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)

Islet cell antibodies (ICAs) are predictive markers of the disease in first-degree relatives of patients with insulin-dependent diabetes mellitus (IDDM). The large majority of newly diagnosed cases, however, will develop in children with no family history of diabetes. In France, the risk for development of IDDM up to the age of 20 years is 60 times higher in first-degree relatives than in the general population. The aim of this study was to test whether data collected in the first-degree relatives of IDDM patients could be transferred to children for the prediction of overt diabetes. A large population-based cohort of French school-aged children (n = 13,380; ages 6-17 years) were screened for ICAs, and results were compared with those of 1,185 first-degree relatives of IDDM patients. ICA prevalence rates were significantly different in the two populations (5.5% vs. 1.5%; P < 0.0001), with a significantly higher proportion of high ICA titers in first-degree relatives (37%) than in schoolchildren (14%) (P = 0.0005). ICA titers remained remarkably stable in children over 4 years. Insulin autoantibodies (IAAs) were found in 3.4 and 15.4% of ICA+ children and first-degree relatives, respectively. Susceptibility alleles at the human leukocyte antigen (HLA)-DQB1 locus were observed significantly more frequently in children in whom ICA titers > or = 20 Juvenile Diabetes Foundation units (JDF U) were found on two separate occasions (67%) than in ICA- children (52%) (P = 0.05). Five subjects developed overt diabetes during follow-up. ICA titers of > 20 JDF U were found in all of them on the first sample and at follow-up.(ABSTRACT TRUNCATED AT 250 WORDS)
Diabetes 1995 Sep
PMID:Immunogenetic determinants and prediction of IDDM in French schoolchildren. 765 24

The association between human leukocyte antigen (HLA) and insulin-dependent diabetes was studied in a large population-based investigation using genotyping of 425 new-onset patients, 0-14 years of age, and 367 matched control subjects. As many as 97% of patients compared with 75% of control subjects were positive for one or several of DQA1*0301, DQA1*0501, DQB1*0302, or DQB1*0201. Asp-57 DQB was present among 28% of patients, indicating that this residue alone does not confer protection. Combining Asp-57 DQB1 with either Arg-52 DQA1 or Leu-69 DQA1 did not explain susceptibility or protection either. DQA1*0301-DQB1*0302 (DQ8) and DQA1*0301-DQB1*0301 (DQ7) are identical except for four amino acid substitutions in the beta-chain, but DQ8 was positively (odds ratio 8.07; P < 0.001) and DQ7 negatively (odds ratio 0.38; P < 0.001) associated with the disease. Molecular modeling was used to determine whether physiochemical properties such as steric factors and surface electrostatic potentials also differ in a systematic way for various DQ molecules. Amino acids were substituted systematically at the four polymorphic sites, and the solvent-accessible surfaces and electrostatic potentials were computed for each molecule. Dramatic alterations in electrostatic potential were seen for double substitutions at position 45 (G45E) and 57 (A57D) of DQB1. The variation of physicochemical properties due to polymorphic substitutions may be significant to the mechanism of HLA-DQ association with insulin-dependent diabetes, via the effect these property variations have on peptide antigen binding selectivity and subsequent interactions with specific T-cell receptors.
Diabetes 1995 Jan
PMID:Polymorphic amino acid variations in HLA-DQ are associated with systematic physical property changes and occurrence of IDDM. Members of the Swedish Childhood Diabetes Study. 781 6

HLA-DR2 is negatively associated with insulin-dependent diabetes mellitus (IDDM). The aim of the present study was to analyze DR2-positive patients among 425 consecutively diagnosed unrelated Swedish children with IDDM and in 367 matched controls. HLA-DRB, -DQA and -DQB were determined by Taq I restriction fragment length polymorphism analysis. Amplification by polymerase chain reaction (PCR) and hybridization with sequence-specific oligonucleotide probes was done for DQA1, DQB1 and DRB1 and DRB5. DR2 was positive in 11/425 patients (3%) and 101/367 (28%) controls (OR 0.07, p < 0.0001). Of the 11 DR2-positive patients, PCR was done in 10, of whom 8 were positive for DRB1*1601-DRB5*0201 compared to 4/96 (4%) controls (OR 92.0: p < 0.001) while the remaining 2 were positive for DRB1*1501-DRB5*0101 compared to 92/96 (96%, OR 0.01; p < 0.001). In 2 patients, a recombination between the haplotypes DQB1*0502-DQA1*0102 (DQ5)-DRB1*1601-DRB5*0201 (DR16 Dw21) and DQB1*0301-DQA1*0501 (DQ7)-DRB1*1602-DRB5*0202 (DR16 Dw22) was observed resulting in the DQB1*0301-DQA1*0501 (DQ7) DRB1*1601-DRB5*0201 (DR16 Dw22) haplotypes. The second haplotype was DR3 DQ2 in 6/11 and DR4 DQ8 in 2/11 DR2-positive patients. In all 3 DQB1*0602-DQA1*0102-DR15-positive patients the second haplotype was DR4-positive. In order to test whether physicochemical properties of the DR2 molecules were associated with IDDM, we constructed three-dimensional models of the peptide binding and T-cell recognition sites (alpha 1 and beta 1 domains) of five subtypes of DR2-DRB1, based on the published DR1 crystal structure. No correlations were observed for DR molecule physicochemical properties and diabetes susceptibility. Islet cell antibodies, insulin autoantibodies and GAD65 antibodies, were measured in DR2-positive patients (n = 11) and controls (n = 101). Despite the presence of the DR2 haplotype the antibody markers were significantly elevated in the patients compared to the controls (GAD65 3/10 patients and 2/101 controls; ICA 7/11 patients and 1/101 controls and IAA 3/11 patients and 0/101 controls). In conclusion, of the five subtypes of DR2, only one, the DRB1*1501, DRB5*0101, DQB1*0602-DQA1*0102 haplotype, was negatively associated with IDDM. DQ may therefore confer more protection from the disease than DR.
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PMID:Analysis of antibody markers, DRB1, DRB5, DQA1 and DQB1 genes and modeling of DR2 molecules in DR2-positive patients with insulin-dependent diabetes mellitus. 781 75

Polymorphisms in HLA class II genes have been shown to contribute to susceptibility or protection against insulin-dependent diabetes mellitus (IDDM). In the present study the role of HLA class II haplotypes and the role of DQ alpha Arg52, DQ beta Asp57 and of polymorphic amino acids, located in the antigen-binding groove and the CD4-binding domain of the DR beta 1 chain, were studied in 210 unrelated Caucasian IDDM patients and 205 controls. The results showed that the genotype homozygous for DR beta 1Lys71+, which is in linkage disequilibrium with DQ alpha 1Arg52+ provided a major risk (relative risk, RR = 15.46) for IDDM and that combination of DR beta 1Lys71+/+ with homozygosity for DQ beta qAsp57-/- of the DQ beta 1 chain significantly increased the RR for developing IDDM (RR = 20.41). The DQ alpha 1Arg52(-)-DQ beta 1Asp57+ haplotype in cis or trans position conferred the highest protection against IDDM (RR = 0.08). Our findings confirm that protection against IDDM is provided by HLA-DQ loci but that susceptibility for IDDM is provided by both HLA-DRB1 and DQB1 loci. Our results also provide a new and more specific approach to determine the risk of any random Caucasian individual to develop IDDM. Indeed, increased susceptibility or protection against IDDM can be determined by the rapid and simple typing of DR beta 1Lys71, DQ alpha 1Arg52 and DQ beta 1Asp57 in a random person.
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PMID:Improved risk assessment for insulin-dependent diabetes mellitus by analysis of amino acids in HLA-DQ and DRB1 loci. 783 77

The risk of progression to IDDM can be evaluated by diabetes-related autoantibodies such as cytoplasmic islet cell antibodies (ICA) or genetic determinants as markers. In this prospective study we wanted to estimate the predictive value of the combination of these markers in siblings of diabetic children. A sample of 770 siblings was observed from the time of diagnosis in the index case for a median period of 5.8 years (range 0.01-7.3 years) for development of ICA and insulin autoantibodies (IAA) and progression to clinical diabetes. The most important susceptibility and protection associated DQB1 alleles were defined by four sequence-specific oligonucleotide probes. DNA samples were available from 89 originally non-diabetic ICA positive siblings of whom 28 presented with IDDM during the study period, as well 100 randomly chosen ICA negative control siblings. More than half (11/28; 55%) of the siblings who had the high risk DQB1 genotypes progressed to clinical IDDM compared to 6/37 (16%) of those who had protective/neutral genotypes (P = 0.006). Of all genotyped secondary cases, 36% (n = 33) had a genotype associated with the highest risk (DQB1*0302/0201), whereas 27% had genotypes without any susceptibility alleles (P values < 0.0001 and = 0.0002, respectively, compared with ICA negative siblings). The results demonstrate the feasibility of the combination of genetic and immunological markers in the prediction of the risk for IDDM within families.
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PMID:HLA-DQB1 genotypes and islet cell antibodies in the identification of siblings at risk for insulin-dependent diabetes (IDDM) in Finland. Childhood Diabetes in Finland (DiMe) Study Group. 784 Aug 59

LMP2 and LMP7, two subunits of the proteasomes encoded in the major histocompatibility complex, are speculated to play a role in the generation of endogenous peptides for presentation by class I molecules to cytotoxic T cells. Their possible role in the pathogenesis of insulin-dependent diabetes mellitus (IDDM) has not been documented. In this study of Caucasian subjects, we have analyzed the polymorphisms of four genes within the HLA class II region (LMP2, LMP7, and HLA-DRB1 and -DQB1) in 198 unrelated IDDM patients and 192 normal controls ascertained from the southeastern United States. A genomic polymorphism of LMP7 was found strongly associated with IDDM, and the Arg/His-60 polymorphism in LMP2 was found associated with IDDM only in subjects containing an HLA DR4-DQB1*0302 haplotype. To determine whether the apparent associations between LMP genes and IDDM resulted from the strong linkage disequilibria observed between LMP and HLA-DR/DQ genes, we compared LMP gene frequencies in extended LMP-HLA haplotypes derived from control and diabetic families. Our results suggest that LMP genes have independent effects on IDDM susceptibility.
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PMID:Association of LMP2 and LMP7 genes within the major histocompatibility complex with insulin-dependent diabetes mellitus: population and family studies. 784 89

Although the HLA class II genes are clearly associated with insulin-dependent diabetes mellitus (IDDM) in all ethnic groups, considerable variation in the associated haplotypes is observed among the ethnic groups. In Japanese, DRB1*0405-DQA1*0301-DQB1*0401, DRB1*0901-DQA1*0301-DQB1*0303 and DRB1*0802-DQA1*0301-DQB1*0302 are the major susceptibility haplotypes to IDDM, while DRB1*1501-DQA1*0102-DQB1*0602 and DRB1*1502-DQA1*0103-DQB1*0601 are the major resistance haplotypes. The hypothesis that alleles encoding amino acids other than aspartic acid at the DQB1 position 57 contribute to IDDM susceptibility is not applicable to the Japanese, mainly because the first and second susceptibility haplotypes listed above have aspartic acid at DQB1 position 57. In the 5' insulin gene polymorphism, the shorter insertion (class 1 allele) is predominant, and is not associated with diabetes in Japanese. Subdivision of the class 1 alleles also failed to show an association with IDDM in Japanese. The insulin gene region appeared to be of less value as a genetic marker for IDDM in Japanese. Little is known about other genetic markers.
Diabetes Res Clin Pract 1994 Oct
PMID:Genetic markers for insulin-dependent diabetes mellitus in Japanese. 785 39

The incidence of insulin-dependent diabetes in individuals with cystic fibrosis is nearly 100 times greater than in the general population. In the latter group, strong associations with specific HLA DQA1 and DQB1 alleles have been observed. To determine if a similar distribution of alleles occurs in cystic fibrosis patients with diabetes, a cohort of these individuals was typed for DQA1 and DQB1 alleles. HLA DQB1*0201 (Asp57-) was more frequent in diabetics compared to controls (40.4 vs 28%), while the frequency of alleles encoding Asp57+ molecules was lower in diabetics relative to both the cystic fibrosis-only controls (P = 0.025) and the general population (P = 0.008). The presence of at least one protective DQA1-DQB1 heterodimer (i.e., Arg52- and Asp57+, respectively) in cis or trans was significantly lower in the diabetics than in either of the control groups. Thus, the HLA alleles known to be associated with insulin-dependent diabetes mellitus in the general population are also found in diabetics with cystic fibrosis.
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PMID:Cystic fibrosis-related diabetes is associated with HLA DQB1 alleles encoding Asp-57- molecules. 788 62

Although HLA class II genes are important in insulin-dependent diabetes (IDD), their influence on the expression of IDD-associated autoantibodies (aAb) is unclear. We compared HLA-DRB1 and DQB1 gene frequencies in several Caucasian groups: 191 normal controls, 378 IDD patients, and 357 non-diabetic relatives of which 250 had no aAb, 107 had at least one aAb (79 ICA+, 31 GAD65+ and 49 IAA+), and 23 had both ICA+ and IAA+. We found that the frequencies of DR3/4 or DQB1*0201/0302 heterozygotes were significantly higher in aAb+ relatives compared to aAb- relatives. The frequencies of DR4/4 or DR4/X (X = non 3 or 4) and DQB1*0302/X (X = 0201 or 0302) in aAb+ relatives were not different from the aAb- relatives (which were enriched for these haplotypes), but were significantly higher than normal controls. The frequencies of DR3/X or DQB1*0201/X were decreased in both aAb+ relatives and IDD patients. Interestingly, the dominant IDD-protective DQB1*0602 allele allowed the development of individual aAbs (10% of ICA+ and 8% IAA+ relatives had the allele), but was not observed in any high risk double aAb+, or GAD65Ab+ relatives. The latter finding was similar to that in our patients with IDD, in that only two of them (0.5%) had a DQB1*0602 allele. In conclusion, HLA-encoded susceptibilities to disease-relevant autoantibody production and IDD are concordant with the susceptibility alleles, but discordant for the protective DQB1*0602. Thus HLA genotyping for DQB1*0602 would impact on the selection of aAb+ relatives for disease prevention trials.
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PMID:High risk HLA-DR/DQ genotypes for IDD confer susceptibility to autoantibodies but DQB1*0602 does not prevent them. 788 45

Although one of the major genes which cause type 1 (insulin-dependent) diabetes mellitus is located in the class II HLA region in humans, its precise location is still unknown. In order to investigate whether TAP (Transporter associated with Antigen Processing) and LMP (Low Molecular Weight Polypeptide) genes, which are located in the class II HLA region, are HLA-linked diabetogenic genes, the association of TAP1, TAP2 and LMP2 genes with type 1 diabetes was analyzed in the Japanese population. No difference in allele frequencies of these genes was detected between diabetic patients and control subjects. On the other hand, DQA1 and DQB1 genes showed significant association with type 1 diabetes. These data suggest that the diabetogenic gene in the class II HLA region may be located near the DQA1 and DQB1 loci, rather than the TAP and LMP loci.
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PMID:Absence of association of TAP and LMP genes with type 1 (insulin-dependent) diabetes mellitus. 791 50


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