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)

Gestational diabetes mellitus (GDM) is a risk factor for the development of insulin-dependent diabetes mellitus (IDDM) and noninsulin-dependent diabetes mellitus postpartum. To evaluate whether there is any association of human leukocyte antigen (HLA) class II alleles (DR and DQ) with GDM and the postpartum development of IDDM, we analyzed 184 women with GDM from Germany for HLA class II alleles, islet autoantibodies [islet cell autoantibodies (ICA), glutamic acid decarboxylase autoantibodies (GADA), and protein tyrosine phosphatase IA-2 autoantibodies (IA-2A), and the postpartum development of diabetes. No elevation in the frequency of any HLA class II alleles was observed in GDM patients compared to 254 nondiabetic unrelated subjects. DR3 allele frequency was significantly increased in 43 women with islet autoantibodies [corrected P value (Pc) = 0.02], in particular in those with GADA (Pc = 0.002), or in the 24 women who developed IDDM postpartum (Pc = 0.005). In women with GADA, DR4 and DQB1*0302 were significantly elevated (Pc = 0.009). Twenty-five (59.5%) islet antibody-positive women and 17 (74%) women who developed IDDM postpartum had a DR3- or DR4-containing genotype. The cumulative risk to develop IDDM within 2 yr postpartum in GDM women with either DR3 or DR4 was 22% compared to 7% in women without those alleles (P = 0.02) and rose to 50% in the DR3- or DR4-positive women who had required insulin during pregnancy (P = 0.006). Combining the determination of susceptible HLA alleles (DR3, DR4) with islet autoantibody measurement increased the sensitivity of identifying GDM women developing postpartum IDDM to 92%, but did not improve risk assessment above that achieved using GADA measurement alone, which was the strongest predictor of IDDM. These results indicate that women with GDM who have islet autoantibodies at delivery or develop IDDM postpartum have HLA alleles typical of late-onset type 1 diabetes, and that both HLA typing and islet antibodies can predict the development of postpartum IDDM.
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PMID:Predictive value of human leukocyte antigen class II typing for the development of islet autoantibodies and insulin-dependent diabetes postpartum in women with gestational diabetes. 1040

Our objective was to investigate whether notification of high-risk status for type 1 diabetes in newborn infants results in an increased maternal-parenting stress level when compared with notification of low-risk status for type 1 diabetes. Maternal parenting stress level was assessed at 5-7 weeks postpartum (baseline) and was reassessed 4-5 months after parents were informed of their newborn infants' genetic screening results (follow-up). Parenting stress level was measured using the total stress score (TSS) of the Parenting Stress Index/Short Form. The outcome variable, change in TSS, was calculated by subtracting the baseline TSS from the follow-up TSS. Demographic variables such as maternal race, maternal age, maternal education level, maternal marital status, child's birth order, and total family income were assessed through a structured phone interview at the time of baseline assessment. The risk factor of interest was the child's human leukocyte antigen (HLA) status for type 1 diabetes, i.e., whether child was at a high or moderate (combined into "high") genetic risk or at a low genetic risk for type 1 diabetes. A sample of 88 mothers (23 with a high-risk child and 65 with a low-risk child) was evaluated. Baseline median TSSs were 65 and 74 for mothers of low-risk infants and mothers of high-risk infants, respectively. Both groups' median TSS decreased between baseline and follow-up. No significant differences were found between change in TSS and maternal age, race, education level, marital status, total family income, or child's birth order. Although the median decrease in TSS was smaller in mothers with a high-risk child when compared with mothers of a low-risk child, this difference was not statistically significant. We did not find an association between newborn's HLA status and change in maternal TSS. The results of this study suggest that notification of high-risk status for type 1 diabetes in newborn infants may not result in an increased level of parenting stress among mothers.
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PMID:Impact on maternal parenting stress of receipt of genetic information regarding risk of diabetes in newborn infants. 1048 69

During immune responses, antigen-presenting cells (APCs) process antigens and present peptide epitopes complexed with human leukocyte antigen (HLA) molecules. CD4 cells recognize these naturally processed and presented epitopes (NPPEs) bound to HLA class II molecules. Epitope identification is important for developing diagnostic and therapeutic tools for immune-mediated diseases and providing insight into their etiology, but current approaches overlook effects of natural processing on epitope selection. We have developed a technique to identify NPPEs using mass spectrometry (MS) after antigen is targeted onto APCs using a lectin-based antigen delivery system (ADS). We applied the technique to identify NPPEs of the intracellular domain of the type 1 diabetes mellitus-associated (type 1 DM-associated) autoantigen insulinoma-associated-2 (IA-2ic), presented by HLA-DR4 (0401). IA-2ic-derived NPPEs eluted from HLA-DR4 constitute 6 sets of peptides nested around distinct core regions. Synthetic peptides based on these regions bind HLA-DR4 and elicit primary T-cell proliferation frequently in HLA-DR4-positive type 1 DM patients, but rarely in non-HLA-DR4 patients, and in none of the HLA-DR4 nondiabetic controls we tested. This flexible, direct approach identifies an HLA allele-specific map of NPPEs for any antigen, presented by any HLA class II molecule. This method should enable a greater understanding of epitope selection and lead to the generation of sensitive and specific reagents for detecting autoreactive T cells.
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PMID:Naturally processed and presented epitopes of the islet cell autoantigen IA-2 eluted from HLA-DR4. 1058 9

Previous studies have shown a high prevalence of gastric parietal cell antibodies (PCA) in type 1 diabetes, which can be accompanied by (sub)clinical autoimmune gastric disease. This study aimed to determine the grade of associated autoimmunity and to assess the pattern of prevalence of PCA by gender, age, duration of disease, age at onset of diabetes, and human leukocyte antigen (HLA) type in an adult type 1 diabetic population. Furthermore, to examine the clinical significance of being PCA positive, manifestations of gastric autoimmune disease were studied in PCA-positive and PCA-negative patients. The population studied consisted of 497 type 1 diabetics (men/women, 252/245; mean age, 40.8 +/- 12.1 yr; mean duration of disease, 16.4 +/- 10.4 yr; mean age at onset, 26.9 +/- 13.5 yr; mean hemoglobin A1c, 8.1 +/- 1.6%). Associated autoantibodies were present in 39% and PCA were present in 20.9% of the subjects, particularly in older patients. Gender, duration, and age at onset of diabetes did not influence the appearance of PCA. Antithyroid peroxidase antibodies (aTPO) were more frequent in PCA-positive patients than in those without PCA (33.6% vs. 22.4%; P = 0.025), suggesting an association between gastric and thyroid autoimmunity. We could demonstrate an association between PCA and the HLA DR5 haplotype (P = 0.001) as well, but not with HLA DR3 and/or DR4. In the PCA-positive group, iron deficiency anemia was detected in 15.4%, and pernicious anemia was found in 10.5% of subjects. These autoimmune gastric manifestations were significantly more prevalent in PCA-positive diabetics than in PCA-negative subjects, in whom the percentages were 6.9% and 0.5%, respectively (P = 0.01 and P < 0.0001). PCA were prevalent in 84.6% of patients with pernicious anemia. A gastroscopic and anatomopathological examination performed in a subgroup of 30 patients with gastric symptoms revealed atrophic gastritis in 13 of 14 PCA-positive patients and in 9 of 16 PCA-negative subjects (P = 0.04). PCA were present in 59.1% of patients with atrophic gastritis. In conclusion, a high prevalence of parietal cell antibodies and associated autoimmune gastric disease is present in PCA-positive type 1 diabetics, recommending its screening. Early detection of PCA and iron deficiency anemia, pernicious anemia, and atrophic gastritis and the subsequent care could reduce the morbidity of type 1 diabetes.
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PMID:High prevalence of manifestations of gastric autoimmunity in parietal cell antibody-positive type 1 (insulin-dependent) diabetic patients. The Belgian Diabetes Registry. 1056 50

Previous studies have suggested that the human leukocyte antigen (HLA) class I region may be involved in determining the age at onset and clinical severity of type 1 diabetes. We have investigated the frequency of polymorphisms of the nonclassical HLA class I gene, HLA-E, in 199 British Caucasian patients with type 1 diabetes and 82 healthy controls. A highly significant increase in the frequency of the HLA-E 0101 genotype was found in the patients compared to controls (chi(2) = 15.3, p < 0.00009). The frequency of the HLA-E 0101 genotype was increased in those patients diagnosed after 10 years of age, while the frequency of the 0101, 0103 genotype was significantly increased in those subjects diagnosed before 10 years of age (chi(2) = 26.0 p < 0.000003 and chi(2) = 13.0 p < 0.0003, respectively). No obvious interaction between the HLA-E locus and the class II DQB1*0201, 0302, and 0501 susceptibility alleles was found. This is the first report of an association between the HLA-E locus and susceptibility to an autoimmune disease.
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PMID:The HLA-E locus is associated with age at onset and susceptibility to type 1 diabetes mellitus. 1068 18

To evaluate the emergence of diabetes-associated autoantibodies in young children and to assess whether such antibodies can be used as surrogate markers of type 1 diabetes in young subjects at increased genetic risk, we studied 180 initially unaffected siblings (92 boys and 88 girls) of children with newly diagnosed type 1 diabetes. All siblings were younger than 6 yr of age at the initial sampling, and they were monitored for the emergence of islet cell antibodies (ICA), insulin autoantibodies (IAA), glutamate decarboxylase antibodies (GADA), and IA-2 antibodies (IA-2A) up to the age of 6 yr and for progression to clinical type 1 diabetes up to the age of 10 yr. All 160 siblings with DNA samples available were typed for susceptible (DQB1*02 and *0302) and protective (DQB1*0301 and *0602-03) HLA DQB1 alleles. Twenty-two siblings (12.2%) tested positive for ICA in their first antibody-positive sample before the age of 6 yr, 13 (7.2%) tested positive for IAA, 15 (8.3%) tested positive for GADA, and 14 (7.8%) tested positive for IA-2A. There were 16 siblings (8.9%) who had 1 detectable autoantibody, 5 (2.8%) had 2, and 12 (6.7%) had 3 or more. In the group of 82 siblings with increased human leukocyte antigen-defined genetic susceptibility [DQB1*02/*0302, *0302/x (x = other than *02 or a protective allele), *02/y (y = other than *0302 or a protective allele)], 18 (22.0%) tested positive for ICA in their first antibody-positive sample, 10 (12.2%) tested positive for IAA, 14 (17.1%) tested positive for GADA, and 12 (14.6%) tested positive for IA-2A. One antibody was detectable in 6 siblings (7.3%), 2 were detectable in 5 (6.1%), and 3 or more were detectable in 12 (14.6%). Fifteen siblings (18.3%) presented with clinical type 1 diabetes before the age of 10 yr. All of the progressors showed increased human leukocyte antigen-defined genetic susceptibility. Thirteen of those 15 siblings, who presented with clinical type 1 diabetes before the age of 10 yr, had at least 2 antibodies detectable before the age of 6 yr (disease sensitivity, 87%; 95% confidence interval, 60-98%). Thirteen of the 17 siblings who tested positive for 2 or more autoantibodies before the age of 6 yr developed type 1 diabetes before the age of 10 yr (positive predictive value, 76%; 95% confidence interval, 50-93%). These observations suggest that disease-associated autoantibodies can well be used as surrogate markers of clinical type 1 diabetes in primary prevention trials targeting young subjects with increased genetic disease susceptibility.
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PMID:Disease-associated autoantibodies as surrogate markers of type 1 diabetes in young children at increased genetic risk. Childhood Diabetes in Finland Study Group. 1072 50

The presence of human leukocyte antigen (HLA) haplotype DQA1*0102, DQB1*0602 is associated with protection from type 1 diabetes. The Diabetes Prevention Trial-type 1 has identified 100 islet cell antibody (ICA)-positive relatives with this protective haplotype, far exceeding the number of such subjects reported in other studies worldwide. Comparisons between ICA+ relatives with and without DQB1*0602 demonstrated no differences in gender or age; however, among racial groups, African-American ICA+ relatives were more likely to carry this haplotype than others. The ICA+ DQB1*0602 individuals were less likely to have additional risk factors for diabetes [insulin autoantibody (IAA) positive or low first phase insulin release (FPIR)] than ICA+ relatives without DQB1*0602. However, 29% of the ICA+ DQB1*0602 relatives did have IAA or low FPIR. Although half of the ICA+ DQB1*0602 relatives had a high risk second haplotype, this was not associated with the additional risk factors for diabetes. Hispanic ICA+ individuals with DQB1*0602 were more likely to be IAA positive or to have low FPIR than other racial groups. In conclusion, the presence of ICA in the relatives described here suggests that whatever the mechanism that protects DQB1*0602 individuals from diabetes, it is likely to occur after the diabetes disease process has begun. In addition, there may be different effects of DQB1*0602 between ethnic groups.
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PMID:Islet cell antibody-positive relatives with human leukocyte antigen DQA1*0102, DQB1*0602: identification by the Diabetes Prevention Trial-type 1. 1072 72

We hypothesized that genetic determinants of expression of persistent antiislet autoantibodies would similarly influence the expression of transient autoantibodies. To test this hypothesis, we prospectively evaluated sera from 478 relatives (SOC: sibling-offspring cohort) of patients with type 1 diabetes as well as 793 newborns from the general population (NEC: newborn nonrelative cohort) selected for expression of specific human leukocyte antigen haplotypes. Eight relatives of 478 (1.7% of SOC) expressed a transient autoantibody, and none had the high risk genotype DR3/4(DQ2/8). In contrast, 28 relatives (5.9%) had persistent antiislet autoantibodies, and 14 (50%) were DR3/4(DQ2/8) heterozygotes. Thirteen children of 793 (1.6% of NEC) expressed a transient autoantibody, and none had the high risk genotype DR3/4(DQ2/8). Seven of the NEC (0.9%) had persistent antiislet autoantibodies, and 4 (57.1%) were DR3/4(DQ2/8) heterozygous. Expression of persistent autoantibodies was strongly related to human leukocyte antigen status and family history of type 1 diabetes. In contrast, the expression of transient antiislet autoantibodies did not differ by family history of diabetes, and none of the DR3/4(DQ2/8) relatives and DR3/4(DQ2/8) newborns expressed transient autoantibodies. Our results indicate that children can express transient antiislet autoantibodies, but such transient autoantibodies are relatively infrequent and are not correlated with known genetic risk factors for type 1 diabetes.
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PMID:Transient antiislet autoantibodies: infrequent occurrence and lack of association with "genetic" risk factors. 1090 88

Recently, several studies have demonstrated that tumor necrosis factor microsatellite polymorphism (TNFalpha) contributes to the susceptibility of type 1 diabetes. This study investigates the influence of TNFalpha on the predisposition to insulin dependency in adult-onset diabetic patients with type 1 diabetes-protective human leukocyte antigen haplotypes. The TNFalpha of three groups of DRB1*1502DQB1*0601-positive diabetic patients who had initially been nonketotic and noninsulin dependent for more than 1 yr was analyzed. Group A included 11 antibodies to glutamic acid decarboxylase (GADab)-positive patients who developed insulin dependency within 4 yr of diabetes onset. Group B included 11 GADab-positive patients who remained noninsulin dependent for more than 12 yr. Group C included 12 GADab-negative type 2 diabetes, and a control group included 18 nondiabetic subjects. In the group C and control subjects, DRB1*1502-DQB1*0601 was strongly associated with the TNFalpha13 allele. DRB1*1502-DQB1*0601 was strongly associated with the TNFalpha12 allele among the group A patients, but not among the group B patients. Interestingly, sera from all patients with non-TNFalpha12 and non-TNFalpha13 in group B reacted with GAD65 protein by Western blot. These results suggest that TNFalpha is associated with a predisposition to progression to insulin dependency in GADab/DRB1*1502DQB1*0601-positive diabetic patients initially diagnosed with type 2 diabetes and that determination of these patients' TNFalpha genotype may allow for better prediction of their clinical course.
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PMID:Tumor necrosis factor microsatellite polymorphism influences the development of insulin dependency in adult-onset diabetes patients with the DRB1*1502-DQB1*0601 allele and anti-glutamic acid decarboxylase antibodies. 1099 32

Autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED) is caused by lack of functional products of the autoimmune regulator gene located on chromosome 21q22.3. The patients are at high risk of developing insulin-dependent (type 1) diabetes, but the positive predictive value of GAD65 or islet cell antibodies for type 1 diabetes is only 27%. Autoantibodies against the IA-2 tyrosine phosphatase-like protein (IA-2 ab) or insulin (IAA) have been suggested to be better markers for active ss-cell destruction. We studied these antibodies in sera from 60 Finnish patients with APECED, 12 of whom subsequently developed type 1 diabetes. Four (36%) of the 11 patients for whom we had prediabetic samples had IA-2 ab, and 4 (36%) had IAA. None of the 48 nondiabetics had IAA, and only 2 (4%) had IA-2 ab. Both had the antibodies for years without diabetes. Thus, IA-2 ab or IAA have a low sensitivity (36%), but high specificity (96% or 100%), with a positive predictive value of 67% for type 1 diabetes in patients with APECED. Data for human leukocyte antigen haplotypes were available for 59 of the patients, including 11 diabetics, and for 8 additional nondiabetic Finnish patients. No association between type 1 diabetes and high risk genotypes was seen. None of the 11 patients with type 1 diabetes, but 15 of the 56 (27%; P: < 0.05) nondiabetic patients and 24 of 93 (26%; P: < 0.05) of the control subjects had the DQB1*0602 allele, which is considered protective for type 1 diabetes. This is remarkable, as previously no positive or negative associations have been reported for any disease components of APECED with human leukocyte II antigens.
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PMID:ss-cell autoantibodies, human leukocyte antigen II alleles, and type 1 diabetes in autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy. 1113 89


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