditis (HT), occur in genetically susceptible individuals. In order to identify the AITD susceptibility genes, we have studied DNA markers in the regions of 8 candidate genes: (1) the HLA region, (2) the TSH receptor, (3) thyroid peroxidase, (4) thyroglobulin, (5) IDDM-4, (6) IDDM-5, (7) Immunoglobulin heavy chain gene and (8) CTLA-4. One hundred and seven subjects from 19 informative families were studied, 14 subjects had GD and 32 subjects had HT. LOD scores were maximized assuming both dominant and recessive modes of inheritance. No linkage was found for any marker in patients with HT. In patients with GD, negative LOD scores were obtained for all the candidate genes, except for markers in the TSH receptor region on chromosome 14q31. Positive LOD scores were found for several markers on 14q31. Marker D14S81 gave the highest score (Z max = 2.05, theta = 0.01) assuming a dominant mode of inheritance and a penetrance of 0.8. These data confirm our previous observations of a lack of a necessary disease locus for AITD in the HLA gene region. Further, the data suggest the presence of an important susceptibility gene on 14q31 but at a considerable distance from the TSH receptor gene.
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PMID:Mapping of a major susceptibility locus for Graves' disease (GD-1) to chromosome 14q31. 914 66

Defects in lymphocyte apoptosis may lead to autoimmune disorders and contribute to the pathogenesis of type 1 diabetes. Lymphocytes of nonobese diabetic (NOD) mice, an animal model of autoimmune diabetes, have been found resistant to various apoptosis signals, including the alkylating drug cyclophosphamide. Using an F2 intercross between the apoptosis-resistant NOD mouse and the apoptosis-susceptible C57BL/6 mouse, we define a major locus controlling the apoptosis-resistance phenotype and demonstrate its linkage (logarithm of odds score = 3.9) to a group of medial markers on chromosome 1. The newly defined gene cannot be dissociated from Ctla4 and Cd28 and in fact marks a 20-centimorgan region encompassing Idd5, a previously postulated diabetes susceptibility locus. Interestingly, we find that the CTLA-4 (cytotoxic T lymphocyte-associated antigen 4) and the CD28 costimulatory molecules are defectively expressed in NOD mice, suggesting that one or both of these molecules may be involved in the control of apoptosis resistance and, in turn, in diabetes susceptibility.
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PMID:Apoptosis resistance of nonobese diabetic peripheral lymphocytes linked to the Idd5 diabetes susceptibility region. 923 35

Genome-wide scans for linkage of chromosome regions to type 1 diabetes in affected sib pair families have revealed that the major susceptibility locus resides within the major histocompatibility complex (MHC) on chromosome 6p21 (lambda s = 2.5). It is recognised that the MHC contains multiple susceptibility loci (referred to collectively as IDDM1), including the class II antigen receptor genes, which control the major pathological feature of the disease: T lymphocyte-mediated autoimmune destruction of the insulin-producing pancreatic beta cells. However, the MHC genes, and a second locus, the insulin gene minisatellite on chromosome 11p15 (IDDM2; lambda s = 1.25), cannot account for all of the observed clustering of disease in families (lambda s = 15), and the scans suggested the presence of other susceptibility loci scattered throughout the genome. There are four additional loci for which there is currently sufficient evidence from linkage and association studies to justify fine mapping experiments: IDDM4 (FGF3/11q13), IDDM5 (ESR/6q22), IDDM8 (D6S281/6q27) and IDDM12 (CTLA-4/2q33), IDDM4, 5 and 8 were detected by genome scanning, and IDDM12 by a candidate gene strategy. The results suggest that the clustering of type 1 diabetes in families is due to the sharing of alleles at multiple loci, and that the as yet unidentified environmental factors are not causing clustering, but instead appear to influence the overall penetrance of genetically programmed susceptibility. The data are consistent with a polygenic threshold model for the inheritance of type 1 diabetes.
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PMID:Genetics of type 1 diabetes. 929 67

Graves' disease (GD) develops as a result of a complex interaction between genetic susceptibility genes and likely environmental factors. Most epidemiological data support an important genetic contribution to the development of GD. The concordance rate of GD in monozygotic twins is 30-60% and in dizygotic twins 3-9%, and thyroid autoantibodies have been reported in up to 50% of the siblings of patients with GD. For many years now, HLA studies have consistently shown an increased frequency of HLA-DR3 in Caucasian patients with GD; but with only a risk ratio of 3-5. However, recent advances in human genome mapping techniques have enabled the study of many other candidate genes. Of these additional, non-HLA genes, only CTLA-4 has been consistently found to be associated with GD. Using a linkage based approach which only detects highly significant susceptibility genes we have recently reported preliminary results which demonstrated that a marker located approximately 25 cM from the TSH receptor gene on chromosome 14q31 is linked to GD and in the same vicinity as the IDDM-11 locus. Such results, if confirmed, may signal the presence of a gene family related to endocrine autoimmunity on chromosome 14q31.
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PMID:The genetic susceptibility to Graves' disease. 953 33

Type 1 diabetes mellitus (IDDM) results from a chronic process of autoimmune destruction of beta cells of the Langerhans islets. The presence of autoantibodies (ICA, GADA, anti-IA2, IAA) in serum precedes the clinical onset of the disease. Genetic predisposition for IDDM is connected with HLA, CTLA-4 and insulin gene region. The aim of the study was the genetic and immunological analysis of a triplet. One of them developed Type 1 diabetes mellitus. We analysed HLA class II, CTLA-4 and insulin gene polymorphisms in the whole family. Besides, we investigated immunological status of three brothers. All patients present identical genotype for VNTR loci: D1S80, D17S5 and Apo B, as well as for HLA-DRB1, -DQA1, -DQB1, CTLA-4 gene and all studied insulin gene polymorphisms. That proves their monozigosity. The triplet presents strong genetic predisposition for IDDM. The two patients without overt diabetes have increased levels of ICA, GADA, IA2 and IAA.
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PMID:Type 1 diabetes and prediabetic state in a monozygotic triplet. 1091 59

Theiler's murine encephalomyelitis virus (TMEV) is a natural mouse pathogen which causes a lifelong persistent infection of the central nervous system (CNS) accompanied by T-cell-mediated myelin destruction leading to chronic, progressive hind limb paralysis. TMEV-induced demyelinating disease (TMEV-IDD) is considered to be a highly relevant animal model for the human autoimmune disease multiple sclerosis (MS), which is thought to be initiated as a secondary consequence of a virus infection. Although TMEV-IDD is initiated by virus-specific CD4(+) T cells targeting CNS-persistent virus, CD4(+) T-cell responses against self myelin protein epitopes activated via epitope spreading contribute to chronic disease pathogenesis. We thus examined the ability of antibodies directed against B7 costimulatory molecules to regulate this chronic virus-induced immunopathologic process. Contrary to previous studies showing that blockade of B7-CD28 costimulatory interactions inhibit the initiation of experimental autoimmune encephalomyelitis, treatment of SJL mice at the time of TMEV infection with murine CTLA-4 immunoglobulin or a combination of anti-B7-1 and anti-B7-2 antibodies significantly enhanced clinical disease severity. Costimulatory blockade inhibited early TMEV-specific T-cell and antibody responses critical in clearing peripheral virus infection. The inhibition of virus-specific immune responses led to significantly increased CNS viral titers resulting in increased damage to myelin-producing oligodendrocytes. Following clearance of the costimulatory antagonists, epitope spreading to myelin epitopes was accelerated as a result of the increased availability of myelin epitopes leading to a more severe chronic disease course. Our results raise concern about the potential use of B7-CD28 costimulatory blockade to treat human autoimmune diseases potentially associated with acute or persistent virus infections.
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PMID:CD28 costimulatory blockade exacerbates disease severity and accelerates epitope spreading in a virus-induced autoimmune disease. 1095 34

CTLA-4 is important to down-regulating T cell responses and has been implicated in type 1 (insulin dependent) diabetes mellitus in both linkage and association studies. The aim of our study was to relate the polymorphic (AT)n microsatellite in the 3' untranslated sequence of the CTLA-4 gene to diabetes risk. We studied 616 consecutively diagnosed 0-34 year-old Swedish patients and 502 matched controls by PCR-based genotyping fo determine the length of the 3'-end (AT)n repeat region of the CTLA-4 gene and categorizing alleles as predominantly monomorphic short (S) or highly polymorphic (in length) long (L) alleles. The odds of type 1 diabetes of subjects with the L/L genotype was estimated to be 1.84 times that of subjects with the S/S genotype (95% CI 1.44-2.73, p=0.002). Further analysis of the long alleles, partitioned into intermediate (I) length and very long (VL) alleles, suggested that L alleles act recessively in conferring diabetes risk (p=0.0009). This study suggests that the 3'-end (AT)n repeat region of the CTLA-4 gene represents a recessive risk factor for type 1 diabetes.
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PMID:The length of the CTLA-4 microsatellite (AT)N-repeat affects the risk for type 1 diabetes. Diabetes Incidence in Sweden Study Group. 1109 97

The genes conferring susceptibility to autoimmune (insulin-dependent) diabetes mellitus (IDDM) are, in most cases, not defined. Among the loci so far identified as associated with murine IDDM (Idd1-19), only the nature of Idd1 has been assessed. Here we show that thymocytes and peripheral lymphocytes of the non-obese diabetic (NOD) mouse are relatively resistant to apoptosis induced by gamma-irradiation. By linkage analysis of F2 progeny mice, we map this trait to a locus on chromosome 1 containing the Idd5 diabetes susceptibility region. By the use of congenic mice, we confirm the linkage data and map this locus to a 6 cM region on proximal chromosome 1. Ctla4, being localized in this chromosomal region and mediating crucial functions in T cell biology, is a logical candidate gene in the Idd5 susceptibility region. In line with this, we demonstrate that T cells from Ctla4(-/-)deficient mice show a similar resistance to gamma-irradiation-induced apoptosis as observed in the NOD mice. This reinforces the notion that CTLA-4 contributes to the pathogenesis of autoimmune diabetes.
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PMID:CTLA-4-/- mice display T cell-apoptosis resistance resembling that ascribed to autoimmune-prone non-obese diabetic (NOD) mice. 1124 36


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