Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0011854 (type 1 diabetes)
 20,749 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

A major component of inherited susceptibility to IDDM is associated with one or more loci in the MHC. Identification of the primary susceptibility genes has been complicated by the low frequency of recombination, i.e. linkage disequilibrium, within the MHC. It is difficult to distinguish whether a detected genetic association with the disease is primary, or secondary due to linkage disequilibrium with an allele at another locus which is directly predisposing. During the evolution of different races, however, recombination within the MHC has occurred and population-specific MHC haplotypes exist. Primary susceptibility allels should be associated with disease in all racial groups, regardless of genetic background. It is unlikely that disease associations secondary to linkage disequilibrium will be consistent in these groups. This chapter reviews the known associations of candidate class II susceptibility alleles with IDDM in the five largest racial groups; white Caucasians, Asian Indians, Negroids, Japanese and Chinese. These trans-racial studies suggest that the DQ molecule has a primary role in predisposition to IDDM. There are consistent findings of a positive association with the DQA1*0301 allele and negative associations with the DQB1*0602 and DQB1*0603 alleles. These two alleles differ by a single codon and so the encoded DQ beta chains are likely to have similar functions. DR4-associated susceptibility is associated with the DQA1*0301 allele in all races tested so far but this allele cannot be the only susceptibility factor on this haplotype. The identity of the DR3-associated susceptibility factor remains unclear but the DQB1*0201 allele is a candidate. If DQB1*0201 is involved, the existence of a protective factor on the neutral DR7-DQB1*0201 haplotypes is indicated. Analysis of DR9 associated susceptibility implicates a non-DR/DQ predisposing factor.
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PMID:Genetics of diabetes. Trans-racial gene mapping studies. 189 69

The second-generation screen of human genome has confirmed that HLA region genes play a key role in the susceptibility to insulin-dependent diabetes mellitus. The aim of the present study was to estimate the frequency of chosen alleles of DQA1 and DQB1 genes in the patients with insulin-dependent diabetes mellitus and their first degree relatives in comparison to the healthy population in the north-eastern region of Poland. HLA typing of DQA1 and DQB1 alleles of the HLA region was performed by "phototyping" PCR-SSP method. The highest predisposition to IDDM in the population of the north-eastern region of Poland was associated with DQB1*0302 allele and DQB1*02-DQA1*0301 or DQB1*0302-DQA1*0301 haplotypes, while the dominant protection was connected with DQB1*0602, DQB1*0603 and DQB1*0301 alleles. The high frequency of protective DQB1*0602 and DQB1*0603 alleles and the low percentage of "diabetogenic" DQB1*0302 genes in the healthy control population of north-estern region of Poland may suggest their dominant influence on the relatively low incidence of IDDM in this region. The relatively high percentage of the first degree relatives of IDDM patients with pancreatic autoantibodies but with protective alleles observed in our study, which significantly decreases the risk of IDDM, suggests the necessity of DQB1*0602-03 measurements in such subjects for the better IDDM risk assessment.
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PMID:[DQA1 and DQB1 HLA genes as markers of insulin-dependent diabetes mellitus in the Polish population]. 1069 96

Insulin-dependent diabetes mellitus is positively associated with DQ8, DQ2, and DQ6 (DQB1*0604), and negatively associated with DQ6 (DQB1*0602), DQ6 (DQB1*0603), and DQ7 in Swedish caucasians. The protection conferred by DQ6 (DQB1*0602) is stronger in younger individuals and there is decrease in the effect of protection with increasing age. Three-dimensional modeling of the susceptible DQ6 (DQB1*0604) and protective DQ6 (DQB1*0602), which share the same DQA chain (DQA1*0102) but differ in the DQB chain at 6 residues, identifies residue 57 and 70 to be important for protection. Three-dimensional models of the DQ8 molecules were constructed from the coordinates of the DR1 crystal structure and other susceptibility and resistance molecules were made by homology modeling. The positively associated DQ molecules had weakly negative to significantly positive surface electrostatic potentials over the peptide binding and T cell recognition areas, whereas the negatively associated molecules had distinctly more negative areas over the relevant surface. This suggests that the variation in the physicochemical properties such as molecular electrostatic potentials among different DQ molecules are important.
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PMID:HLA-DQ6-mediated protection in IDDM. 1071 7

The incidence of type 1 diabetes (T1DM) seems to depend in part on the population frequencies of susceptible and protective HLA haplotypes. The present study aimed to (i): characterize the genetic susceptibility to T1DM in the Slovenian population, (ii) test the general hypothesis that T1DM incidence is related to the frequencies of susceptible/protective haplotypes, (iii) compare allele, haplotype and genotype frequencies in Slovenians and Italians that represent two white populations with a similar incidence of T1DM (7.9/100,000/year and 8.1/100,000/year, respectively). The haplotype found most frequently among Slovenian T1DM patients was DRB1*0301-DQA1*0501-DQB1*0201 (53%). The DR4-DQA1*0301-DQB1*0302 haplotypes conferring susceptibility to T1DM were those bearing DRB1*0401 (OR = 12), DRB1*0404 (OR = 4.7) and DRB1*0402 (OR = 4.5). Negative associations with the disease were found for the following haplotypes: DRB1*1501-DQA1*0102-DQB1*0602, DRB1*1301-DQA1*0102-DQB1*0603, DRB1*1101/1104-DQA1*0501-DQB1*0301, and DRB1*1401-DQA1*0101-DQB1*0503. Our findings indicate that the low frequencies of susceptible genotypes, in particular, DR3-DQA1*0501-DQB1*0201/DR4-DQA1*0301-DQB1*0302, together with a high frequency of protective haplotypes, could in part explain the low incidence of T1DM in the Slovenian population. The combined frequencies of susceptible genotypes were similar in the two populations (Slovenia = 19.2%, Italy = 17.6%), and the 95% confidence limits of the OR values for each genotype in the two populations overlapped, indicating no significant differences between the values. We conclude that the similar incidences of T1DM in Italian and Slovenian populations are in part a reflection of similar frequencies of HLA susceptible/protective haplotypes.
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PMID:Similar incidence of type 1 diabetes in two ethnically different populations (Italy and Slovenia) is sustained by similar HLA susceptible/protective haplotype frequencies. 1244 7

In this report, we describe the case of a 43-year-old woman affected by type 1 diabetes mellitus diagnosed 8 years before, who developed Graves' disease 2 years after chemotherapy and mantle radiotherapy treatment for Hodgkin's disease. Bilateral Graves' ophthalmopathy appeared four months before our observations. Intravenous methyl-prednisolone therapy was started, but was interrupted due to severe metabolic failure. Autoantibodies (anti-islet cells, anti-thyroid, thyroid-stimulating, non-organ-specific) were positive. Since the clinical picture suggested a genetic immunological ground predisposing to autoimmunity, we evaluated her HLA haplotype. Genomic typing of the patient permitted identification of the 8.1 ancestral haplotype, a Caucasoid haplotype unique in its association with many immunopathological diseases. Moreover, we also observed a haplotype unusual in Caucasians, trans DRB1*1101, DQA1*0103, DQB1*0603. To our knowledge, HLA-related genetic risk of developing thyroid autoimmunity after neck irradiation has never been studied. Although we cannot confirm a direct association between the 8.1 ancestral haplotype or DRB1*1101, DQA1*0103, DQB1*0603 and the diseases described, we suggest considering immunological parameters and HLA typing in candidate patients for mantle radiation therapy for Hodgkin's disease or other tumors. HLA haplotype determination could be useful in identifying the patients at raised risk of developing autoimmune diseases after irradiation, thus permitting a more appropriate follow-up schedule.
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PMID:Autoimmune diabetes mellitus, Hodgkin's disease and Graves' ophthalmopathy in a patient with 8.1 ancestral haplotype. 1500 59

To examine human leukocyte antigen (HLA) class II association of type 1 diabetes mellitus (DM) in Czech children, we performed a case-control study of 261 patients diagnosed before the age of 15 and 289 non-diabetic control children. Complete HLA-DQA1, DQB1 genotyping and DRB1*04 subtyping were carried out by polymerase chain reactions with sequence-specific primers. The effect of the DRB1*04 subtypes was studied in DRB1*04 alleles carried on DQB1*0302-DQA1*03 haplotypes. The risk was statistically evaluated by testing 2 x 2 tables, considering corrected p-values < 0.05 significant. The DQB1*0302 (odds ratio, OR = 9.0), DQB1*0201 (OR = 3.4) and DQA1*03 (OR = 7.5) alleles were significantly associated with diabetes risk, while the DQB1*0602 (OR = 0.02), DQB1*0301 (OR = 0.08), DQB1*0503 (OR = 0.13), DQB1*0603 (OR = 0.20), DQA1*01 (OR = 0.28) and DQA1*02 (OR = 0.26) alleles were significantly protective. Of the DQA1-DQB1 genotypes, we point out the extremely high risk of OR = 116 conferred by HLA-DQA1*05-DQB1*0201/DQA1*03-DQB1*0302. Among DRB1*04 subtypes, DRB1*0403 was significantly protective (OR = 0.05, CI 95% 0.01-0.45). Since none of the remaining DRB1*04 subtypes was associated with type 1 DM, our study may present another piece of evidence that the DRB1*0401 and DRB1*0404 alleles do not modify type 1 diabetes risk generally in European populations.
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PMID:HLA class II genetic association of type 1 diabetes mellitus in Czech children. 1501 91

Most cases of type 1 diabetes (T1DM) are due to an immune-mediated destruction of the pancreatic beta cells, a process that is conditioned by multiple genes and environmental factors. The main susceptibility genes are represented by the class II HLA-DRB1 and DQB1 alleles. The aim of our study was to reconfirm the contribution of HLA-DQB1 polymorphisms to T1DM genetic susceptibility for the Romanian population. For this, 219 Romanian T1DM families were genotyped at high resolution for HLA DQB1 using the PCR-SSOP method (Polymerase Chain Reaction - Sequence Specific Oligonucleotide Probes). Allele transmission to diabetics and unaffected siblings was studied using the Transmission Disequilibrium Test (TDT). We found an increased transmission of DQB1*02 (77.94% transmission, p(TDT) = 7.18 x 10(-11)) and DQB1*0302 (80.95% transmission, p(TDT) = 2.25 x 10(-10)) alleles to diabetics, indicating the diabetogenic effect of these alleles. Conversely, DQB1*0301, DQB1*0603, DQB1*0602, DQB1*0601 and DQB1*05 alleles are protective, being significantly less transmitted to diabetics. In conclusion, our results confirmed the strong effect of HLA-DQB1 alleles on diabetes risk in Romania, with some characteristics which can contribute to the low incidence of T1DM in this country.
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PMID:Type 1 diabetes genetic susceptibility encoded by HLA DQB1 genes in Romania. 1525 73

Patients with type 1 diabetes are suffering from defects in immune regulatory cells. Their siblings may be at increased risk of type 1 diabetes especially if they are carriers of certain human leucocyte antigen (HLA) alleles. In a prospective non-randomized study, we intended to evaluate 31 healthy siblings of paediatric patients with type 1 diabetes and explore immune regulatory populations of CD4+CD25+ T cells and natural killer (NK) T cells. Tested siblings of type 1 diabetes patients were stratified according to the HLA-associated risk of possible diabetes development. Immune regulatory function of CD4+CD25+ T cells was tested in vitro. Significant differences in CD4+CD25+ but not in NK T cells have been identified. Siblings of type 1 diabetes patients carrying high risk HLA alleles (DQA1*05, DQB1*0201, DQB1*0302) had significantly lower number of immune regulatory CD4+CD25+ T cells than the age-matched healthy controls or siblings carrying low-risk HLA alleles (DQB1*0301, DQB1*0603, DQB1*0602). Regulatory function of CD4+CD25+ T cells demonstrated a dose-escalation effect. In siblings of type 1 diabetes patients, the defect in immune regulatory CD4+CD25+ T cells exists in association with genetic HLA-linked risk for type 1 diabetes.
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PMID:Immune regulatory T cells in siblings of children suffering from type 1 diabetes mellitus. 1703 46