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 major histocompatibility complex (MHC) HLA region on chromosome 6p21 contains the major locus of type 1 diabetes (IDDM1). Common allelic variants at the class II HLA-DRB1, -DQA1, and -DQB1 loci account for the major part of IDDM1. Previous studies suggested that other MHC loci are likely to contribute to IDDM1, but determination of their relative contributions and identities is difficult because of strong linkage disequilibrium between MHC loci. One prime candidate is the polymorphic HLA-DPB1 locus, which (with the DPA1 locus) encodes the third class II antigen-presenting molecule. However, the results obtained in previous studies appear to be contradictory. Therefore, we have analyzed 408 white European families (200 from Sardinia and 208 from the U.K.) using a combination of association tests designed to directly compare the effect of DPB1 variation on the relative predisposition of DR-DQ haplotypes, taking into account linkage disequilibrium between DPB1 and the DRB1, DQA1, and DQB1 loci. In these populations, the overall contribution of DPB1 to IDDM1 is small. The main component of the DPB1 contribution to IDDM1 in these populations appears to be the protection associated with DPB1*0402 on DR4-negative haplotypes. We suggest that the HLA-DP molecule itself contributes to IDDM1.
Diabetes 2001 May
PMID:The HLA-DPB1--associated component of the IDDM1 and its relationship to the major loci HLA-DQB1, -DQA1, and -DRB1. 1133 27

It is known that certain combinations of alleles within the human leucocyte antigen (HLA) complex are associated with susceptibility or resistance to type 1 diabetes. Variable associations of DR and DQ with type 1 diabetes are documented in Caucasians but rarely in African populations; however, the role of HLA-DP genes in type 1 diabetes remains uncertain. In order to investigate the HLA class II associations with type 1 diabetes in Cameroonians, we used sequence-specific oligonucleotide probing (SSOP) to identify DRB1, DQA1, DQB1 and DPB1 alleles in 10 unrelated C-peptide negative patients with type 1 diabetes and 90 controls from a homogeneous population of rural Cameroon. We found a significantly higher frequency of the alleles DRB1*03 (chi2 = 17.9; P = 0.001), DRB1*1301 (chi2 = 37.4; P < 0.0001), DQA1*0301 (chi2 = 18.5; P = 0.001) and DQB1*0201 (chi2 = 37.4; P < 0.001) in diabetes patients compared to the control group. The most frequent alleles in the control population were DQA1*01, DQB1*0602 and DRB1*15. The DRB1*04 allele was not significantly associated with type I diabetes in our study population. We observed no significant difference between patients and controls in DPB1 allele frequency. In conclusion, the data in Cameroonian diabetes patients suggest the existence of HLA class II predisposing and specific protective markers, but do not support previous reports of a primary association between HLA-DP polymorphism and development of type I diabetes.
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PMID:HLA-DRB1, -DQA1, -DQB1 and DPB1 susceptibility alleles in Cameroonian type 1 diabetes patients and controls. 1153 22

As part of a genetic study of type 1 diabetes in Mexican-Americans, 360 first-degree relatives of 108 type 1 diabetic probands were studied. Islet cell antibody (ICA), insulin autoantibody, glutamic acid decarboxylase (GAD(65)), and protein tyrosine phosphatase autoantibodies were measured and human leucocyte antigen (HLA) class II alleles DRB1 and DQB1 genotyping was performed. ICA was positive in 37% of the probands and 5.8% of the relatives. A subgroup of 26 probands (12 ICA+, 14 ICA-) was tested for GAD(65) and was found positive. 4/14 ICA+ first-degree relatives were GAD(65) positive. Four relatives, positive for two antibodies, subsequently developed type 1 diabetes. Life-Table analysis of first-degree relatives with autoantibodies indicated an 80% disease-free survival at 3.5 yr. HLA-DRB1 was found to be associated with the presence of ICA in both probands and relatives, whereas HLA-DPB1 was associated with autoantibody in relatives of type 1 diabetic probands. These results suggest that autoimmunity occurs in type 1 diabetes families of Mexican descent in similar frequencies to that of non-Hispanic, Caucasian families. The presence of autoantibodies appears to be regulated in part by HLA class II genes, even in the absence of overt diabetes.
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PMID:Autoantibodies and human leucocyte antigen class II in first-degree family members of Mexican-American type 1 diabetic patients. 1160 May 69

The association of HLA class II haplotypes with type I diabetes was analyzed in 56 Southeastern Brazilian families using affected family-based controls (AFBAC) method. DRB1-DQA1-DQB1 alleles were determined by polymerase chain reaction/sequence-specific primer genotyping. This study first revealed the great haplotype diversity of Brazilians (65 different haplotypes even with incomplete DRB1 subtyping), probably due to the admixture of Africans genes with European and Amerindian genes in this population. The results revealed increased frequencies of the DRB1*03-DQA1*0501-DQB1*02 and DRB1*0401-DQA1*03-DQB1*0302 haplotypes in the patient group The highest risk for type I diabetes was associated with the heterozygote DRB1*03/*04 genotype as largely reported, and DRB1*03/X and DRB1*04/Y genotypes conferred a significant, but much lower disease risk. Protection from type I diabetes revealed some peculiarities in Southeastern Brazilians: a lack of significant protecting effect of the DRB1*1501-DQA1*0102-DQB1*0602 haplotype, and an apparent protection conferred by the DRB1*13-DQB1*0301, DRB1*11-DQB1*0301, and DRB1*01-DQB1*0501 two-locus haplotypes. The risk to type I diabetes in the highly diversified Southeastern Brazilians evidenced specific information to the prediction of the disease in this region of the country.
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PMID:Family-based association of HLA class II alleles and haplotypes with type I diabetes in Brazilians reveals some characteristics of a highly diversified population. 1170 84

The prevalence of diabetes mellitus in the young is higher in Bangladesh like other Asian developing nations. Albeit, undernutrition has been shown to be associated with diabetes in the young, not all such individuals are diabetic. Diabetes Mellitus is a multigenic disease. In IDDM, DR3/4 heterozygotes were shown to have a greatly increased risk of developing the disease, suggesting the concept of genetic factor(s) being involved in the development of diabetes. Therefore, this study was undertaken to determine the distribution of HLA class II alleles (DRB) and to identify the HLA associated risk for developing diabetes mellitus in the young Bangladeshis. A total of fifty individuals were investigated. Half of them (n=25) were diabetic patients, registered in BIRDEM and half the participants were their non-diabetic sibs. A genomic DNA PCR and Enzyme Linked Probe Hybridization Assay (ELPHA, Bio-test, Germany) was used to determine HLA class II alleles (DRB1, DRB 3, 4, 5) by in vitro amplification of DRB gene. Among all the sero-equivalent antigens found in the study subjects, the prevalence of DR15 (DR2) was overrepresented, both in the diabetic subjects and in their non-diabetic sibs. Moreover, compared with the non-diabetic group the diabetic patients showed higher frequency of DR15 alleles (39 and 25%) though the difference was not significant (chisq. 1.7, p>0.05). Next to DR15, DR4 was the most prevalent HLA-DRB gene found in the study population. Interestingly, the frequency of DR4 was higher in the diabetic than in the non-diabetic group (20 vs. 14%). The study showed that the DR15 and DR4 were the most prevalent in the study population. Moreover, DR7 though not very significant, was higher in non-diabetic compared to their diabetic sibs. Comparison between the diabetic and non-diabetic sibs could have been interesting and significant but we could not confirm our findings, possibly, due to small sample size. A study in a larger paired sample of unrelated population is also needed to substantiate our findings, and also to prove the susceptibility or resistant haplotype in the young diabetic subjects.
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PMID:Genetic background of diabetic and nondiabetic sibs in young Bangladeshis. 1176 1

To assess the effect of Asian-specific HLA haplotypes on susceptibility to type 1 diabetes, we investigated the association of genotypic combinations of DRB1-DQB1 haplotypes with susceptibility to type 1 diabetes. We studied 132 Japanese patients with type 1 diabetes and 157 control subjects, along with 67 Korean patients and 109 control subjects. DRB1*0405-DQB1*0401 and DRB1*0901-DQB1*0303 were confirmed to be two major susceptible HLA haplotypes in the Japanese population. The frequencies of heterozygotes and homozygotes with DRB1*0405-DQB1*0401 were similarly higher in patients than in control subjects (homozygotes, 5.3% vs. 3.8%; heterozygotes, 48.5% vs. 26.1%). In contrast, homozygotes, but not heterozygotes, with DRB1*0901-DQB1*0303 were more frequent in patients with type 1 diabetes than in control subjects (homozygotes, 12.9% vs. 0.6%; heterozygotes, 22.0% vs. 24.8%). A similar tendency was also observed in the Korean population. In multiple logistic regression analysis, DRB1*0405-DQB1*0401 fitted a dominant model and DRB1*0901-DQB1*0303 fitted a recessive model. These data, which indicate that the contribution of HLA haplotypes to the genetic susceptibility to type 1 diabetes differs depending on the genotypic combination of HLA haplotypes, suggest the importance of extensive analysis of genotypes in studies on HLA and disease association in general.
Diabetes 2002 Feb
PMID:Asian-specific HLA haplotypes reveal heterogeneity of the contribution of HLA-DR and -DQ haplotypes to susceptibility to type 1 diabetes. 1181 68

Genetic susceptibility to type 1 diabetes is determined by a combination of HLA-DQ and DRB1 alleles. In the present study, HLA associations with type 1 diabetes were investigated in the Jamaican population. DRB1 and DQ genotyping was performed on 45 type 1 diabetic patients and 132 control subjects born and resident in Jamaica. The small number of patients available for study reflected the low prevalence of type 1 diabetes in Jamaica. The results were compared with those from other African heritage populations and white Caucasians. The highest relative risk was associated with the DRB1*03-DQ2/DRB1*04-DQ8 genotype. Both DRB1*0401-DQ8 and DRB1*0408-DQ8 were positively associated with disease. DRB1*0408-DQ8 is uncommon amongst white Caucasians, where DRB1*0401-DQ8 is the major predisposing haplotype. The DRB1*1503-DQ6 haplotype was associated with protection from diabetes in the Jamaican population. This haplotype is rare amongst white Caucasians, where DRB1*1501-DQ6 is the protective haplotype. Data from African heritage populations suggest that DRB1*1503-DQ6 might be less protective than DRB1*1501-DQ6. DRB1*03-DQA1*0401-DQB1*0402 was associated with protection from diabetes in the Jamaican population, whereas in white Caucasians DRB1*08-DQA1*0401-DQB1*0402 is predisposing. These data demonstrate that comparison of genetic associations with type 1 diabetes in races with population-specific DRB1-DQ haplotypes provides new information as to the exact determinants of disease susceptibility. Further support is provided for roles of the DQ genes and the DRB1 gene (or a gene in linkage disequilibrium with it) in determining susceptibility to type 1 diabetes.
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PMID:HLA-DQ and DRB1 polymorphism and susceptibility to type 1 diabetes in Jamaica. 1184 88

Complex protein antigens contain multiple potential T cell recognition epitopes, which are generated through a processing pathway involving partial antigen degradation via proteases, binding to MHC molecules, and display on the APC surface, followed by recognition via the T cell receptor. We have investigated recognition of the GAD65 protein, one of the well-characterized autoantigens in type I diabetes, among individuals carrying the HLA-DR4 haplotypes characteristic of susceptibility to IDDM. Using sets of 20-mer peptides spanning the GAD65 molecule, multiple immunostimulatory epitopes were identified, with diverse class II DR molecules functioning as the restriction element. The majority of T cell responses were restricted by DRB1 molecules; however, DRB4 restricted responses were also observed. Antigen-specific T cell clones and lines were derived from peripheral blood samples of pre-diabetic and IDDM patients and T cell recognition and response were measured. Highly variable proliferative and cytokine release profiles were observed, even among T cells specific for a single GAD65 epitope.
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PMID:Complexity of human immune response profiles for CD4+ T cell epitopes from the diabetes autoantigen GAD65. 1190 49

The role of the DPB1 gene in genetic susceptibility to type I diabetes has yet to be elucidated. Studies of DPB1 alleles are conflicting. Analysis at the amino acid level, rather than consideration of allelic polymorphism, has been informative in determining disease susceptibility encoded by the DRB1 and DQ genes. In this study, therefore, amino acid variation at polymorphic sites of the DPbeta peptide chain encoded by the second exon of the DPB1 gene was analyzed in diabetic and control subjects from white Caucasian, North Indian Asian, and Jamaican populations. Human leukocyte antigen genotypes and haplotypes were analyzed using a logistic-regression approach and the data were conditioned for the effects on disease risk of the DRB1, DQA1, and DQB1 genes. Eight DPbeta amino acid residues were significantly associated with type I diabetes independent of DR and DQ (DPbeta 9, 33, 35, 36, 55, 56, 57, and 69). None of these residues, however, correlated consistently with disease risk in all three racial groups. This contrasts with findings for the DRbeta, DQalpha and DQbeta peptide chains, where the identity of the amino acid at particular sites has been found to correlate with predisposition to type I diabetes.
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PMID:Analysis of the role of DPB1-encoded amino acids in the genetic predisposition to type I diabetes mellitus. 1197 85

Type 1 (insulin-dependent) diabetes mellitus is associated with specific high-risk HLA DQ and DR haplotypes and islet cell antibodies. IDDM susceptibility in Caucasians is more strongly associated with DQ2/DQ8 (DQA1*0501-DQB1*0201/DQA1*0301-DQB1*0302) and DQ6 (B1*0604) than with DRB1*03/DRB1*04, while a single copy of DQ6 (B1*0602) gives sufficient protection against type 1 diabetes. As a part of the ABIS (All Babies in Southeast Sweden) study we have done typing of DQA1, DQB1, and DRB1 by polymerase chain reaction (PCR) amplification of the second exon of the genes, manually dot-blotting onto nylon membranes synthetic sequence-specific oligonucleotide (SSO) probes, 3' end-labeling with (32)P-dCTP, and hybridization followed by stringency washes and autoradiography using the SSO probe. Among 3756 newborns born in southeast Sweden we have found the high-risk genotype DQ2/DR3-DO8/DR4 to be present in 1%, haplotype DQ8/DR4 in 7.8%, and haplotype DQ2/DR3 in 9.6%. DQ2/DR3 or DQ8/DR4 was carried by 16.4% of newborns; the low-risk DQ6 molecule was carried by newborns as follows: DQ2/DR3-DQ6/DR15, 1.3%; DQ8/DR4-DQ6/DR15, 1.3%; and DQ6/DR15, 9.4%. We conclude from our results that the high incidence of IDDM in Sweden is at least in part due to increased prevalence of high-risk HLA haplotypes compared to protective haplotypes (20% vs. 13%) in the general population.
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PMID:Newborn screening for high-risk human leukocyte antigen markers associated with insulin-dependent diabetes mellitus: the ABIS study. 1202 Nov 31


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