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)

The presence of islet cell autoantibodies (ICA), and especially of glutamic acid decarboxylase autoantibodies (GAD65Ab), in patients with non-insulin-dependent diabetes mellitus identifies the so-called latent autoimmune diabetes in the adult (LADA). LADA patients have an increased risk for developing insulin deficiency, and in 60-80% of cases the exogenous insulin therapy must be started within 5-6 years. GAD65Ab identify a subgroup of type 2 diabetic (T2DM) patients with low body mass index (BMI) at the time of diagnosis. The presence of GAD65Ab at high titres and directed against COOH-terminal epitopes of the autoantigen, or the presence of both GAD65Ab and ICA, discriminates patients with clinical characteristics very similar to those of a slowly progressive form of type 1 diabetes (T1DM). On the other hand, the presence of low levels GAD65Ab, in the absence of ICA or other immune markers, such as IA-2 antibodies, characterizes a subgroup of patients with clinical characteristics almost indistinguishable from those of typical T2DM patients. The autoimmune origin of LADA is also demonstrated by the increased frequency of thyroid and adrenal autoantibodies, as compared to GAD65Ab-negative T2DM patients, and by the strong genetic association with HLA-DR3-DQ2, -DR4-DQ8 and the polymorphisms of the MHC class I chain-related A (MICA) and CTLA-4 genes. Metabolic studies have shown the coexistence of insulin resistance and insulin secretion defect supporting the hypothesis that LADA may be the result of the interaction of a genetic background predisposing for islet autoimmunity and a genetic background predisposing for T2DM.
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PMID:[Immunologic and genetic aspects of latent autoimmune diabetes in the adult]. 1475

The thymus-specific serine protease Prss16 is highly expressed by the epithelial cells in the thymic cortex. It has been suggested to play an important role in the positive selection of T cells through the antigen presention pathway of the cortical antigen presenting cells. Recently, the gene encoding Prss16 has been linked to insulin dependent diabetes mellitus (IDDM) susceptibility independent of HLA-DR3 suggesting the Prss16 may be involved in the development of autoimmune disease. Due to the similarities of the gene structure and expression pattern between the human and mouse genes, we compared Prss16 between non-obese diabetic (NOD) and non-obese non-diabetic (NON) mice. Analysis of the Prss16 coding region failed to identify any differences in sequence. Northern analysis and semi-quantitative reverse transcriptase polymerase chain reaction showed that the mRNA was equal in size and abundance in the two strains. In situ hybridization showed similar patterns of staining. Therefore, our data suggests that there is no significant different in the gene structure, transcription level, and expression pattern of Prss16 gene between NOD and NON mice.
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PMID:Analysis of the IDDM candidate gene Prss16 in NOD and NON mice. 1514 14

Recent studies have described linkage and association between cytotoxic T-lymphocyte antigen-4 (CTLA-4) gene polymorphism and type 1 diabetes mellitus (DM1) in some ethnic populations, but not others. This finding suggests that CTLA-4 gene association with DM1 may be influenced by the racial composition of the population. Thus, it is important to study the polymorphism of the CTLA-4 gene in different ethnic groups. In this case-control association study, the CTLA-4 gene exon 1 A/G polymorphism was analyzed in 48 children with DM1 and 80 healthy controls using polymerase chain reaction-restriction fragment length polymorphism analysis. The possible interaction of the CTLA-4 gene polymorphism with the presence of established genetic markers (HLA-DR genotyping) was also evaluated in 29 patients. The results of the present study do not suggest an association of the known polymorphism in exon 1 of the CTLA-4 gene with DM1 in this Turkish population, and G-allele containing CTLA-4 genotypes were not preferentially associated with age at clinical presentation or with presence of other genetic (HLA-DR3 or -DR4) markers of DM1.
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PMID:Analysis of cytotoxic T lymphocyte antigen-4 (CTLA-4) exon 1 polymorphism in patients with type 1 diabetes mellitus in a Turkish population. 1523 7

Diabetes Autoimmunity Study in the Young (DAISY) has followed 1972 children for islet autoimmunity and diabetes: 837 first-degree relatives of persons with type 1 diabetes and 1135 general population newborns identified through human leukocyte antigen (HLA) screening. During follow-up of 4.06 yr (range, 0.17-9 yr), serial determination of autoantibodies to glutamic acid decarboxylase, protein tyrosine phosphatase IA2, and insulin has generated approximately 20,000 results. Among 162 children with at least one positive autoantibody, in 31% the test was false positive (autoantibodies were negative twice on blinded duplicate aliquots), in 31% it was transiently positive (confirmed on blinded duplicate aliquots but negative on follow-up), and in 36% it was persistently positive. Using proportional hazards modeling, the HLA-DR3/4 DQ8 genotype, another positive autoantibody at the first positive visit, and level of autoantibody were predictive of persistent positivity. Only HLA-DR3/4 DQ8 genotype was predictive of progression to diabetes in proportional hazards modeling. This prospective study reveals that cross-sectional determination of islet autoantibodies in a population with relatively low previous probability of autoimmunity identifies as "positive" a large number of individuals who are either false or transiently positive. Predictive value of autoantibodies increases with blinded duplicate and independent sample retesting and incorporation of the level of autoantibody in the predictive algorithm.
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PMID:Prediction of autoantibody positivity and progression to type 1 diabetes: Diabetes Autoimmunity Study in the Young (DAISY). 1529 24

The genetic susceptibility for gestational diabetes (GDM) was estimated by comparisons of genotypes within human leukocyte antigen (HLA) and major histocompatibility complex class I chain-related gene A (MICA) in 199 women with GDM and 213 healthy women. At least one of ICA, glutamic acid decarboxylase antibodies, or islet cell antigen-2 antibodies/tyrosine phosphatase antibodies was found in 6.0% (12/199) of women with GDM and were considered as autoimmune GDM, whereas the remaining 187 were considered as nonautoimmune GDM. HLA genotyping was done with polymerase chain reaction and sequence-specific oligonucleotides. MICA polymorphism was determined with polymerase chain reaction and fragment size determination. HLA-DR3-DQ2/x or DR4-DQ8/x and MICA5.0/5.1 were more frequent in autoimmune GDM compared with controls; 92% versus 46% and 42% versus 13% and conferred increased risk (odds ratio [OR] = 13; 95% confidence interval [CI] 1.7-104) and (OR = 4.7; 95%CI 1.4-16). Four other genotypes were more frequent in nonautoimmune GDM compared with controls: HLA-DR7-DQ2/y, 24% versus 14%; DR9-DQ9/y, 9.6% versus 1.9%; DR14-DQ5/y, 7.5% versus 0.94%; and MICA5.0/z, 24% versus 13% and gave increased risk: OR = 2.0; 95%CI 1.2-3.4, OR = 5.6; 95%CI 1.8-17, OR = 8.5; 95%CI 1.9-38, and OR = 2.0; 95%CI 1.2-3.4, respectively. We concluded that autoimmune diabetes with onset during pregnancy is associated with the type 1 diabetes-associated genotypes and also with MICA5.0/5.1, whereas DR7-DQ2/y, DR9-DQ9/y, DR14-DQ5/y, and MICA5.0/z are risk factors for nonautoimmune GDM.
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PMID:Different HLA-DR-DQ and MHC class I chain-related gene A (MICA) genotypes in autoimmune and nonautoimmune gestational diabetes in a Swedish population. 1560 71

Type 1 diabetes mellitus (T1DM) is an autoimmune disease known to occur in genetically susceptible individuals after exposure to certain unknown environmental factors. HLA-DR3-DQ2 or DR4-DQ8 are established genetic markers for the disease. MHC class I chain-related gene-A (MICA) gene polymorphism has been proposed to be associated with T1DM. To identify the environmental factors and for implementing intervention trials to prevent T1DM, it is important to screen subjects at genetically increased risk for developing T1DM. The All Babies in Southeast Sweden (ABIS) study aims to assess the risk of future progression to T1DM in the general child population. In the present report, we studied the frequency of MICA alleles among newborn babies carrying high-risk HLA DQ2 or DQ8. Of 2821 newborns, we found 563 subjects positive for DQ2, 583 subjects positive for DQ8, 133 subjects positive for DQ2-DQ8 (heterozygous), and 1013 subjects positive for either DQ2 or DQ8. Of these 1013 babies, we typed 499 babies for MICA. Frequency of MICA5 was 38% among DQ8+, 35% among for DQ2-DQ8 (heterozygous) positives, and 22.5% among DQ2+ babies. Frequency of MICA5.1 was 81% among DQ+, 62% among DQ8+, and 71% among DQ2-DQ8 (heterozygous) positives. Frequency of MICA6 was between 20% and 22% among the three groups. Frequency of MICA5/5.1 was 19% among DQ2-DQ8 (heterozygous) positives and between 12% and 13% among those positive for DQ2, DQ8, DQ2, or DQ8. The results from genetic typing in this study would be useful, in conjunction with results from autoantibody analysis that are prospectively being followed-up in all the babies, to develop an approach for identifying children at risk for developing T1DM. Inclusion of MICA typing in addition to HLA could be useful for screening of genetic markers associated with T1DM.
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PMID:Frequency of MICA in all babies in southeast Sweden (ABIS) positive for high-risk HLA-DQ associated with type 1 diabetes. 1569 8

Approximately 50% of the genetic risk for type 1 diabetes is attributable to the HLA region. We evaluated associations between candidate genes outside the HLA region-INS, cytotoxic T-lymphocyte-associated antigen (CTLA)-4, interleukin (IL)-4, IL-4R, and IL-13 and islet autoimmunity among children participating in the Diabetes Autoimmunity Study in the Young (DAISY). Children with persistent islet autoantibody positivity (n = 102, 38 of whom have already developed diabetes) and control subjects (n = 198) were genotyped for single nucleotide polymorphisms (SNPs) in the candidate genes. The INS-23Hph1 polymorphism was significantly associated with both type 1 diabetes (OR = 0.30; 95% CI 0.13-0.69) and persistent islet autoimmunity but in the latter, only in children with the HLA-DR3/4 genotype (0.40; 0.18-0.89). CTLA-4 promoter SNP was significantly associated with type 1 diabetes (3.52; 1.22-10.17) but not with persistent islet autoimmunity. Several SNPs in the IL-4 regulatory pathway appeared to have a predisposing effect for type 1 diabetes. Associations were found between both IL-4R haplotypes and IL-4-IL-13 haplotypes and persistent islet autoimmunity and type 1 diabetes. This study confirms the association between the INS and CTLA-4 loci and type 1 diabetes. Genes involved in the IL-4 regulatory pathway (IL-4, IL-4R, IL-13) may confer susceptibility or protection to type 1 diabetes depending on individual SNPs or specific haplotypes.
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PMID:Association of non-HLA genes with type 1 diabetes autoimmunity. 1604 18

Enteroviruses, particularly Coxsackie virus B4 (CVB4), are considered to be involved in the pathogenesis of type 1 diabetes. We wanted to compare the characteristics of T-cell immune response to CVB4 in children with type 1 diabetes and healthy children with and without HLA risk-associated haplotypes (HLA-DR3-DQ2 or HLA-DR4-DQ8) for type 1 diabetes. Peripheral blood mononuclear cells (PBMCs) were isolated and cultured with CVB4 and analyzed for cytokine and chemokine receptors by flow cytometry and for expression of transcription factors Tbet and GATA-3 by RT-PCR and Western blot. Culture supernatants were analyzed for secretion of gamma-interferon (IFN-gamma). In children with type 1 diabetes, a decreased percentage of T-cells expressed CCR2, CXCR6, interleukin (IL)-18R, and IL-12Rbeta2-chain after in vitro stimulation with CVB4 in comparison with healthy children with or without HLA risk genotype. Moreover, we found that children with type 1 diabetes had decreased IFN-gamma secretion and expression of Tbet, both on mRNA and protein level, in CVB4-stimulated PBMCs. Accordingly, children with type 1 diabetes show an impaired type 1 immune response against CVB4 compared with healthy children. This may lead to a delayed clearance of the virus and, at least partly, explain why children with type 1 diabetes may be more prone to CVB4 infections and related complications, such as beta-cell damage.
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PMID:Decreased in vitro type 1 immune response against coxsackie virus B4 in children with type 1 diabetes. 1656 21

We explored the importance of the genetic markers microsatellite TNFa, HLA-DR3-DQ2, and DR4-DQ8 in diabetes mellitus. The studied groups comprised autoimmune type 1 (n = 63), nonautoimmune type 1 (n = 35), latent autoimmune diabetes in adults (LADA; n = 54), and nonautoimmune type 2 (n = 340) and these patients were compared to 117 healthy controls. HLA genotyping was done with polymerase chain reaction and sequence-specific oligonucleotides. TNFa microsatellites were determined with polymerase chain reaction and fragment size determination. Univariate analysis of these genetic risk factors demonstrated that homozygosity for TNFa2/2 was a significant risk factor for autoimmune type 1 diabetes (odds ratio (OR) = 5.82; 95% confidence interval (95%CI) 1.97-17.2), for autoimmune negative type 1 diabetes (OR = 4.63; 95%CI 1.32-16.2), and for LADA (OR = 3.90; 95%CI 1.21-12.5). Moreover, heterozygosity for HLA-DR3-DQ2/DR4-DQ8 was an important risk factor for autoimmune type 1 diabetes (OR = 16.4; 95%CI 3.60-75) as was DR4-DQ8/x (OR = 2.52; 95%CI 1.27-4.98). Heterozygosity for HLA-DR3-DQ2/DR4-DQ8 was a risk factor also for LADA (OR = 10.0; 95%CI 2.05-48.9). Neither HLA-DR3-DQ2 nor DR4-DQ8 were risk factors for nonautoimmune type 1 or type 2 diabetes. We concluded that heterozygosity for DR3-DQ2/DR4-DQ8 and to some extent homozygosity for TNFa2/2 were risk factors for autoimmune diabetes irrespective of the clinical classification.
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PMID:Polymorphisms of TNF microsatellite marker a and HLA-DR-DQ in diabetes mellitus-a study in 609 Swedish subjects. 1682 7

The genetic predisposition to type 1 diabetes (DM1) is associated with genes of the human leukocyte antigen (HLA) system, specially the HLA-DR and -DQ. In Caucasians, the HLA-DR3 and -DR4 antigens are associated with susceptibility and the -DR2, with protection. In Brazil, a country with a large miscegenation of European Caucasians, Native Amerindians and African Blacks, the genetic basis of DM1 has not been adequately studied. The aim of this paper is to present a critical review of articles indexed in the MEDLINE and LILACS-BIREME data basis about the association of HLA with DM1 in Brazilians. Eight papers, all of them from the Southeast region, were found. Immunogenetic susceptibility to DM1 in Brazilians was associated with HLA-DRB1*03, -DRB*04, -DQB1*0201, -DQB1*0302 alleles, and protection against DM1 was associated with HLA-DQB1*0602, -DQB1*0301 alleles and -DR2 and -DR7 antigens. Since the Brazilian population is not racially homogeneous, it is not possible to extrapolate studies from a single region to the remainder of the country. It is necessary to study populations from different regions to identify new associations or to strengthen associations with the ones already identified. This knowledge will contribute to future prophylactic or therapeutic interventions in the group of Brazilians at risk of developing DM1.
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PMID:[Distribution and frequency of HLA alleles and haplotypes in Brazilians with type 1 diabetes mellitus]. 1693 83


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