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 association of insulin-dependent diabetes mellitus (IDDM) with certain HLA alleles is well documented in pediatric patients. Whether a similar association is found in adult-on-set IDDM is not clear, although the disease occurs after the age of 20 in 50% of cases. HLA class II DRB1, DQA1, and DQB1 alleles were studied in 402 type I diabetics and 405 healthy controls (all Caucasian) using oligonucleotide typing after gene amplification. Alleles DRB1*03, DRB1*04, DQB1*0201, DQB1*0302, DQA1*0301, and DQA1*0501 were indeed enriched in diabetics and the highest relative risk was observed in patients carrying both the DRB1*03-DQB1*0201 and the DRB1*0402 or DRB1*0405-DQB1*0302 haplotypes. However none of these alleles, or specific residues, could alone account for the susceptibility to IDDM. Furthermore, there were major differences in HLA class II gene profiles according to the age of onset. Patients with onset after 15 yr (n = 290) showed a significantly higher percentage of non-DR3/non-DR4 genotypes than those with childhood onset (n = 112) and a lower percentage of DR3/4 genotypes. These non-DR3/non-DR4 patients, although presenting clinically as IDDM type 1 patients, showed a lower frequency of islet cell antibodies at diagnosis and a significantly milder initial insulin deficiency. These subjects probably represent a particular subset of IDDM patients in whom frequency increases with age. The data confirm the genetic heterogeneity of IDDM and call for caution in extrapolating to adult patients the genetic concepts derived from childhood IDDM.
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PMID:Age-dependent HLA genetic heterogeneity of type 1 insulin-dependent diabetes mellitus. 146 84

According to recent evidence, the presence of an Arg residue at position 52 in the HLA-DQ alpha chain may confer susceptibility to Type 1 diabetes and thus be possibly used to define quantitatively the genetic risk of this disease. Arg52 and non-Arg52 DQA1 alleles cannot be typed by the conventional cytotoxicity test and they must be distinguished at the genomic level. We describe a simple procedure which discriminates the DQA1 alleles based on the differential electrophoretic migration of the DNA heteroduplexes they form with a reference DNA fragment. A major advantage of this procedure is the fact that no hybridization probe is required. Practically, this typing procedure consists of an electrophoretic run of the products of a selective PCR in polyacrylamide gel.
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PMID:Probe-less genomic typing of Arg52 (type 1 diabetes-associated) and non-Arg52 (non-type 1 diabetes-associated) HLA-DQA1 alleles. 147 36

Insulin-dependent diabetes mellitus (IDDM), or type I diabetes, is the end result mainly of a T-cell mediated autoimmune destruction of pancreatic islet beta cells. Genetical and environmental factors are both of importance in the pathogenesis. Genes in the HLA complex seem to be the most important genetical factors. Among Blacks, Caucasoids and Orientals, IDDM susceptibility is associated with some particular combinations of DQA1 and DQB1 genes in cis or trans position. This strongly argues that susceptibility is primarily associated to the corresponding HLA-DQ molecules themselves. However, weaker contributions by other genes in the HLA complex cannot be excluded. Similarly, a dominant protection is strongly associated with some other DQ molecules, in particular HLA-DQ6, in all three ethnic groups. The function of HLA-DQ (and other class II) molecules is to present peptide-fragments of antigens to CD4+ T cells (mainly helper T cells). Thus, the recognition of certain islet beta cell derived peptides by self-reactive CD4+ T cells, may be an initial event in the pathogenesis. The DQ molecules involved in IDDM susceptibility or protection may exert their function either during thymic development of potential self-reactive CD4+ T cells, or by preferential presentation of certain beta-cell derived peptides to CD4+ T cells, or both. The finding that certain DQ molecules as such confer IDDM susceptibility may lead to new methods to prevent IDDM, for example by using blocking peptide analogues.
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PMID:Role of HLA genes in predisposition to develop insulin-dependent diabetes mellitus. 148 49

Susceptibility to insulin-dependent diabetes mellitus (IDDM) correlates with the absence of aspartic acid in position 57 of the DQB1 and/or the presence of arginine in position 52 of the DQA1. It has been postulated that transcomplementation between the DQ alpha and beta chains of the two haplotypes could create new molecules conferring susceptibility to IDDM. Finland has the highest incidence of IDDM in the world (35/100,000). In a nationwide study of IDDM in childhood (DiMe study) HLA genotyping using conventional serology was carried out according to genetic-epidemiological principles. We simulated DQA1 and DQB1 alleles in 707 consecutively diagnosed IDDM probands and 98 non-diabetic children based on serology, restriction fragment length polymorphism results and sequence data assuming no recombination between DQ and DR. In 34% of Finnish children with IDDM all four combinations (two in cis and two in trans) could lead to SS heterodimers. Two-thirds of these combinations were explained by DR3,DR4 heterozygotes. In 50% of IDDM children half and in 11% a quarter of the combinations could lead to heterodimers. In 38 IDDM patients (5%) the formation of hybrid molecules was not possible. In 59% of the controls SS heterodimers were possible and should therefore have an underlying genetic susceptible for IDDM assuming the theory of transcomplementation is correct. These findings, together with the fact that the lowest frequency of DR3,DR4 heterozygosity (21%) was seen in Finland, show that heterozygosity for DQ and DR cannot explain the differences seen in IDDM incidence.
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PMID:DQA1 and DQB1 heterodimers in insulin-dependent diabetes mellitus: a genetic-epidemiological study in Finland. DiMe Study Group. 148 50

Although HLA-DQB1 alleles encoding aspartic acid at position 57 (Asp-57) are protective against Type 1 (insulin-dependent) diabetes mellitus in Caucasians, most Japanese Type 1 diabetic patients carry at least one Asp-57 DQB1 allele. We analysed the DRB1, DQA1 and DQB1 genes of 99 Japanese patients and 86 control subjects with polymerase chain reaction and sequence-specific oligonucleotide hybridization. We found that (1) the DQA1*0301 allele was significantly increased in Type 1 diabetic patients (RR7.8, pc less than 0.0001); (2) the DRB1*0405 (Dw15) allele, which is a subtype of DR4 haplotype, was significantly increased in DR4-positive patients (RR 12.0, pc less than 0.001); and (3) although the DRw8-DQw8 haplotype was positively associated with Type 1 diabetes, the DRB1*0406-DQw8 haplotype was decreased in the diabetic patients. These data indicate that DRB1 and DQA1 genes also confer susceptibility to Type 1 diabetes in Japanese.
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PMID:Genetic analysis of HLA class II alleles and susceptibility to type 1 (insulin-dependent) diabetes mellitus in Japanese subjects. 152 22

Insulin-dependent diabetes mellitus (IDDM) in whites is strongly associated with particular HLA-DQ alpha beta heterodimers 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 (Asp57-). With the aim of confirming this association, clarifying which heterodimers account for the highest risk of IDDM and explaining the excess risk of DR3-DQw2/DR4-DQw8, 115 unrelated white IDDM patients and 108 unrelated healthy nondiabetic control subjects were studied. With polymerase chain reaction and sequence-specific oligonucleotide probes, both patients and control subjects were typed for their HLA-DQA1 and DQB1 alleles and their DQA1-DQB1 haplotype and genotype frequencies were compared. Four major findings emerged from our analysis. 1) Arg52+ DQ alpha/Asp57- DQ beta heterodimers, formed in cis and/or in trans, are strongly associated with susceptibility to IDDM; 97% of patients and 46% of control subjects had at least one such susceptibility heterodimer (relative risk [RR] 32, confidence interval [Cl] 14.25-71.86, P less than 10(-7). 2) The degree of disease susceptibility depends on the number of such DQ heterodimers that a subject can express according to his or her DQA1-DQB1 genotype. The highest RR was observed in patients with four susceptibility DQ heterodimers (RR 41, Cl 17.05-95.9). 3) Only part of the susceptibility DQ heterodimers were significantly increased in patients, conferring IDDM susceptibility of different strength. The strongest association was with the DQA1*0501-DQB1*0302 combination formed in trans position (RR 35.2, CI 12.88-96.78, P less than 10(-7).(ABSTRACT TRUNCATED AT 250 WORDS)
Diabetes 1992 Mar
PMID:Dose effect of cis- and trans-encoded HLA-DQ alpha beta heterodimers in IDDM susceptibility. 155 98

MHC associations with IDDM in a Chinese population were studied to investigate genetic susceptibility to the disorder. The frequency of HLA-DR3 was significantly higher in the diabetic patients (19/49 [38.7%] vs. control subjects, 11/105 [10.5%], Pc less than 1.3 x 10(-3), RR = 5.3 [CI 2.3-12.1]), whereas DR4 was not (11/49 [22.4%] vs. 28/105 [26.7%], NS). The frequency of DR3/4 heterozygosity was higher in the diabetic patients (6/49 [12.2%] vs. control subjects, 0/105 [0%], P = 1.7 x 10(-3), RR = 31.5 [CI 3.8-263.6]). The frequency of DR3/9 heterozygosity also was higher in the diabetic patients (6/49 [12.2%] vs. control subjects, 2/105 [1.9%], P = 0.03, RR = 6.2 [CI 3.0-12.7]). No significant associations were noted between DQB1 alleles and IDDM. Among DR4-positive subjects, the frequency of DQB1 allele DQB1*0302 was higher in the diabetic patients (10/11 [90.0%] vs. control subjects, 12/24 [50%], Pc less than 0.05, RR = 7.0 [CI 1.3-38.0]), and the frequency of DQB1*0401 was significantly lower in the diabetic patients (2/11 [18.2%] vs. control subjects, 16/24 [66.7%], Pc = 0.04, RR = 0.1 [CI 0.02-0.46]). No DR4 subtype was associated significantly with IDDM. The frequency of DQA1*0501, a DQA1 allele, was higher in diabetic patients (22/41 [53.7%] vs. control subjects, 20/95 [21.1%], Pc less than 3 x 10(-3), RR = 4.3 [CI 2.0-9.3]). The frequency of DQA1*0301, which has been associated consistently with IDDM in other ethnic groups, was not significantly higher in the diabetic patients in this study (27/41 [65.9%] vs. control subjects, 53/95 [55.8%], NS).(ABSTRACT TRUNCATED AT 250 WORDS)
Diabetes 1992 Aug
PMID:Susceptibility to IDDM in a Chinese population. Role of HLA class II alleles. 162 65

In this study HLA-DQA1 and TNF genes in addition to HLA-DQB1 gene were investigated at DNA level for elucidation of the genetic backgrounds of Type 1 (insulin-dependent) diabetes mellitus in Japanese subjects. DNA, amplified by polymerase chain reaction, was subjected to allele specific oligonucleotide dot blot analysis, restriction fragment length polymorphism analysis or DNA sequencing. Polymorphism of the TNF gene to NcoI did not correlate with Type 1 diabetes in Japanese patients. DQw1.2 had a protective effect against the disease, the DQA1*1 allele was significantly decreased and DQA1*3 allele was significantly increased. Seventeen out of twenty-two Type 1 diabetic patients (77%) were homozygous for DQA1*3 and five out of twenty-two (23%) heterozygous. The DQA1*3 gene of Type 1 diabetic patients had a normal nucleotide sequence. Furthermore, DQA1*3 was found unexpectedly in two patients without DR4 or DR9. These data indicate that DQA1 gene confers susceptibility and resistance to Type 1 diabetes in Japanese subjects.
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PMID:HLA-DQA1*1 contributes to resistance and A1*3 confers susceptibility to type 1 (insulin-dependent) diabetes mellitus in Japanese subjects. 167 85

DQA1, DQA2, DQB1, and DRB1 alleles have been determined and the DQA1 and DQB1 DNA gene sequences assigned by using restriction fragment length polymorphisms in 67 diabetic individuals and 72 controls. It has been found that: 1) DQA2 (U allele) is not a susceptibility factor, 2) non-aspartic acid homozygosity in residue 57 (Asp 57 negative) of the DQ beta chains is positively correlated with insulin-dependent diabetes mellitus (IDDM), and 3) DQ beta Asp-57-negative and DQ alpha arginine-52-positive (Arg-52-positive) individuals are increased among diabetic patients; this latter analysis shows a higher etiologic fraction (delta) value than the one obtained when considering only homozygous DQ beta Asp-57-negative individuals. However, if only non-DR3 or DR4 individuals were considered (both in DQ beta Asp-57-negative homozygous and in DQ beta Asp-57-negative/DQ alpha Arg-52-positive individuals) the correlation with disease disappears. In addition, the postulated risk DQ beta Asp 57-negative and DQ alpha Arg 52 positive is absent in six patients. These data do not discard the possibility that DR3/DR4 may contain the primary susceptibility factors. It is concluded that it is not possible to assign the susceptibility to IDDM to a specific HLA locus and that several loci within the same or the trans haplotype may be involved.
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PMID:Exclusive HLA-DQ factors do not explain susceptibility to insulin-dependent diabetes. 167 4

In this study we report for the first time, the molecular analysis of HLA-DR and -DQ gene frequencies in a large cohort of well characterized type 1 (insulin-dependent) diabetes mellitus (IDDM) patients (n = 72), and ethnically matched controls (n = 59) collected in sub-Saharan Africa. High molecular mass DNA was prepared and analyzed in Southern blots with DRB1, DQA1, and DQB1 probes. By identifying DR and DQ allele-specific restriction fragment length polymorphisms (RFLPs), we have shown a strong positive association between IDDM and the Asp 57- DQB1 allele *0201 (DQw2). A rare DR4, DQw2 haplotype was also identified at high frequency in the IDDM cohort. We can now confirm that the association between Asp 57-DQB1 alleles and IDDM, previously reported in ethnically diverse cohorts collected in Western Europe, North America, and South Asia, is also present in an IDDM cohort collected in Africa.
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PMID:Analysis of HLA-DR and -DQ gene polymorphisms in Sudanese patients with type 1 (insulin-dependent) diabetes. 168 74


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