Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0011849 (diabetes)
 277,896 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The enzyme glutamic acid decarboxylase (GAD65) is a major autoantigen in insulin-dependent diabetes mellitus (IDDM). To study T-cell reactivity towards GAD, peripheral blood leucocytes from seven patients with IDDM and five control subjects were stimulated in vitro with recombinant GAD. All diabetics studied were heterozygous for diabetes-associated HLA alleles, i.e. HLA-DRB1*03,*04-DQB1 *0302,*0201. A single IDDM subject (no. GAD65.05) revealed a strong response against GAD65. After stimulation, his T-cell receptor beta (TCRBV) usage was found to be oligoclonal. The sequence analysis of the putative peptide binding region of the T-cell receptor (CDR3 region) of 37 GAD-reactive T-cell clones revealed no common CDR3 motif. The stimulation of GAD-reactive T-cells could be inhibited with anti-class II monoclonal antibodies, indicating a class II restricted T-cell response. In addition, GAD65-responsive T-cells revealed a Th1 cytokine response pattern. The author's data suggest that GAD-reactive T-cells of Th1 phenotype can be obtained after in vitro stimulation of peripheral blood leucocytes from an HLA-DRB1*03/*04 heterozygous IDDM patient. The lack of a common CDR3 motif suggests the absence of an immunodominant T-cell epitope in that patient, or may indicate receptor repertoire spreading of peripheral T-lymphocytes.
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PMID:In vitro stimulation with glutamic acid decarboxylase (GAD65) leads to an oligoclonal response of peripheral T-cells in an IDDM patient. 855 91

HLA class II genes are strongly associated with susceptibility and resistance to insulin-dependent diabetes mellitus (IDDM). The present study reports the HLA-DRB1 genotyping of 41 IDDM patients and 99 healthy subjects from the Southeast of Brazil (Campinas region). Both groups consisted of an ethnic mixture of Caucasian, African Negro and Amerindian origin. HLA-DRB1*03 and *04 alleles were found at significantly higher frequencies among IDDM patients compared to the controls (DRB1*03: 48.8% vs 18.2%, P < 0.005, RR = 4.27; DRB1*04: 43.9% vs 15.1%, P < 0.008, RR = 4.37) and were associated with a susceptibility to the disease. DRB1*03/*04 heterozygosity conferred a strong IDDM risk (RR = 5.44). In contrast, the HLA-DRB1*11 allele frequency was lower among IDDM patients (7.3% vs 26.3% in controls), but the difference was not significant. These data agree with those described for other populations and allow genetic characterization of IDDM in Brazil.
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PMID:Distribution of HLA-DRB1 alleles in a mixed population with insulin-dependent diabetes mellitus from the southeast of Brazil. 969 83

This communication reports the identification of a new allele HLA-DRB1*03 in three members of a Caucasian Spanish family. The new allele has been officially named HLA-DRB1*0318 by the World Health Organization Nomenclature Committee. The exon 2 sequence of this new allele is identical to that of DRB1*03011 except for the first nucleotide of codon 45. The nucleotide change (C replacing G) leads to the amino acid substitution of glycine to arginine (GGG-->CGG) at position 45. This position of the beta1 domain shows very little polymorphism among DRB1* alleles (nucleotide changes at this position have only been reported for DRB1*1436 and DRB1*0105) and locates in the vicinity of the highly polymorphic position 47, which is a constituent of the groove's pocket interacting with the amino acid position 7 of the antigen peptide. The familial study showed that the new allele was maternally transmitted into the HLA-A*3002, -B*1801, -Cw*0501, -DRB1*0318, -DRB3*0202, -DQB1*0201 haplotype. Interestingly, the two siblings of the family, which were HLA identical and suffered of insulin-dependent diabetes mellitus (IDDM), were carriers of the two HLA haplotypes (DRB1*03/DQB1*0201 and DRB1*04/DQB1*0302) reported as susceptibility markers to IDDM in Caucasians.
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PMID:Identification of a new HLA-DRB1 allele (DRB1*0318) in three members of a Caucasian Spanish family. 1155 78

Latent autoimmune diabetes in adults (LADA) is identified by the presence of GAD65 autoantibodies in diabetic patients who do not require insulin treatment for at least six months after the diagnosis. Previous studies have shown that the risk for LADA, similarly to type 1 diabetes mellitus (T1DM), is increased in subjects carrying the HLA-DRB1*03-DQA1*0501-DQB1*0201 and/or HLA-DRB1*04-DQA1*0301-DQB1*0302 haplotypes. In the present study, we investigated the association between LADA and the CTLA-4 A/G polymorphism, another gene polymorphism associated with T1DM and other autoimmune diseases. The heterozygous A/G genotype was significantly more frequent among 80 LADA (69%) than among 85 healthy subjects of similar age and geographical provenience (47%) (OR = 2.47, corrected P = 0.023). Conversely, the homozygous A/A genotype was significantly less frequent in LADA subjects than in healthy controls (26% vs. 47%, OR = 0.4, corrected P = 0.028). The results of our study show that LADA is positively associated with the CTLA-4 A/G genotype, similarly to T1DM, thus providing further supporting evidence of the autoimmune origin of this form of diabetes mellitus of the adult.
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PMID:CTLA-4 gene polymorphism contributes to the genetic risk for latent autoimmune diabetes in adults. 1202 Nov 37

We investigated distribution of HLA class II alleles among 52 unrelated patients with dilated cardiomyopathy (DCM) (25 consecutive men, 27 consecutive women, mean age 38 +/- 16 years) to determine if there is any immunogenetic predisposition to the disease. DCM was diagnosed according to WHO criteria. HLA-DR and DQ alleles were examined by PCR-SSP typing. Frequency of DRB1* and DQB1* alleles in the study group was compared to local control group (n = 126 for DRB1* and n = 76 for DQB1* alleles). There was a non-significant increase in the frequency of HLA-DRB1*03 (chi square = 4.78, p < 0.05, p corrected for multiple comparisons (pcorr)--NS) and HLA-DQB1*02 (chi square = 4.92, p < 0.05, pcorr--NS) among DCM patients as compared to controls. Frequency of DRB1*04 allele was lower than expected (chi square = 4.58, p < 0.05, pcorr--NS). DRB1*03 is associated with several autoimmune diseases, of interest it confers risk for idiopathic myopathy in Polish patients. Heterozygosity for DRB1*03/DRB1*04, known for association with insulin-dependent diabetes mellitus was found in 3 patients (5.7%), two of them had adult-onset insulin-dependent diabetes mellitus. There was a tendency to overrepresentation of DRB1*08 among men with DCM. In conclusion, these data give some support for autoimmune involvement in the pathogenesis of dilated cardiomyopathy.
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PMID:[Frequency of DRB1* and DQB1* alleles in Polish patients with dilated cardiomyopathy]. 1236 98

The HLA genotype DRB1*03,DQB1*0201/DRB1*04,DQB1*0302 confers a 25-fold increase in the risk of type 1 diabetes. In persons with this genotype, DRB1*0405, *0402, and *0401 subtypes have been reported to further increase risk, whereas the *0403 and *0406 alleles confer a relative protection. We compared the frequencies of the DRB1*04 alleles in 193 type 1 diabetic patients with the HLA-DRB1*03,DQB1*0201/DRB1*04,DQB1*0302 genotype (140 non-Hispanic white [NHW] and 53 Hispanic) and 205 nondiabetic controls (142 NHW and 63 Hispanic). In addition, 87 NHW first-degree relatives of type 1 diabetes patients were studied: 33 positive and 54 negative for autoantibodies to insulin, GAD65, or IA-2. The HLA-DRB1 was typed using standard PCR SSOP methods. DRB1*0401 (OR, 2.19; 95% CI, 1.36-3.54) in NHW and *0405 (OR, 3.78; 95% CI, 1.43-10.0) in Hispanics were significantly associated with T1DM, whereas DRB1*0403 was protective (OR, 0.19; 95% CI, 0.04-0.89 in NHWs; OR, 0.10; 95% CI, 0.01-0.83 in Hispanics). Associations between the DRB1*04 alleles and prediabetic islet autoimmunity were generally in the same direction as those with diabetes. Among diabetic patients, the mean age of diagnosis appeared to be higher among those with the *0403 and *0407 allele compared with the others. In summary, on the DRB1*03,DQB1*0201/DRB1*04,DQB1*0302 genotypes, the *0403 allele confers relative protection from type 1 diabetes and development of islet autoantibodies in both Hispanics and NHWs and is associated with older age at diabetes diagnosis. Although the associations between diabetes and *0401 and *0405 appear to differ somewhat between Hispanics and NHWs, overall there is no significant difference between these two ethnic groups.
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PMID:Ethnic differences in the associations between the HLA-DRB1*04 subtypes and type 1 diabetes. 1467 80

Type 1 Diabetes Mellitus (T1D) with an onset in adulthood and Late Autoimmune Diabetes of Adults (LADA) are connected with autoimmune insulitis (associated with islet cell autoantibodies) and the specific high-risk HLA class II genotype. The study was aimed at analyzing time and clinical characteristics of the diabetics with an onset of the disease after 35 y. (T1D and LADA). Main target of the study was to assess possible role of the old age onset and compare it with diabetics with the onset in the middle age (incl. analyzing HLA-DRB1 genotype). In the study, we included 103 diabetics with an onset of autoimmune diabetes at 35+ y. who were hospitalized and afterwards long-term observed in the diabetological outpatient department. 46 men and 57 women of the average age 65.7 +/- 13.8 y. (range 35-93 y.) were out of this number. 41 were assessed as the T1D patients and 61 as the LADA ones. As a control group we used 99 healthy individuals. Patients of the T1D subgroup developed diabetes in the age of 50.8 +/- 15.1 y. and of the LADA subgroup in the age of 52.6 +/- 12.8 y. Its duration in the time of this study was 10.7 +/- 11.6 y.; respectively 5.3 +/- 7.1 y. Fasting and postprandial C-peptide levels were statistically higher (p < 0.01) in the LADA subgroup vs. T1D. Obesity 1st and 2nd grade were present together only in 12.6%. BMI was not statistically significantly different between both groups. We found in our diabetic patients the predisposition alleles HLA-DRB1*03, HLA-DRB1*04 and particularly their combination. The occurrence of these HLA alleles is significantly higher in T1D patients in comparison to control groups (p = 0.01, OR = 4.0). In our study, the occurrence of the susceptible HLA-DRB1*03 and HLA-DRB1*04 alleles in T1D patients is higher than in LADA. The presence of these alleles identifies patients of high risk and requirement of insulin therapy. Since risk alleles are similarly present in middle and old age, environmental factors probably play similar role in these onsets of autoimmune diabetes.
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PMID:Type 1 diabetes and LADA--occurrence of HLA-DRB1 *03 and DRB1 *04 alleles in two age different groups of diabetics. 2103 93

The determination of GADA may be useful for clinical classification of diabetes mellitus (DM) in clinically unclear cases. This GADA positivity may persist in any diabetics Type 1 Diabetes Mellitus (T1D) with an onset in adulthood and Late Autoimmune Diabetes of Adults (LADA) many years after appearance of DM. The study was aimed at comparing the levels of GADA between both diabetic subsets with their clinical parameters, age of onset DM, period of insulin need, body mass index, HbA1C, fasting and postprandial C-peptide, risky HLA-DRB1* alleles, occurrence of micro- and macrovascular diabetic complications. Further analysis of GADA titers in different time consequences to the development of DM and relations to IA-2 were made. In the study, we included 130 diabetics with an onset of diabetes (T1D or LADA) 35+ y. who were hospitalized and afterwards long-term observed in the diabetological outpatient department. Out of this number there were 62 men and 68 women of the average age 65.5 +/- 14.0 y. (range 35-93 y.). 54 were assessed as the T1D patients and 76 as the LADA ones. Patients of the T1D subgroup were GADA positive 22 times and of the LADA subgroup 21 times. LADA 2 patients that were GADA negative were more obese than GADA positive LADA diabetics (p < 0.01). Also postprandial C-peptide was higher in LADA patients GADA negative (p < 0.05). Other clinical characteristics were without statistically significant differences. We found in our diabetic patients a relation between alleles HLA-DRB1*03 and particularly combination with HLA-DRB1*04 with positive GADA levels. In the GADA negative group obesity, coronary heart disease, hypertension, syndrome of diabetic foot and dyslipidaemia appeared more frequently (OR = 2.8; 3.1; 6.2 and 2.4). We found no significant differences in observed parameters--comparison GADA positivity and negativity according to the duration of DM. GADA positive were even 10 y. duration 16 times and after 20 y. even 6 times. Recent DM had positive GADA in 11 cases and 13 cases of recent DM had GADA negative. IA-2 antibodies were positive (> 1.0 U/ml) 18 times altogether and always with positive GADA, but only 7 times in recent DM. The presence of elevated GADA identifies patients unequivocally suitable for early insulin therapy. Our observations and experiences confirm that GADA can be found increased after more than 10-20 years duration of DM, although in decreasing trend.
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PMID:GAD antibodies in T1D and LADA--relations to age, BMI, c-peptide, IA-2 and HLA-DRB1*03 and DRB1*04 alleles. 2195 94

Evaluating risk of developing type 1 diabetes (T1D) depends on determining an individual's HLA type, especially of the HLA DRB1 and DQB1 alleles. Individuals positive for HLA-DRB1*03 (DR3) or HLA-DRB1*04 (DR4) with DQB1*03:02 (DQ8) have the highest risk of developing T1D. Currently, HLA typing methods are relatively expensive and time consuming. We sought to determine the minimum number of single nucleotide polymorphisms (SNPs) that could rapidly define the HLA-DR types relevant to T1D, namely, DR3/4, DR3/3, DR4/4, DR3/X, DR4/X, and DRX/X (where X is neither DR3 nor DR4), and could distinguish the highest-risk DR4 type (DR4-DQ8) as well as the non-T1D-associated DR4-DQB1*03:01 type. We analyzed 19,035 SNPs of 10,579 subjects (7,405 from a discovery set and 3,174 from a validation set) from the Type 1 Diabetes Genetics Consortium and developed a novel machine learning method to select as few as three SNPs that could define the HLA-DR and HLA-DQ types accurately. The overall accuracy was 99.3%, area under curve was 0.997, true-positive rates were >0.99, and false-positive rates were <0.001. We confirmed the reliability of these SNPs by 10-fold cross-validation. Our approach predicts HLA-DR/DQ types relevant to T1D more accurately than existing methods and is rapid and cost-effective.
Diabetes 2013 Jun
PMID:Definition of high-risk type 1 diabetes HLA-DR and HLA-DQ types using only three single nucleotide polymorphisms. 2337 6

We have previously reported the high levels of glutamic acid decarboxylase 65 autoantibodies (GAD65A) in patients with type 1 diabetes and autoimmune thyroid disease. Here we describe a 32-year-old Japanese female with a thirteen-year history of type 1 diabetes whose levels of GAD65A were elevated just after the emergence of anti-thyroid autoimmunity. At 19 years of age, she developed diabetic ketoacidosis and was diagnosed with type 1 diabetes. She had GAD65A, insulinoma-associated antigen-2 autoantibodies (IA-2A), and zinc transporter-8 autoantibodies (ZnT8A), but was negative for antibodies to thyroid peroxidase (TPOAb) and thyroglobulin (TGAb) at disease onset. ZnT8A and IA-2A turned negative 2-3 years after the onset, whereas GAD65A were persistently positive at lower level (approximately 40 U/mL). However, just after the emergence of TGAb at disease duration of 12.5 years, GAD65A levels were reelevated up to 5717 U/mL in the absence of ZnT8A and IA-2A. Her thyroid function was normal and TPOAb were consistently negative. She has a HLA-DRB1*03:01/*04:01-DQB1*02:01/*03:02 genotype. Persistent positivity for GAD65A might be associated with increased risk to develop anti-thyroid autoimmunity.
World J Diabetes 2013 Oct 15
PMID:Sequential elevation of autoantibodies to thyroglobulin and glutamic acid decarboxylase in type 1 diabetes. 2414 7


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