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 (IDDM) is strongly associated with particular HLA-DQ alpha/beta markers in white population. The heterodimers conformation composed of a DQ alpha chain with an arginine at residue 52 (Arg52) combined to a DQ beta chain lacking an aspartic acid at residue 57 (non Asp57) increase markedly the risk to develop IDDM. To confirm this association, 63 IDDM patients from Santiago de Chile registry, 20 IDDM patients from Temuco registry and 74 unrelated healthy non diabetic control subjects were studied. With polymerase chain reaction (PCR) and sequence specific oligonucleotide probes the individuals were typed for their HLA-DQA1 and DQB1 alleles, their DQA1/DQB1 genotype and heterodimers conformation were compared. In diabetic population both markers Arg52 homocygote and non Asp57 homocygote were markedly increased regard to control subjects (R/R: 0.76 and 0.85 vs 0.33; ND/ND: 0.78 and 0.75 vs 0.50, p < 0.05). A high relative risk (RR) was determined for both homocygote markers in IDDM groups. Arg52 DQ alpha (R)/non Asp57 DQ beta (ND) heterodimers were strongly associated with susceptibility to IDDM. A high RR was observed in patients with four susceptibility DQ heterodimers (RR1: 13.7 in IDDM-Santiago and RR2: 18.6 in IDDM-Temuco, p < 0.00003). The HLA-DQ alpha/beta markers and their risk heterodimers are increased in our diabetic population and could be considered as susceptibility markers to develop IDDM.
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PMID:[Genetic predisposition to develop insulin-dependent diabetes mellitus. A population study in Santiago and Temuco, Chile]. 873 11

Type 1 diabetes may appear at any age. The onset may be insidious and even asymptomatic for a long time. The prediabetic stage is characterized by genetic susceptibility, the presence of autoantibodies in serum, and gradual impairment of the beta-cell function. HLA-DQ-encoded heterodimers are strongly associated with increased risk/protection. Additional diabetogenic genes are present in other chromosomes, different from HLA region genes. Screening of prediabetes is usually restricted to first-degree relatives of type 1 diabetic subjects. Islet cell antibody (ICA)-positive gestational diabetic women form a subset of patients with increased risk of developing type 1 diabetes shortly after pregnancy. Optimization of metabolic control is the key strategy for preventing late diabetic complications. Diabetic education, intensive insulin therapy and regular screening for early detection are critical in achieving this goal. Individual monitoring of subjects at high risk for developing hypoglycaemias, and development of more adequate short- and long-acting insulin analogues represent important measures to avoid hypoglycaemia and associated risks. Effective delivery of care for type 1 diabetic subjects requires the operation of a continuous quality assessment programme.
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PMID:Frontiers of clinical research in type 1 diabetes. 880 27

HLA-DQ genes are the main inherited factors predisposing to IDDM. This gene region harbors long terminal repeat (DQ LTR) elements of the human endogenous retrovirus HER V-K, which we analyzed for a possible association with disease. We first investigated whether LTR segregate with DQ alleles in families. Members (n = 110) of 29 families with at least one diabetic child, unrelated patients with IDDM (n = 159), and healthy controls (n = 173) were analyzed. Genomic DNA was amplified for DQ LTR3 by a nested primer approach as well as for DQA1 and DQB1 second exons, to assign DQA1 and DQB1 alleles. DQ LTR segregated in 24 families along with DQ alleles. Of the 29 families, 20 index patients were positive for DQ LTR. The DQ LTR was in all patients on the haplotype carrying the DQA1 *0301 and DQB1 *0302 alleles. A majority of patients had DQ LTR (62%) compared with controls (38%) (p < 1.3 x 10(-5)), even after matching for the high-risk alleles DQA1 *0501, DQB1 *0201-DQA1 *0301, and DQB1 *0302 (79% of patients and 48% of controls; p < 0.02). Subtyping for DRB1 *04 alleles in all DQB1 *0302+ individuals showed 56% DRB1 *0401, DQB1 *0302 [LTR' patients vs. 29% controls with the same haplotype (p < 0.002)]. In conclusion, these data demonstrate the segregation of DQ LTR with DQA1, DQB1 alleles on HLA haplotypes. Furthermore their presence on DRB1 *0401-, DQA1 *0301-, and DQB1 *0302-positive haplotypes suggest that they contribute to DQ-related susceptibility for IDDM.
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PMID:Endogenous retroviral long terminal repeats of the HLA-DQ region are associated with susceptibility to insulin-dependent diabetes mellitus. 889 33

Disturbed immune regulation has been postulated to be crucial in the pathogenesis of IDDM and other autoimmune or allergic diseases. We therefore tested the hypothesis of a general bias in the peripheral immune system in patients with recent-onset IDDM or Graves' disease in comparison to healthy control subjects by studying whole blood cultures stimulated with phytohemagglutinin. Cells from IDDM patients (n = 53) produced significantly higher amounts of Th1 cytokines gamma-interferon (IFN-gamma) (P = 0.028) and tumor necrosis factor alpha (TNF-alpha) (P = 0.007) than normal control subjects (n = 56), while Th2 cytokine levels (interleukin [IL]-4, IL-10) were similar. Low levels of islet cell antibodies (ICAs) in IDDM patients were associated with high levels of Th1 and Th2 cytokines. Antibodies to GAD, ICA512, or insulin did not correlate with individual cytokine profiles. Also, HLA-DQ types did not significantly correlate with either Th1 or Th2 cytokine production. Conversely, whole blood cultures from patients with Graves' disease (n = 18) produced significantly less TNF-alpha and IL-4 than normal subjects (P = 0.001-0.006). However, when the balance between Th1 and Th2 cytokine production was analyzed in individuals, the ratio between IFN-gamma or TNF-alpha and IL-4 or IL-10 was clearly biased toward Th1 reactivity in patients with IDDM (P = 0.0001), while a dominance of Th2 cytokine production was seen in Graves' disease (P = 0.0001). The ratio of counterregulatory cytokines appeared to be the most reliable marker of the individual disease process. This study provides first evidence of a systemic bias in the immune regulation of humans, which might be either toward cell-mediated immunity (Th1) in IDDM or humoral immunity (Th2) in Graves' disease.
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PMID:Systemic bias of cytokine production toward cell-mediated immune regulation in IDDM and toward humoral immunity in Graves' disease. 900 Jul

HLA-DQA11 and DQB1 alleles coding for arginine (R) in position 52, and an amino acid other than aspartic acid (ND) in position 57, respectively, are strong genetic markers for IDDM in Caucasians. However, their contribution to the occurrence of the disease in Asian populations is less clear. As part of the WHO DiaMond Molecular Epidemiology Sub-Project, HLA-DQ molecular typing was performed for IDDM cases and non-diabetic controls from three populations in the Western Pacific Rim Region where incidence rates have been established (Hokkaido, Japan; Seoul, Korea; Auckland, New Zealand). DQA1*R homozygosity was significantly associated with IDDM in all areas. DQB1*ND homozygosity was also related to IDDM in Korea and New Zealand, but not in Japan. Individuals who were homozygous for DQA1*R and DQB1*ND were at highest IDDM risk in Korea and New Zealand, with the most striking findings in Auckland. In Japan, individuals carrying two DQA1*R, but only one DQB1*ND allele, were most likely to develop IDDM. These data revealed considerable genetic heterogeneity between Japan and Korea and suggest that DQA1*R and DQB1*ND alleles may explain a larger proportion of IDDM incidence in Caucasian compared to Asian populations.
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PMID:Molecular epidemiology of IDDM in the Western Pacific Rim Region. WHO DiaMond Molecular Epidemiology Sub-Project Group. 901 80

Apart from genes in the HLA complex (IDDM1) and the variable number of tandem repeats in the 5' region of the insulin gene (INS VNTR, IDDM2), several other loci have been proposed to contribute to IDDM susceptibility. Recently, linkage and association have been shown between the cytotoxic T lymphocyte-associated protein 4 (CTLA-4) gene on chromosome 2q and IDDM. In a registry-based group of 525 recent-onset IDDM patients <40 years old we investigated the possible interactions of a CTLA-4 gene A-to-G transition polymorphism with age at clinical disease onset and with the presence or absence of established genetic (HLA-DQ, INS VNTR) and immune disease markers (autoantibodies against islet cell cytoplasm (ICA); insulin (IAA); glutamate decarboxylase (GAD65-Ab); IA-2 protein tyrosine phosphatase (IA-2-Ab)) determined within the first week of insulin treatment. In new-onset IDDM patients. G-allele-containing CTLA-4 genotypes (relative risk (RR)= 1.5; 95% confidence interval (CI) = 1.2-2.0; P < 0.005) were not preferentially associated with age at clinical presentation or with the presence of other genetic (HLA-DR3 or DR4 alleles; HLA-DQA1*0301-DQB1*0302 and/or DQA1*0501-DQB1*0201 risk haplotypes; INS VNTR I/I risk genotype) or immune (ICA, IAA, IA-2-Ab, GAD65-Ab) markers of diabetes. For 151 patients, thyrogastric autoantibodies (anti-thyroid peroxidase, anti-thyroid-stimulating hormone (TSH) receptor, anti-parietal cell, anti-intrinsic factor) were determined, but association between CTLA-4 risk genotypes and markers of polyendocrine autoimmunity could not be demonstrated before or after stratification for HLA- or INS-linked risk. In conclusion, the presence of a G-containing CTLA-4 genotype confers a moderate but significant RR for IDDM that is independent of age and genetic or immune disease markers.
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PMID:CTLA-4 gene polymorphism confers susceptibility to insulin-dependent diabetes mellitus (IDDM) independently from age and from other genetic or immune disease markers. The Belgian Diabetes Registry. 935 55

The genes encoding the HLA-DQ heterodimer molecules, DQB1 and DQA1, have been found to have the strongest association with IDDM risk, although there is cumulative evidence for the effect of other gene loci within the major histocompatibility complex gene region. After the HLA-DQ locus, the HLA-DR locus has been suggested most often as contributing to the disease susceptibility. In this study we analyzed at the population level the effect of DR4 subtypes and class I, HLA-B alleles, on IDDM risk when the influence of the DQ locus was stratified. In all three populations studied (Estonian, Latvian, and Russian), DQB1*0302 haplotypes most frequently carried DRB1*0401 or DRB1*0404. DRB1*0401 was the most prevalent subtype in IDDM patients, whereas DRB1*0404 was decreased in frequency. DRB1*0402 was also prevalent among Russian haplotypes, but was not associated with IDDM risk. When HLA-B alleles were analyzed, strong associations between the presence of specific B alleles and DRB1*04 subtypes were detected. The HLA-B39 allele was found significantly more often in DRB1*0404-DQB1*0302-positive patients than in healthy control subjects positive for this haplotype: 27 of 54 (50%) vs. 4 of 49 (8.2%) (P < 0.0001). The results demonstrate that DQ and DR genes cannot explain all of the HLA-linked susceptibility to IDDM, and that the existence of a susceptibility locus telomeric to DR is probable.
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PMID:The effect of HLA-B allele on the IDDM risk defined by DRB1*04 subtypes and DQB1*0302. 935 41

The WHO DiaMond Molecular IDDM Epidemiology Sub-Project is testing the hypothesis that population variation in the frequency of high-risk HLA-DQ alleles is a primary determinant of the global patterns of IDDM incidence. Data are currently available for 16 populations, and reveal significant variations in the frequencies of HLA-DQA1 and DQB1 alleles among the case and the control groups. However, DQA1 x Arg-(52) and DQB1 x non-Asp-57 (ND) were consistent and independent markers of IDDM susceptibility in all populations, except Japan. Individuals who carried only DQA1 x R and DQB1 x ND alleles had an IDDM risk similar to that observed for first degree relatives of affected individuals (3%-5%). Such information is essential for the development of clinical strategies or disease prevention approaches for the general population or individuals at high-risk. Thus, the DiaMond Molecular Epidemiology Sub-Project provides an excellent model that can be followed to assess the impact of new genetic discoveries on medicine and public health practice for diabetes and other chronic diseases.
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PMID:Molecular epidemiology of insulin-dependent diabetes mellitus: WHO DiaMond Project. WHO DiaMond Molecular Epidemiology Sub-Project Group. 950 18

We analyzed 11 markers in the IDDM1 region in 120 IDDM patients and 83 healthy control subjects who were fully matched for the highest risk HLA-DQA1*0301-DQB1 *0302/DQA1*0501-DQB1*0201 genotype. Our study provides strong evidence that two regions in the major histocompatibility complex contribute to IDDM susceptibility or protection. First, despite selection for highest IDDM-associated risk DQ genotypes, this region displays extensive linkage disequilibrium (LD) differences between IDDM patients and control subjects. A second critical region was mapped around the microsatellite locus D6S273 centromeric of TNF, and it is approximately 200 kb in size. LD analysis shows that "diabetogenic haplotypes" may have resulted from a recombination telomeric of D6S1014 in the region of D6S273 and TNFa. Haplotype analysis using HLA and microsatellite loci refines IDDM risk assessment in carriers of the HLA-DQ highest risk genotype.
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PMID:Genetic structure of IDDM1: two separate regions in the major histocompatibility complex contribute to susceptibility or protection. Belgian Diabetes Registry. 951 23

First-degree relatives (FDRs) of diabetic patients are at risk of IDDM, and frequently present several autoantibodies. We detected anticardiolipin antibodies (aCL) in 42 FDRs, aged 12.4 +/- 4.2 years and in 52 controls. aCL (IgG and IgM) were measured by ELISA and their results expressed in arbitrary units. All FDRs underwent islet cell antibodies (ICA) measurement, intravenous glucose tolerance test and HbA1c levels. HLA typing and HLA-DQ molecular analysis were performed in all FDRs. Positive levels of aCL-IgG were observed in 8/42 FDRs and no control subject (p = 0.04); aCL-IgM values were similar in FDRs and controls. No correlation was found between aCL levels and chronologic age or HbA1c levels. No association was observed between aCL frequency and immunologic (ICA), metabolic or genetic (HLA) parameters. No FDR showed any feature of antiphospholipid syndrome. aCL-IgG presence in FDRs is suggestive of a need to carry out a follow-up study to establish the significance of these antibodies.
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PMID:Anticardiolipin antibodies in first-degree relatives of type 1, insulin-dependent, diabetic patients. 964 25


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