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)

NIDDM is one of the most common forms of diabetes. The diagnosis is based on WHO classification, which is a clinical classification and misses the autoimmune diabetes in adults. Therefore, among the clinically diagnosed NIDDM cases, there can be a certain number of patients with latent autoimmune diabetes in adults (LADA). The MICA gene is located in the MHC class I region and is expressed by monocytes, keratinocytes, and endothelial cells. Sequence determination of the MICA gene identifies trinucleotide repeat (GCT) microsatellite polymorphism, which identifies 5 alleles with 4, 5, 6, and 9 repetitions of GCT (A4, A5, A6, and A9) or 5 repetitions of GCT with 1 additional G insertion for allele A5.1. From our previous studies, we have shown that microsatellite allele A5 of MICA is associated with IDDM. The aim of this study was to test the hypothesis that certain MICA alleles are associated with LADA among clinically diagnosed NIDDM. Out of 100 clinically diagnosed NIDDM patients, 49 tested positive for GAD65 and IA-2 antibodies by use of 35S RIA. Samples from these 49 patients and 96 healthy controls were analyzed for MICA by PCR amplification, and fragment sizes were determined in an ABI prism DNA sequencer. Our results show that MICA allele A5.1 is significantly increased in antibody-positive (GAD65 or IA-2) NIDDM patients [35/49 (72%)] when compared to healthy controls [22/96 (23%)] (OR = 8.4; P < 0.0001). However, we do not see any association with each of the antibodies separately. From our study, we conclude that (a) MICA allele A5.1 is associated with LADA and (b) MICA may play an important role in the etiopathogenesis of LADA.
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PMID:Microsatellite allele A5.1 of MHC class I chain-related gene A is associated with latent autoimmune diabetes in adults in Latvia. 1202 Nov 41

Insulin-dependent diabetes mellitus (IDDM) is one of the most common chronic diseases. It is an autoimmune disease. Genes contributing the most for development of IDDM are located on chromosome 6p21.3 in the region called the major histocompatibility complex (MHC). HLA-DQ8/DR4 and DQ2/DR3 have shown positive association with IDDM, while DQ6 has negative association with IDDM in most Caucasian populations. The location of the tumor necrosis factor alpha (TNF-alpha) gene in the MHC suggests the role of TNF in the etiology of IDDM as an autoimmune disease. The TNF region contains several polymorphisms that are associated with different levels of TNF-alpha production and susceptibility to autoimmune and infectious diseases. Ninety-two Latvian IDDM patients corresponding to WHO diagnostic criteria and 107 unrelated age- and sex-matched healthy controls were analyzed for the frequency of TNF-alpha alleles to test the hypothesis that TNF-alpha is associated with IDDM. We found that TNF-alpha microsatellite allele 2 is associated with IDDM, 29/92 (32%), versus 14/107 (13%) in healthy controls. The test of the strongest association of the MICA A5 allele and TNF-alpha allele 2 with IDDM showed that both are independently associated with the disease.
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PMID:Tumor necrosis factor-alpha allele 2 shows an association with insulin-dependent diabetes mellitus in Latvians. 1202 Nov 42

The contribution of HLA genes to the genetic risk for celiac disease (CD) has been known for a long time. Recent publications have pointed to the possibility that a second, independent susceptibility locus could be located in the same genomic region, and a triplet repeat polymorphism in exon 5 of the gene MHC class I chain-related protein A (MICA; located between TNFA and HLA-B) has been associated with several autoimmune disorders, including type 1 diabetes mellitus (DM1) and Addison's disease. On the other hand, a single amino acid change in exon 3 of MICA (M129V) has been shown to strongly reduce MICA binding to NKG2D, an activating natural killer receptor expressed also on T cells, and this could have significant effects on autoimmune reactions. In this study, we have analyzed the contribution of these polymorphisms to CD in 37 Basque families, and have constructed MICA-HLA-DRB1 haplotypes to determine whether MICA has an effect independent from the HLA class II conferred risk. In our population, HLA-DRB1*0301 was associated with an increased risk for CD, while HLA-DRB1*1501 conferred protection from the disease (OR: 7.38 and 0.06, respectively). On the other hand, MICA allele A4 was positively associated with the disease (OR: 4.69) whereas allele A9 showed a trend towards protection (OR: 0.18), although significance did not hold after correction. No association of the exon 3 biallelic polymorphism was observed. A positive allelic association was found for haplotypes A5.1-DRB1*0301 (associated with risk for disease), A4-DRB1*0301 and A6-DRB1*07. In view of our results, both HLA-DRB1 and MICA are associated with CD, but stratification analysis did not show any independent contribution of the MICA polymorphisms analyzed to CD risk. Besides, MICA allele A4 (also A5.1 was associated with risk for CD and other diseases) is in strong linkage disequilibrium with HLA-DRB1*0301. Finally, the major histocompatibility complex region's conferred susceptibility to CD, at least in Basque, is very similar to that observed for DM1, with shared risk and protective haplotypes.
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PMID:HLA-DRB1 and MHC class 1 chain-related A haplotypes in Basque families with celiac disease. 1236 85

The Japanese have one of the lowest incidence of childhood type 1 diabetes in the world, but the incidence of this disease is clearly increasing within the Japanese population, as reported in several European countries. Latent autoimmune diabetes mellitus in adult (LADA) patients are also likely to have a lower incidence compared to Caucasians. Among the non-autoimmune (type 1B) diabetes in Japanese adults, there exists a novel subtype of type 1 diabetes characterized by extremely rapid onset and pancreatic exocrine inflammation. HLA and non-HLA gene associations to type 1 diabetes may vary depending on ethnic origin. Highly susceptible HLA haplotypes of type 1 diabetes observed in Caucasian patients are not found in Japanese patients, while protective HLA haplotypes are similar. Association studies of non-HLA genes have identified several candidate genes that influence the heterogeneity of disease phenotypes as well as disease susceptibility to type 1 diabetes. The INS-VNTR gene or polymorphisms of MICA gene are associated with susceptibility, whereas a certain allele of MICA gene and IL-10 gene polymorphism are associated with clinical heterogeneity of the disease. An expression of multiple autoantibodies to a biochemically determined autoantigen confers a high risk for progression to type 1 diabetes. The combined evaluation of multiple autoantibodies is more sensitive than is ICA testing for the diagnosis of type 1 diabetes. A high titer of GAD autoantibody has the predictive value of future insulin deficiency in patients with LADA. For accurate predictive strategies of future insulin deficiency, combinational multiple autoantibodies analysis or genetic determination should be considered for effective immune intervention.
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PMID:Current knowledge of Japanese type 1 diabetic syndrome. 1239 78

We apply a high-throughput protocol of chip-based mass spectrometry (matrix-assisted laser desorption/ionization time-of-flight; MALDI-TOF) as a method of screening for differences in single-nucleotide polymorphism (SNP) allele frequencies. Using pooled DNA from individuals with asthma, Crohn's disease (CD), schizophrenia, type 1 diabetes (T1D), and controls, we selected 534 SNPs from an initial set of 1435 SNPs spanning a 25-Mb region on chromosome 6p21. The standard deviations of measurements of time of flight at different dots, from different PCRs, and from different pools indicate reliable results on each analysis step. In 90% of the disease-control comparisons we found allelic differences of <10%. Of the T1D samples, which served as a positive control, 10 SNPs with significant differences were observed after taking into account multiple testing. Of these 10 SNPs, 5 are located between DQB1 and DRB1, confirming the known association with the DR3 and DR4 haplotypes whereas two additional SNPs also reproduced known associations of T1D with DOB and LTA. In the CD pool also, two earlier described associations were found with SNPs close to DRB1 and MICA. Additional associations were found in the schizophrenia and asthma pools. They should be confirmed in individual samples or can be used to develop further quality criteria for accepting true differences between pools. The determination of SNP allele frequencies in pooled DNA appears to be of value in assigning further genotyping priorities also in large linkage regions.
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PMID:High-resolution SNP scan of chromosome 6p21 in pooled samples from patients with complex diseases. 1270 9

Autoimmune disorders such as type 1 diabetes (T1DM), celiac disease (CD), and Addison's disease (ADD) develop in individuals with genetic susceptibility that are exposed to environmental triggering factors not completely defined. Patients with an autoimmune disease (and their relatives) are at increased risk of developing another disorder, and this might be caused by a common genetic origin of autoimmunity; for example, HLA class II region in 6p21 shows a very strong association with most diseases. The aim of this study was to determine whether shared susceptibility markers extend from the central (DRB1) through the telomeric (MICA) HLA region. We analyzed three independent sets of families with one autoimmune disease, T1DM, CD, or ADD, and genotyped them for HLA-DRB1 and for the exon 5 GCT polymorphism of MICA. For HLA-DRB1, allele DRB1*0301 was the only one associated with risk for all three diseases; in the case of MICA, allele A9 was found to be the common protective allele. Haplotype analysis shows that haplotype A5.1-DRB1*0301 confers risk to autoimmunity. Our results show that there are common risk and protection alleles in both loci, suggesting a core of genetic association with autoimmunity (HLA-DRB1*0301 risk; A9 protection) that could be modulated by other alleles/loci or environmental factors toward one or another disease. Some alleles are part of conserved haplotypes (A5.1-DR3, A5.1-DR2), whereas others seem to have independent effect (A9) and support the idea of two independent loci in this region.
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PMID:HLA-DRB1 and MICA in autoimmunity: common associated alleles in autoimmune disorders. 1467 82

Although multiple sclerosis (MS) usually appears isolated from other autoimmune disorders, an overlap with type 1 diabetes mellitus (T1DM) has been described in Sardinia, where T1DM-associated haplotype HLA-B18-DR3-DQ2 contributes to MS risk. To determine whether in our population MS patients show signs of pancreatic autoimmunity and share this haplotype, sera from 49 MS patients were tested for GAD, IA2, and CPH autoantibodies, and MICA exon 5 polymorphism was genotyped in 30 patients. Pancreatic autoimmune markers were not present among MS patients, nor was any MICA allele associated with MS. Overall, there is no evidence supporting a T1DM/MS overlap in our population.
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PMID:No evidence of pancreatic autoimmunity among patients with multiple sclerosis. 1569 7

To ascertain association of MICA with type 1 diabetes (T1D) in the Belgian population, well-characterized antibody-positive patients were analyzed for MICA transmembrane gene polymorphism in both an association study and a nuclear family study. The frequency of MICA5 was significantly increased in the T1D patient group (18%) compared with the control population (12%, OR=1.6, pc<10(-3)), whereas MICA9 was decreased (11% versus 16%, OR=0.7, pc<0.01). A p value<10(-3) for the association of MICA conditional on HLA class II and p=0.01 for the conditional extended transmission disequilibrium test were obtained, indicating that MICA is associated with type 1 diabetes, independent of HLA-DQ. Analysis of estimated extended HLA-DQ-MICA haplotypes revealed individual effects of MICA alleles. The most significant effect was seen for MICA5 on the HLA-DQA1*03-DQB1*0302-MICA haplotype (OR=2.5, p<10(-3)). A significant protective effect was seen for the combination of DQA1*01-DQB1*0602/3 and MICA5.1 (OR=0.3, p<10(-3)). However, patients stratified according to the presence or absence of the different MICA alleles did not differ in terms of age at onset, sex, or other diabetes-related clinical and epidemiological data. In conclusion, MICA is associated with type 1 diabetes in the Belgian population and the observed association does not result from the HLA-DQ associated risk.
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PMID:MICA is associated with type 1 diabetes in the Belgian population, independent of HLA-DQ. 1669 30

DQ8 and DQ2 are associated with susceptibility to and DQ6 with protection from type 1 diabetes mellitus (T1DM). A set of polymorphic genes, called MHC class I chain-related genes (MIC-A) in HLA class I region interact with NK cells. In Italians, MICA allele 5 increases T1DM risk by 6.1. Together with HLA-DQ8 and DQ2 the risk increases severalfold. HLA class I genes, also identified as susceptibility genes for T1DM, interact with polymorphic killer immunoglobulin-like receptors (KIR) on NK cells. HLA-DQ8 and DQ2 and MICA-5 in Swedish and other populations also show positive association with disease. Studies on KIR in Latvian patients with T1DM also suggest a role for KIR in the etiology of T1DM. The results from MICA and KIR studies suggest that polymorphism of these genes of the innate immune system identify possible defects in the first line of antiviral defense in the etiology of T1DM. Screening for these genes could be important in the prediction strategies for T1DM.
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PMID:Genes influencing innate and acquired immunity in type 1 diabetes and latent autoimmune diabetes in adults. 1713 May 34

Type 1 diabetes is a polygenic disease with a major susceptibility locus, IDDM1, located in the human leukocyte antigen (HLA) region. Although class II loci, DR and DQ genes in particular, are major components of IDDM1, accumulating lines of evidence indicated that IDDM1 consists of multiple components and that non-class II genes in addition to class II genes contribute to susceptibility to and/or age-at-onset of type 1 diabetes. To identify a second component of IDDM1, we investigated the association of a panel of polymorphisms in 2.2 Mb region of the HLA encompassing from class II to class I regions with type 1 diabetes. Polymorphisms types were: DRB1 and DQB1 in class II; two microsatellite markers, BAT2-GT and TNFa in class III; and, five microsatellite markers, STR-MICA, MIB, C1-3-1, C2-4-4, and C3-2-10 in class I region. A total of >200 Japanese patients and healthy control subjects were studied. Class II DRB1*0405 and DQB1*0401 were significantly associated with susceptibility to, but not with age-at-onset of, type 1 diabetes. C1-3-1, located near C locus, was significantly associated with not only susceptibility to, but also age-at-onset of type 1 diabetes. These data suggest that a second component of IDDM1 maps to the HLA class I region, contributing to susceptibility to as well as age-at-onset of type 1 diabetes.
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PMID:A second component of HLA-linked susceptibility to type 1 diabetes maps to class I region. 1713 May 66


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