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 polymorphism of the major histocompatibility complex class I chain-related A gene is associated with type 1 diabetes mellitus. The major histocompatibility complex class I chain-related A gene 5 allele is significantly more frequent in Caucasian type 1 diabetes mellitus children than in healthy subjects, but no information is available on the association with adult-onset type 1 diabetes mellitus or with the so-called slowly progressive latent autoimmune diabetes of the adult in the same ethnic group. In this study we estimated the frequency of major histocompatibility complex class I chain- related A gene alleles and human leukocyte antigen-DRB1*03-DQA1*0501-DQB1*0201 and human leukocyte antigen-DRB1*04- DQA1*0301-DQB1*0302 in 195 type 1 diabetes mellitus subjects, in 80 latent autoimmune diabetes of the adult subjects, and in 158 healthy subjects from central Italy. Major histocompatibility complex class I chain-related A gene 5 was significantly associated with type 1 diabetes mellitus only in the 1-25 yr age group at diagnosis, and the odds ratio of the simultaneous presence of both major histocompatibility complex class I chain-related A gene 5 and human leukocyte antigen-DRB1*03- DQA1*0501-DQB1*0201 and/or human leukocyte antigen-DRB1*04-DQA1*0301-DQB1*0302 was as high as 54 and higher than 388 when compared with double negative individuals. Adult-onset type 1 diabetes mellitus (age at diagnosis, >25 yr) and latent autoimmune diabetes of the adult were significantly associated with major histocompatibility complex class I chain-related A gene 5.1, which was not significantly increased among diabetic children. Only the combination of major histocompatibility complex class I chain-related A gene 5.1 and human leukocyte antigen-DRB1*03-DQA1*0501-DQB1*0201 and/or human leukocyte antigen-DRB1*04-DQA1*0301-DQB1*0302 conferred increased risk for adult-onset type 1 diabetes mellitus or for latent autoimmune diabetes of the adult. Our study provides demonstration of the existence of distinct genetic markers for childhood/young-onset type 1 diabetes mellitus and for adult-onset type 1 diabetes mellitus/latent autoimmune diabetes of the adult, namely major histocompatibility complex class I chain-related A gene 5 and major histocompatibility complex class I chain-related A gene 5.1, respectively.
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PMID:Two distinct MICA gene markers discriminate major autoimmune diabetes types. 1150 7

Despite extensive efforts by many groups, progress in the mapping of complex diseases has been exceedingly slow, only a few genes and some genetic regions having been identified. The general picture is one of difficulty in locating disease genes and in the replication of linkages. This results from the role in disease of a large number of genes, many with a relatively minor effect and many involving common genetic variation. A multi-strategy approach to the mapping of complex diseases is required: no single method is sufficient or optimal. The role of human leukocyte antigens in type 1 diabetes has been known for nearly 30 years, and the associations, linkage and genetic contribution to disease are all strong, but all the human leukocyte antigen region genes involved in the disease process have not yet been identified. The methods used in study of this component to type 1 diabetes are a model for all complex diseases.
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PMID:An overview of the genetic analysis of complex diseases, with reference to type 1 diabetes. 1155 70

Susceptibility to insulin-dependent (type 1) diabetes mellitus is determined by both environmental and genetic factors. The primary gene associated with predisposition to type 1 diabetes is the human leukocyte antigen (HLA) class II gene (IDDM1). Recent studies have described linkage and association of type 1 diabetes to the cytotoxic T lymphocyte antigen-4 (CTLA-4) gene (IDDM12)in Caucasians. CTLA-4 is a candidate gene for T-cell-mediated autoimmune diseases because it is a negative regulator of T-cell proliferation. We investigated distribution of a CTLA-4 (AT)n microsatellite marker in 118 Japanese patients with type 1 diabetes and 195 control subjects. We also investigated association between this CTLA-4 gene polymorphism and GAD65 antibody positivity in 103 of the patients. CTLA-4 microsatellite marker loci were determined by polymerase chain reaction amplification of genomic DNA and resolution of the products on sequencing gels. GAD65 antibody was detected by radioligand binding assay. There was no significant difference in the distribution of CTLA-4 alleles between patients and controls, and no difference was observed in the prevalence of CTLA-4 alleles when GAD65 antibody-positive and -negative individuals with the type 1 diabetes were compared. The present study did not support an association between the CTLA-4 microsatellite marker and type 1 diabetes in our Japanese study population.
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PMID:No association of type 1 diabetes with a microsatellite marker for CTLA-4 in a Japanese population. 1168 91

Autoimmune destruction of the adrenal cortex is the most common cause of primary adrenocortical insufficiency (Addison's disease) in industrialized countries. We have investigated a large Norwegian cohort of patients with Addison's disease in terms of clinical manifestations, autoantibodies, and human leukocyte antigen (HLA) class II haplotypes. The study comprised 94 patients (54 females) of ages 6-85 yr (mean 45 yr) with, either isolated Addison's disease or part of autoimmune polyendocrine syndrome type II. Among those diagnosed before the age of thirty, 53% were men, while among those diagnosed at 30 or above, 30% were men. Altogether 77 (82%) of the 94 patients had autoantibodies against 21-hydroxylase (21OH). Thirty-eight of the 40 patients with disease duration 5 yr or less had such autoantibodies. This frequency fell to 60% among patients with a disease duration greater than 35 yr. Five women had gonadal failure. This failure correlated with antibodies against side-chain cleavage enzyme (P = 0.03). Antibodies against glutamic acid decarboxylase and IA2 correlated with the presence of type 1 diabetes (P < 0.005 and P = 0.003, respectively). The frequency of the HLA DRB1*03-DQA1*05-DQB1*02 (DR3-DQ2) and DRB1*04-DQA1*03-DQB1*0302 (DR4-DQ8) haplotypes were positively correlated to Addison's disease, whereas the DRB1*01-DQA1*0101-DQB1*0501 (DR1-DQ5) haplotype was negatively correlated. In addition, the DRB1*04 subtype DRB1*0404 was increased among Addison patients relative to controls. We verify that autoimmunity is the main cause of Addison's disease in our cohort. In younger patients, the disease is equally common in men and women. Measurement of autoantibodies against 21OH is a valuable tool in establishing the etiological diagnosis, especially in patients with a short disease duration. Addison's disease is associated with the DR3-DQ2 and DR4 (0404)-DQ8 haplotypes. A particularly high risk for disease development is observed when these occur in a heterozygous combination (DR3-DQ2/DR4-DQ8).
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PMID:Autoimmune adrenocortical failure in Norway autoantibodies and human leukocyte antigen class II associations related to clinical features. 1183 94

Type I diabetes mellitus is an immune-mediated disease that is known to be associated and linked with genes in the human leukocyte antigen (HLA) region on chromome 6. Functionally, HLA class I antigen presentation may be deranged in type I diabetes. The TAP1 and TAP2 transporters, which mediate the translocation of antigenic peptides into the endoplasmic reticulum and whose genes are located in the HLA class II region, are potential candidates for conferrring predisposition to type I diabetes. Five known coding region variants (codons 379, 565, 651, 665, and 687) as well as three new polymorphisms of TAP2, one silent (codon 604) and two intronic (nucleotide positions 49,270 and 49,471), were typed in a cohort of 146 well-characterized Finnish individuals with type I diabetes and 90 control subjects. Absolute linkage disequilibrium was apparent for the polymorphisms at codons 604, 665, and 687 as well as the two downstream intronic polymorphisms in a 613-bp region of the 3' portion of TAP2; the polymorphism at codon 651, which is also present within this region, was excluded from this linkage. The codon 651 polymorphism defines the allele TAP2F, the frequency of which in HLA-DR4+ diabetic subjects was 5.4 times that in DR4+ controls (27 vs. 5%, p = 0.002, p(c) = 0.01). These data are consistent with the existence of susceptibility haplotypes for type I diabetes in the Finnish population consisting of DRB1*04 (*0401 and *0404), DQ8, and TAP2F.
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PMID:Analysis of TAP2 polymorphisms in Finnish individuals with type I diabetes. 1191 71

Insulin-dependent diabetes mellitus (IDDM) is one of the most common chronic diseases. It is an autoimmune, polygenic disease, associated with several genes on different chromosomes. The most important gene is human leukocyte antigen (HLA), also known as major histocompatibility complex (MHC), which is located on chromosome 6p21.3. HLA-DQ8/DR4 and DQ2/DR3 are positively associated with IDDM and DQ6 is negatively associated with IDDM in most Caucasian populations. 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 5 alleles with 4, 5, 6, and 9 repetitions of GCT or 5 repetitions of GCT with 1 additional insertion (GGCT), and the alleles are referred to as A4, A5, A5.1, A6, and A9. Analysis of allele distribution among 93 Latvian IDDM patients and 108 healthy controls showed that allele A5 of MICA is significantly increased in IDDM patients [33/93 (35%)] compared to healthy controls [22/108 (20%)] (OR = 2.15; P = 0.016). In conclusion, we believe that MICA may play an important role in the etiopathogenesis of IDDM.
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PMID:Microsatellite allele 5 of MHC class I chain-related gene a increases the risk for insulin-dependent diabetes mellitus in latvians. 1202 Nov 40

Autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED, OMIM 240300) is a rare autoimmune disease caused by mutations in the autoimmune regulator (AIRE) gene on chromosome 21q22.3. This monogenic disease provides an interesting model for studies of other common and more complex autoimmune diseases. The most common components of APECED are chronic mucocutaneous candidiasis, hypoparathyroidism, and Addison's disease, but several other endocrine deficiencies and ectodermal dystrophies also occur and the phenotype varies widely. The AIRE genotype also varies; 42 different mutations have been reported so far. To understand the complexity of the phenotype, we studied the AIRE and human leukocyte antigen (HLA) class II genotypes in a series of patients with APECED. The only association between the phenotype and the AIRE genotype was the higher prevalence of candidiasis in the patients with the most common mutation, R257X, than in those with other mutations. Addison's disease was associated with HLA-DRB1*03 (P = 0.021), alopecia with HLA-DRB1*04- DQB1*0302 (P < 0.001), whereas type 1 diabetes correlated negatively with HLA-DRB1*15-DQB1*0602 (P = 0.036). The same HLA associations have previously been established for non-APECED patients. We conclude that mutation of AIRE per se has little influence on the APECED phenotype, whereas, in contrast to earlier reports, HLA class II is a significant determinant.
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PMID:AIRE mutations and human leukocyte antigen genotypes as determinants of the autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy phenotype. 1205 Feb 15

The aim of this study was to evaluate the frequency and predictive value of diabetes-associated autoantibodies, such as islet cell antibodies (ICA) and autoantibodies to insulin (IAA), GAD65 (GADA), and the IA-2 molecule (IA-2A) in genetically susceptible children from the general population during the first 2 yr of life. Of 12,170 newborn infants, 1,005 with increased genetic risk of type 1 diabetes (high risk, human leukocyte antigen DQB1*02/*0302; moderate risk, DQB1*0302/x, where x = other than *02, *0301, or *0602) were monitored for ICA, IAA, GADA, and IA-2A at 3- to 6-month intervals from birth up to a minimum age of 2 yr. In addition, all 15 genetically susceptible children from the general population who had participated in regular immunological follow-up and developed clinical type 1 diabetes by the end of April 2000 were analyzed for the development of autoantibodies. Among 1,005 children, 63 (6.3%) tested positive for at least one autoantibody, 31 for ICA (3.1%), 48 for IAA (4.8%), 23 for GADA (2.3%), and 13 for IA-2A (1.3%) at least once by the age of 2 yr. Both ICA and IAA identified 95% [95% confidence interval (CI), 77.2-99.9%] of those who tested persistently positive for multiple (> or = 2) antibodies at the age of 2 yr, GADA identified 86% (CI, 65.1-97.1%), and IA-2A identified 55% (CI, 32.2-75.6%). Close to half of the antibody-positive children (29 of 63) reverted back to antibody negativity. Autoantibodies disappeared more often among those who tested positive for IAA than among those who tested positive for other autoantibodies (P < or = 0.021). Among the 15 children who developed type 1 diabetes, the disease sensitivity of ICA was 80% (CI, 51.9-95.7%), that of IAA was 93% (CI, 68.0-99.8%), that of GADA was 60% (CI, 32.3-83.7%), and that of IA-2A was 40% (CI, 16.3-67.7%). These results suggest that IAA are characterized by high sensitivity, early appearance, and high frequency of transient antibody positivity, whereas ICA detected with a thoroughly standardized assay appear to be more specific for the screening of beta-cell autoimmunity in young children with increased genetic susceptibility to type 1 diabetes in the Finnish population, which has the highest incidence of type 1 diabetes in the world.
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PMID:Natural history of beta-cell autoimmunity in young children with increased genetic susceptibility to type 1 diabetes recruited from the general population. 1236 37

To evaluate the contributions of DR3 and DQ8 to the etiopathogenesis of type 1 diabetes in a diabetes-predisposing milieu, we developed human leukocyte antigen (HLA) transgenic mice on the nonobese diabetic (NOD) background in the absence of the endogenous class II molecule, I-A(g7) and studied the incidence of both spontaneous and experimental (induced) autoimmune diabetes. Transgenic expression of HLA-DR3 and -DQ8 (either alone or in combination) did not confer susceptibility to spontaneous or cyclophosphamide-induced type 1 diabetes. Expression of I-A(g7) was mandatory for development of spontaneous or cyclophosphamide-induced diabetes. However, multiple low doses of streptozotocin could induce diabetes in all groups of mice independent of the class II molecules expressed. In unmanipulated mice, only islets from I-A(g7+/+) mice revealed significant intra-islet infiltration. Although a characteristic peri-insulitis/peri-ductulitis was present in Abeta(0)/NOD mice, islets from DR3, DQ8 and DR3 x DQ8 double transgenic mice demonstrated significantly less infiltration. In conclusion, transgenic expression of HLA-DR3 and -DQ8 associated with predisposition to type 1 diabetes alone is not sufficient to induce spontaneous diabetes in NOD mice lacking endogenous class II molecules.
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PMID:Modulation of insulitis and type 1 diabetes by transgenic HLA-DR3 and DQ8 in NOD mice lacking endogenous MHC class II. 1239 51

In 1993-1996, islet autoantibodies, C-peptide, and HLA-DQ genotypes were evaluated in 345 insulin-treated diabetic patients of all ages from the Skaraborg Diabetes Registry 5-6 years after their diagnosis and in 216 control subjects from the Skaraborg County, Sweden, population. The aims of this study were to clarify the importance of age at diagnosis of diabetes for HLA-DQ associations in patients with classic type 1 diabetes and whether patients considered to have latent autoimmune diabetes of the adult differed in their human leukocyte antigen (HLA) associations. An abnormally low fasting C-peptide value was used as the definition of type 1 diabetes, found in 182 of 345 (53%) patients. No major associations between age at diagnosis and HLA susceptibility or protective genotypes were detected in type 1 diabetic patients. Among the 163 patients with preserved beta-cell function, the frequency of HLA protective genotypes was clearly decreased (5% vs. 42%) in the 46 of 163 with islet antibodies compared with the 117 of 163 antibody-negative patients. The authors conclude that there were no major effects of age at diagnosis on HLA-DQ associations in classic type 1 diabetic patients, whereas lack of HLA-DQ protective genotypes was a feature of patients with slow-progressing type 1 diabetes (latent autoimmune diabetes of the adult).
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PMID:HLA-DQ genotypes in classic type 1 diabetes and in latent autoimmune diabetes of the adult. 1239 95


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