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)

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

Lack of an aspartic acid 57 in the HLA-DQ beta chain was introduced as a genetic marker of insulin-dependent diabetes mellitus (IDDM). Because 25% of the control population carries the same marker, we analyzed the DQ locus for the presence of more specific disease susceptibility markers, taking into account a possible role for the polymorphic DQA gene. We thereby identified the DQA3-DQB3.2/DQA4.1-DQB2 (DQA1*0301-DQB1*0302/DQA1*0501-DQB1*0201) genotype which was detected in 30% of the 268 typed IDDM patients and only in 1% of the 331 typed healthy controls, resulting in a relative risk of 35. This genetic marker was more frequent in patients with clinical onset before age 18 years (36%) than in patients diagnosed between age 18 and 40 years (22%) and was not observed in patients with non-IDDM. The new susceptibility genotype DQA3-DQB3.2/DQA4.1-DQB2 (DQA1*0301-DQB1*0302/DQA1*0501-DQB1*0201) may explain the well-known excess of DR3/DR4 heterozygous IDDM patients and is expected to help identify individuals at risk for developing the disease.
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PMID:Complementation of HLA-DQA and -DQB genes confers susceptibility and protection to insulin-dependent diabetes mellitus. 154 46

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

HLA-DQ alpha and beta alleles were chosen as the most sensitive Type 1 (insulin-dependent) diabetes mellitus susceptibility markers for evaluating the disease associations and Type 1 diabetes risk in a population-based registry from Madrid. The absence of aspartic acid in position 57 of the DQ beta chain (non-Asp 57), and the presence of arginine in position 52 of the DQ alpha chain (Arg 52) were found to be reliable markers of Type 1 diabetes susceptibility among the Spanish population, with significantly higher frequencies among the cases of Type 1 diabetes compared to randomly selected non-diabetic control subjects from the general Madrid population. While non-Asp 57 homozygosity conferred an absolute risk of 32.3 per 100,000 per year and Arg 52 of 31.5 per 100,000 per year, the risk for double homozygotes for both non-Asp 57 and Arg 52 was estimated as 101.7 per 100,000 per year. Individuals homozygous for only one of these alleles, and heterozygous at the other locus, had a markedly lower Type 1 diabetes risk (12.8 per 100,000 per year), approximating the general population incidence for Madrid. Thus, susceptibility to Type 1 diabetes in Spanish patients is associated, quantitatively, with non-Asp 57 DQ beta and Arg 52 DQ alpha alleles.
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PMID:Susceptibility to type 1 (insulin-dependent) diabetes mellitus in Spanish patients correlates quantitatively with expression of HLA-DQ alpha Arg 52 and HLA-DQ beta non-Asp 57 alleles. 161 33

The association of certain autoimmune diseases with HLA molecules is being refined through the use of sequence-specific oligonucleotide probes and amino acid sequencing, together with continuing elucidation of the functional features of HLA molecules derived from the milestone description by Bjorkman of the HLA molecular structure. The association of insulin-dependent diabetes mellitus and HLA began with weak associations of Class I antigens (B8 and B15) and progressed to Class II antigens (DR3 and DR4), then to subtypes of DR4 (Dw4, 10, and 14), and now to DQ molecules including the absence of aspartic acid at position 57 of the DQ beta chain and the presence of arginine at position 52 of the DQ alpha chain. In rheumatoid arthritis (RA) the HLA antigen association remains with certain Class II molecules of the DR series (DR4 and DR1) that share amino acid sequences with a restricted number of other DR antigens seen in RA, as well as a segment of the gp 110 protein of the Epstein-Barr virus. Although ankylosing spondylitis has a strong association with the Class I antigen B27, that association is not explained by any of the B27 subtypes defined by monoclonal antibodies, by the eight variable amino acids in B27 subtypes, or by the two unique amino acids on B27. The remarkable antibody cross-reactivity among lymphocytes bearing B27, a synthetic peptide sequence (63-84) of B27, and the 188-193 sequence of K. pneumoniae nitrogenase has provided strong support for molecular mimicry being an important mechanism in the association of HLA molecules with disease.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:HLA molecules in autoimmune diseases. 163 34

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

Eighteen unrelated Chinese patients with insulin-dependent diabetes mellitus (IDDM) were analyzed for HLA Class II genes using a variety of molecular biological techniques including restriction fragment length polymorphism (RFLP), polymerase chain reaction with allele-specific oligonucleotides (PCR-ASO) and direct DNA sequencing. The high frequency of DR3/DR4 heterozygotes found in the Chinese with IDDM strengthens the importance of this combination of haplotypes in IDDM susceptibility since it is present in two genetically distant populations--Chinese and Caucasians. The frequency of DRw9, a rare allele in the Caucasian population, is much higher in the Chinese. Moreover, the DQ beta chain linkage of DRw9 was different in IDDM patients compared with control subjects. In contrast with previous results, codon 57 of the DQ beta chain was aspartic acid in DRw9 Chinese IDDM patients. Furthermore, one particular DRw9-DQw9 haplotype may be associated with IDDM susceptibility in the Chinese population.
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PMID:Aspartic acid at position 57 of the HLA-DQ beta chain in insulin-dependent diabetes mellitus: an association with one DRw9-DQw9 subtype in the Chinese population. 180 12

It has been proposed that negatively charged aspartic acid at position 57 of the HLA-DQ beta-chain determines resistance to development of insulin-dependent diabetes mellitus (IDDM), whereas genetic susceptibility to IDDM correlates with a neutral amino acid residue. The disease rate is very low in Oriental populations with high frequencies of Asp 57. This raises a question whether the high incidence of IDDM in Finland could be explained by the distribution of this disease marker. In this study, the polymerase chain reaction products of 86 diabetic patients and 115 nondiabetic control subjects were analyzed with seven sequence-specific oligonucleotide probes. Only 25.5% of the diabetic subjects were phenotyped as Asp 57+ compared to 82% of control subjects, which suggests that Asp 57 negativity is a definite risk marker for developing IDDM in Finnish patients. However, the susceptibility conferred by various non-Asp and Asp haplotypes was not equally strong: DQw8 was the most important risk marker and DQw6 the most protective one. The frequency of Asp 57+ DQw4 was similar in diabetic patients and control subjects. The highest genotype-associated relative risk was defined by DQw2/DQw8 heterozygosity (RR 91), whereas it was 13 for non-Asp homozygosity. In the control subjects, the frequency of Asp 57+ phenotypes was higher than in several white populations with lower IDDM incidence figures. We conclude that the disease risk in Finland appears to be most strongly related to specific Asp 57- alleles, although other HLA- or non-HLA-associated genes may also contribute to IDDM susceptibility in this population.
Diabetes 1991 Dec
PMID:HLA-DQB1 alleles and absence of Asp 57 as susceptibility factors of IDDM in Finland. 175 4

Particular HLA-DQ beta chain alleles were reported as immunogenetic markers of type I diabetes mellitus with young onset of the disease. In a homogeneous German population, we studied HLA-DR specificities and HLA-DQ beta chain alleles in young-onset (less than 21 years of age; n = 185) and adult-onset (greater than 40 years of age; n = 48) insulin-dependent diabetics. In both cohorts of type I diabetics, the HLA-DR3 and -DR4 specificities were significantly increased. The presence of an HLA haplotype with an amino acid other than aspartic acid at position 57 of the DQ beta chain was significantly associated with type I diabetes in both cohorts (etiologic fraction: 93% and 73%). We conclude that the presence of DNA sequences coding for an amino acid other than aspartic acid at the 57th position of the DQ beta chain provides a molecular risk marker for type I diabetes of both and adult onset.
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PMID:Prevalence of HLA-DQ beta chain non-Asp alleles in type I (insulin-dependent) diabetics with young and older ages of onset. 179 91

To ascertain why HLA-DR2 seems to confer only a moderate resistance to insulin-dependent diabetes mellitus (IDDM) in the high-incidence population of Sardinia, Italy, 32 families having one individual affected with IDDM (the proband) and 31 families without IDDM history were randomly selected from the same geographical area and serologically and molecularly HLA typed. The 64 haplotypes of the probands were then compared with the 122 haplotypes determined in the parents from the control families. Two haplotypes were found to have the highest percentage in the general population (12.3% and 7.3%, respectively). The first is the already described "Sardinian" extended haplotype A30, Cw5, B18, 3F130, DR3, DRw52, DQw2 (39.0% in IDDM patients). The second is an extended haplotype that has not been identified before (A2, Cw7, B17, 3F31, DR2, DQw1), and, due to the DR2 allele, we expected it to be decreased in IDDM. However, a stratified analysis performed by removing the DR3 and DR4 haplotypes showed that the frequency of this haplotype is significantly increased in IDDM patients. A peculiar feature of this haplotype is its DQw1 allele, which is DQB1*0502 and has serine in position 57 of the DQ beta chain. The absence of an aspartic acid in this position seems to confer susceptibility to IDDM and not resistance. The fact that DQB1*0502 was present in 75% of the Sardinian DR2 haplotypes may explain why, in Sardinia, DR2 is not providing the commonly recognized resistance to IDDM.
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PMID:A new HLA-DR2 extended haplotype is involved in insulin-dependent diabetes mellitus susceptibility. 189 17


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