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)

Insulin-dependent diabetes mellitus is believed to occur as a result of a T cell-mediated destruction of the islets of Langerhans. The factors that regulate the T cell responses, in particular the costimulatory signals required for the T cell activation, which result in islet cell destruction, are still unclear. CD28/B7 interactions have been shown to be important in the regulation of T cell immune responses. We, therefore, have examined the role of CD28/B7 interactions in a model of insulin-dependent diabetes mellitus in which T cell-dependent insulitis and hyperglycemia occur over a brief period, following multiple low doses of streptozotocin (multidose streptozotocin (STZ)-induced diabetes mellitus). Expression of CD28 was necessary for diabetes because CD28 -/- C57BL/KsJ animals developed neither hyperglycemia nor insulitis, and did not express IFN-gamma mRNA following STZ, unlike CD28 +/- C57BL/KsJ mice. The expression of B7-1 (CD80) and B7-2 (CD86) molecules was closely regulated during development of the disease. Expression of both CD80 and CD86 increased on cells in pancreatic lymph nodes in STZ-treated C57BL/KsJ mice. Expression of only CD86 increased on islet cells in diabetic mice. In wild-type animals, treatment with mAb against CD86 prevented, whereas treatment with mAb against CD80 exacerbated, insulitis and hyperglycemia, indicating that mAbs against these molecules differentially affect development of disease. We conclude that CD28 signal transduction is required for development of diabetes in multidose STZ-induced diabetes mellitus. CD80 and CD86 molecules, the CD28/CTLA4 ligands, may have different roles in regulation of the disease and affect T cell function at steps beyond differentiation into mature phenotypes.
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PMID:CD28/B7 costimulation regulates autoimmune diabetes induced with multiple low doses of streptozotocin. 899 20

Linkage disequilibrium (association) analysis was used to evaluate a candidate region near the CTLA4/CD28 genes using a multi-ethnic collection of families with one or more children affected by IDDM. In the data set unique to this study (Spanish, French, Mexican-American, Chinese and Korean), the transmission/disequilibrium test (TDT) revealed a highly significant deviation for transmission of alleles at the (AT)n microsatellite marker in the 3' untranslated region (P = 0.002) and the A/G polymorphism in the first exon (P = 0.00002) of the CTLA4 gene. The overall evidence for transmission deviation of the CTLA4 A/G alleles is also highly significant (P = 0.00005) in the combined data set (669 multiplex and 357 simplex families) from this study and a previous report on families from USA, Italy, UK, Spain and Sardinia. Significant heterogeneity was observed in these data sets. The British, Sardinian and Chinese data sets did not show any deviation for the A/G polymorphism, while the Caucasian-American data set showed a weak transmission deviation. Strong deviation for transmission was seen in the three Mediterranean-European populations (Italian, Spanish and French) (P = 10(-5)), the Mexican-American population (P = 0.002) and the Korean population (P = 0.03). These results suggest that a true IDDM susceptibility locus (designated IDDM12) is located near CTLA4.
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PMID:Insulin-dependent diabetes mellitus (IDDM) is associated with CTLA4 polymorphisms in multiple ethnic groups. 925 73

Type 1 Diabetes mellitus (IDDM) results from an immune-mediated destruction of the pancreatic b-cells. The genetic predisposition is mainly confered by variations within MHC class II region on chromosome 6p as well as the CTLA4 gene located on chromosome 2q33. We analysed the transmission of HLA DQA1, DQB1, DRB1*04 alleles as well as an endogenous retroviral element (DQLTR3) in 130 families with a type 1 diabetic offspring in order to evaluate their role in genetic susceptibility to IDDM. Also the combined transmission of HLA and CTLA4 haplotypes was investigated. MHC class II alleles were typed using sequence-specific primer analysis. The presence or absence of DQLTR3 was defined by a nested PCR approach and CTLA4 microsatellite polymorphisms were detected with fluorescence-labeled primer on an automated sequencing system. By transmission distortion test we confirm the linkage of HLA DQA1*0501 DQB1*0201 (DR3 DQ2) as well as DQA1*0301 DQB1*0302 (DR4 DQ8) with IDDM. Whereas the combination with CTLA4 risk markers leads to the highest transmission rate on DR3 positive haplotypes, the predisposing CTLA4 variant does not modulate the risk on DR4 haplotypes. However, the absence of DQLTR3 on DR3, but its presence on DR4 haplotypes significantly increases the genetic risk for type 1 diabetes. Therefore predisposing MHC class II haplotypes are defined by distinct loci which differentially control genetic susceptibility. The combined transmission of protective CTLA4 and HLA DR3 as well as DR4 haplotypes confirms the dominant role of HLA class II polymorphisms in defining disease susceptibility to type 1 diabetes mellitus.
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PMID:Genetic susceptibility to type 1 diabetes: clinical and molecular heterogeneity of IDDM1 and IDDM12 in a german population. 1052 14

Type 1 diabetes (insulin-dependent) is a multifactorial disease with polygenic susceptibility. The major genetic component (IDDM1) resides within the HLA region, but several non-HLA loci have been implicated in the genetic susceptibility. In the present study, we have analysed two such loci, IDDM12 (CTLA4) on 2q33 and IDDM13 on 2q34, in Danish (n = 254) and Spanish (n = 39) type 1 diabetic multiplex families. No significant evidence of linkage of IDDM12 was observed in any of the two studied data sets. However, when the present data were combined with previously published data, they strengthened the evidence of linkage at this locus, p = 0.00002. For the IDDM13 region, we found some positive evidence of linkage of the D2S137-D2S164-D2S1471 markers (p-values 0.007, 0.02, and 0.007, respectively) using transmission disequilibrium testing (TDT) and the Tsp version of the TDT. Importantly, random transmission of all tested alleles was observed in unaffected offspring (p > 0.3). Stratification for HLA (high risk and non-high risk genotypes) in the Danish families did not reveal heterogeneity at IDDM12 or IDDM13. In conclusion, our data on an entirely new family data set did not support the existence of IDDM12 as a type 1 diabetes susceptibility locus in the Danish population. In addition, we found support for evidence of linkage and association of the IDDM13/D2S137-D2S1471 region (approximately 3.5 cM) to type 1 diabetes, however, further studies are needed to substantiate this observation.
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PMID:IDDM12 (CTLA4) on 2q33 and IDDM13 on 2q34 in genetic susceptibility to type 1 diabetes (insulin-dependent). 1059 67

Recently, the association of CTLA4 gene polymorphism with type 1 diabetes and AITD has been reported in several populations. CTLA4 was originally reported to regulate T-cell activity and T-B cognate interaction. To investigate the role of CTLA4 in autoimmune diseases, we examined the correlation between CTLA4 gene polymorphism and the clinical characteristics of Japanese patients with type 1 diabetes, including the mode of onset of diabetes and presence of islet-specific autoantibodies (GAD, ICA 512 Ab) in the serum. We studied 111 patients with type 1 diabetes and 445 normal subjects. CTLA4 exon 1 position 49 (A/G: codon 17: Thr/Ala) polymorphism was defined, employing PCR-RFLP. Sixty-three (57%) patients had AITD. The allele frequencies of G and A in both 111 patients (G: 65%; A: 35%) and 63 patients (G: 62%; A: 38%) were not significantly different from the control subjects (G: 63%; A: 37%). Serum samples of 69 patients were obtained within a year after onset and used for pancreas specific autoantibodies analysis. These samples were also used for further analysis between CTLA4 gene polymorphism and clinical characteristics. The allele frequencies of G and A in patients who presented with diabetic ketoacidosis (DK+) (G: 75%; A: 25%) were significantly different from those in DK- patients (G: 50%, A: 50%, P = 0.003). Allele and genotype analyses showed significant differences between DK+ patients and control subjects (P = 0.014, P = 0.046, respectively). Allele frequencies of G and A were not significant between patients who were positive and negative for GAD Ab, but significant for ICA 512 Ab (G: 83%, A:17% versus G: 59%, A: 41%: positive patients versus negative patients, P = 0.004). Our results showed a significant correlation between CTLA4 gene polymorphism and ICA 512 Ab. Our results also indicated that CTLA4 gene polymorphism is associated with the onset mode of Japanese type 1 diabetes and the presence of ICA512 Ab. Further analysis of this polymorphism is necessary to fully understand the pathogenesis and progression of type 1 diabetes.
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PMID:CTLA4 gene polymorphism correlates with the mode of onset and presence of ICA512 Ab in Japanese type 1 diabetes. 1072 97

Polymorphic markers within the CTLA4 gene on chromosome 2q33 have been shown to be associated with type 1 diabetes. Therefore, a gene responsible for the disease (IDDM12) most likely lies within a region of <1-2 cM of CTLA4. To define more precisely the IDDM12 interval, we genotyped a multiethnic (U.S. Caucasian, Mexican-American, French, Spanish, Korean, and Chinese) collection of 178 simplex and 350 multiplex families for 10 polymorphic markers within a genomic interval of approximately 300 kb, which contains the candidate genes CTLA4 and CD28. The order of these markers (D2S346, CD28, GGAA19E07, D2S307, D2S72, CTLA4, D2S105, and GATA52A04) was determined by sequence tagged site content mapping of bacterial artificial chromosome (BAC) and yeast artificial chromosome (YAC) clones. The transmission disequilibrium test (TDT) analyses of our data revealed significant association/linkage with three markers within CTLA4 and two immediate flanking markers (D2S72 and D2S105) on each side of CTLA4 but not with more distant markers including the candidate gene CD28. Tsp analyses revealed significant association only with the three polymorphic markers within the CTLA4 gene. The markers linked and associated with type 1 diabetes are contained within a phagemid artificial chromosome clone of 100 kb, suggesting that the IDDM12 locus is either CTLA4 or an unknown gene in very close proximity.
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PMID:Genetic and physical mapping of a type 1 diabetes susceptibility gene (IDDM12) to a 100-kb phagemid artificial chromosome clone containing D2S72-CTLA4-D2S105 on chromosome 2q33. 1086 73

Several studies have demonstrated an association of CTLA4 (IDDM12) alanine-17 with type 1 diabetes, but CTLA4 variants have not yet been investigated in type 2 diabetes. The CTLA4 exon 1 polymorphism (49 A/G) was analyzed in 300 Caucasian patients with type 2 diabetes and 466 healthy controls. All patients were negative for glutamate decarboxylase and islet cell antibodies. CTLA4 alleles were defined by PCR, single-strand conformational polymorphism, and restriction length fragment polymorphism analysis using BBV:I. The distribution of alleles as well as the genotypic and phenotypic frequencies were similar among patients and controls [AA, 42 vs. 39%; AG, 47 vs. 46%; GG, 11 vs. 15%, P = not significant (n.s.); A/G, 65/35% vs. 62/38%, P = n.s.; alanine/threonine 92/58% vs. 85/61%, P = n.s.]. However, detailed analysis of clinical and biochemical parameters revealed a tendency of GG (alanine/alanine) toward younger age at disease manifestation (46.8 +/- 0.8 vs. 49.5 +/- 0.8 yr, mean +/- SEM), lower body mass index (21.4 +/- 0.5 vs. 24.4 +/- 0.5 kg/m(2), P = 0.042), and basal C-peptide level (0.33 +/- 0.07 vs. 0.53 +/- 0.07nmol/L), as well as earlier start of insulin treatment (5.8 +/- 1.2 vs. 8.7 +/- 0.6 yr) and higher portion of patients on insulin (71 vs. 61%). Patients with the AA genotype were significantly less likely to develop microangiopathic lesions (P < 0.0005). No differences were found for hypertension or family history of type 2 diabetes. In conclusion, CTLA4 alanine-17 does not represent a major risk factor for type 2 diabetes. Additional studies on larger groups and different ethnic groups are warranted to clarify the association of the GG genotype with faster ss-cell failure and the lower rate of microvascular complications in AA carriers.
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PMID:The codon 17 polymorphism of the CTLA4 gene in type 2 diabetes mellitus. 1115 25

The CTLA4 (cytotoxic T lymphocyte associated antigen-4) gene encodes the T cell receptor involved in the control of T cell proliferation and mediates T cell apoptosis. C-T polymorphism is present at position -318 from the ATG start codon in the promoter region of the gene. We report a study on the polymorphism in 347 unrelated children with type 1 diabetes mellitus (DM) (age at diagnosis 7.2+/-3.8 years) and their 260 healthy siblings as controls. Genotype C/C conferred a risk of type 1 DM (RR = 2.02, 95% CI 1.32-3.10, pc = 0.0033). The gene frequency of the C allele was higher in patients (RR = 1.91, 95% CI 1.28-2.84, pc = 0.0026). The gene frequency and phenotype frequency of the T allele were negatively associated with type 1 DM (RR = 0.52, 95% CI 0.35-0.78, pc = 0.0026 and RR = 0.49, 95% CI 0.32-0.76, pc = 0.0022, respectively). The frequency of genotype C/T was lower in patients (RR = 0.50, 95% CI 0.32-0.78, pc = 0.0051). This study demonstrates that nucleotide -318 C-T polymorphism of the CTLA4 gene is associated with type 1 DM. The promoter allele -318 C confers a risk of type 1 DM but allele -318 T confers protection against this disease.
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PMID:The promoter region of the CTLA4 gene is associated with type 1 diabetes mellitus. 1132 71

Linkage and association has been reported between CTLA4 DNA markers and susceptibility to type 1 diabetes in some populations, but not others. We performed case-control and family-based association studies to assess if the CTLA4 A49G and intron 1 C/T polymorphisms were associated with development of early onset type 1 diabetes in the Northern Ireland population. The distribution of A49G and C/T alleles in cases (n = 144) was similar to those observed in controls (n = 307). In contrast, significant distortions in allele transmissions from informative parents to probands were observed for both the A49G (P = 0.02) and C/T (P = 0.01) polymorphisms employing 297 nuclear families. Our results suggest that the CTLA4 gene may play a minor role in the overall genetic predisposition to type 1 diabetes in this UK population.
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PMID:Possible association between CTLA4 DNA polymorphisms and early onset type 1 diabetes in a UK population. 1147 80

Here, we report on the detection of a novel point mutation of the CTLA4 gene at nucleotide position 159 (C-->G) leading to amino acid substitution at position 53 (I-->M), as well as its association with type 1 diabetes in two ethnically distinct populations. Subjects included 182 unrelated type 1 diabetes children and 201 control subjects from Ghana, West Africa. The Chinese study population consisted of 350 type 1 diabetic children and 420 healthy control subjects from central China. Polymerase chain reaction-single-strand conformation polymorphism and sequence analysis were used to screen for polymorphisms in the CTLA4 gene. CTLA4 49 (A-->G) mutation conferred a risk of type 1 diabetes in the Chinese children (odds ratio 1.78, 95% CI 1.58-2.0), but not in the West African children (1.17, 0.84-1.64). On the other hand, the novel CTLA4 159 (C-->G) mutation conferred a risk of type 1 diabetes in the West African children (2.1, 1.54-2.86), but not in the Chinese type 1 diabetic children. The novel CTLA4 gene polymorphism at nucleotide position 159 significantly associated with type 1 diabetes in West Africans, but not in Chinese. On the other hand, the CTLA4 gene polymorphism at nucleotide position 49 significantly associated with type 1 diabetes in Chinese, but not in West Africans.
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PMID:Association of a novel point mutation (C159G) of the CTLA4 gene with type 1 diabetes in West Africans but not in Chinese. 1152 87


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