UMLS:C0011849 - FACTA Search

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Query: UMLS:C0011849 (diabetes)
277,896 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

We fitted models for the main effects of alleles at the HLA-A, B, and DR loci and their haplotypes on the risk of insulin-dependent diabetes mellitus (IDDM). Empirical Bayes methods were used, assuming independent exchangeable normal priors for effects at each locus separately and for haplotype effects. A pure main effects model, pure haplotype effects model, and a combined model were fitted using Gibbs sampling. The main effects model showed that the DR locus had the largest variation in risk between alleles, followed by the B locus; significance tests for each allele in this model were in general agreement with those in the companion paper [Langholz et al. (1995) Genet Epidemiol 12:441-453], although all relative risks were shrunk toward 1.0 in the empirical Bayes analysis. The variance estimate for pure haplotype effects was substantially larger than for any of the three main effects considered in this analysis, but in the combined model, the DR locus showed larger variability than the haplotype deviations. We confirmed that haplotype A2/B56/DR4 previously reported to be common in Finnish diabetics does indeed confer unusually high risk (relative risk = 7.6, P < 0.001), but found this to be only 1.9 times higher than predicted by its component main effects (P = 0.046). All of the other haplotypes could be adequately explained by their main effects. Empirical Bayes methods provide a natural means of dealing with the problems of multiple comparisons, multicolinearity, and sparse data that complicate the analysis of HLA data.
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PMID:Variation in HLA-associated risks of childhood insulin-dependent diabetes in the Finnish population: II. Haplotype effects. DiMe Study Group. Childhood Diabetes in Finland. 855 78

Genes that predispose to haemochromatosis are though to be located within the several megabases telomeric of HLA-A. Further recombinant mapping has been used previously to map susceptibility genes for diseases such as insulin-dependent diabetes mellitus, myasthenia gravis and cystic fibrosis, and should be useful in relation to haemochromatosis. However, this method requires the recognition of ancestral haplotypes within the susceptibility region. Using a panel of six microsatellite markers from this region (MOG A, MOG B, MOG C, D6S464, D6S306 and D6S105), we show that ancestral haplotypes extend telomeric of HLA-A, at least as far as D6S105. Nine of 14 haplotypes carrying HLA-B7 and HLA-A3 shared the same microsatellite alleles between HLA-A and at least D6S105. Similarly, nine of 10 haplotypes sharing HLA-B8 and HLA-A1 shared the same microsatellite alleles, although a different set to those with HLA-B7 and HLA-A3. Haplotypes representing historical recombination events were also identified. These two findings demonstrate that recombinant mapping may be applicable to the mapping of disease genes in this region.
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PMID:Conservation of ancestral haplotypes telomeric of HLA-A. 930 96

The impact of matching for the human leukocyte antigen (HLA)-DQ phenotype in cadaveric renal transplantation is unclear. We analyzed the effect of matching serologically defined HLA-DQ phenotypes on renal allograft survival in 12,050 first cadaveric renal transplants (recipients were 63.5% white and 36.5% African-American). Recipients were entered into the South-Eastern Organ Procurement Foundation (SEOPF) database between 1 October 1987 and 6 June 1995. A series of life table analyses were done to test the equality of survival curves for HLA-DQ match, both alone and accommodating for differences in recipient race and HLA-DR match. Cox regression models were then performed to detect differences in allograft survival based upon HLA-DQ match. Initial adjustments were done by recipient race. Subsequent adjustments were done by recipient and donor race, age and sex, cold ischemia time (CIT), body mass index (BMI), cyclosporine A (CyA) use, peak panel reactive antibody (PRA) titer, year of transplant, presence of diabetes mellitus (DM), and degree of HLA-A,B and HLA-DR match as covariates. The effect of varying degrees of HLA-DQ match on graft survival were similar between the two races (p = 0.87). In all recipients, an 8.3% reduction in graft failure was observed for each increase in HLA-DQ match using the Cox regression model adjusted only for recipient race (p = 0.004). A non-significant 3.0% reduction in graft failure (p = 0.38) was observed for each level of increasing HLA-DQ match when using the Cox regression model adjusted for recipient and donor race, age and sex, CIT, BMI, CyA use, year of transplant, DM, HLA-A,B and -DR match. In this model, superior HLA-A,B match and HLA-DR match, recipient and donor age, male donor sex, shorter CIT, white race of recipient, lower peak PRA, CyA use, and absence of DM significantly improved graft survival (all < or = 0.004). We conclude that HLA-DQ matching does not significantly affect cadaveric renal allograft survival once adjusted for other known predictors of graft outcome.
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PMID:HLA-DQ matching in cadaveric renal transplantation. 936 45

Hemochromatosis is a recessive disorder of iron metabolism characterized by progressive iron loading of parenchymal organs, which accounts for clinical complications such as cirrhosis, diabetes mellitus, cardiopathy, endocrine dysfunctions and arthropathy. Clinical complications, which usually develop after the third or fourth decade of life, can be fatal but may be prevented by phlebotomy if iron excess is detected at a very early stage. The hemochromatosis gene (HFE), located 4.5 megabases telomeric to the HLA-A locus, encodes an HLA class I like protein and two missense mutations, C282Y and H63D in complete disequilibrium have been identified within this gene. Due to its high frequency in the general population, the involvement of H63D in the pathogenesis of the disease remains controversial, and it might correspond to a minor mutation. Conversely, the C282Y mutation is tightly linked to the disease, as it accounts for 80 to 100% of the hemochromatosis cases in Northern Europe. The lower frequency observed, in the patients, in Italy and South of France led to imagine either the implication of other mutations or of other genes. The C282Y mutation is absent in Asia and Africa and is present in the general population with a decreasing gradient of frequency from Northern to Southern Europe. The prevalence of the disease was usually estimated to be 3% but the observed frequency of the C282Y homozygotes is 5% in our breton population raising the question of the penetrance of the disease, and consequently the use of the genotypic test for its systematic screening. As HFE encodes a membrane protein similar to HLA class I protein, its contribution to iron overload is not obvious. The normal protein is predicted to to be expressed at the cell surface in association with beta 2-microglobulin, a localization for which C282Y is critical as it disrupts this association. This protein has also been shown to form a stable complex with the transferrin receptor leading to a decreased affinity for transferrin. A better knowledge of its function will help to decipher iron and different metal-ions metabolism. Although the exact role of the HFE protein is unknown, the genotypic test allows the clinicians to ascertain their diagnosis and genetic counselling.
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PMID:[Molecular genetics of hemochromatosis]. 1052 Apr 11

The aim of this study is to identify insulin-dependent diabetes mellitus (IDDM)-susceptible HLA antigens in IDDM patients who do not have established risk allele, HLA-DQA1*0301, and analyze relationship of these HLA antigens and the degree of beta-cell destruction. In 139 Japanese IDDM patients and 158 normal controls, HLA-A, -C, -B, -DR and -DQ antigens were typed. Serum C-peptide immunoreactivity response (deltaCPR) to a 100-g oral glucose load < or = 0.033 nmol/l was regarded as complete beta-cell destruction. All 14 patients without HLA-DQA1*0301 had HLA-A24, whereas only 35 of 58 (60.3%) normal controls without HLA-DQA1*0301 and only 72 of 125 (57.6%) IDDM patients with HLA-DQA1*0301 had this antigen (Pc = 0.0256 and Pc = 0.0080, respectively). DeltaCPR in IDDM patients with both HLA-DQA1*0301 and HLA-A24 (0.097 +/- 0.163 nmol/L, mean +/- SD, n = 65) were lower than in IDDM patients with HLA-DQA1*0301 only (0.219 +/- 0.237 nmol/L, n = 45, P < 0.0001) and in IDDM patients with HLA-A24 only (0.187 +/- 0.198 nmol/L, n = 14, P = 0.0395). These results indicate that both HLA-DQA1*0301 and HLA-A24 contribute susceptibility to IDDM independently and accelerate beta-cell destruction in an additive manner.
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PMID:Human leukocyte antigen-A24 and -DQA1*0301 in Japanese insulin-dependent diabetes mellitus: independent contributions to susceptibility to the disease and additive contributions to acceleration of beta-cell destruction. 1052 20

Several studies provide evidence that in addition to the DQ-DR genes, HLA contains another uncharacterized gene or genes associated with type 1 diabetes. Our aim was to investigate the effect of this gene independently of the DQ-DR genes and to localize it with a matched case-control study. More than 1,400 patients and 30,000 control individuals from Finland were studied. They were first genotyped for the selected alleles of the HLA-DQB1, -DQA1, and -DRB1 genes. For the DR3/4(0404) genotype, 75 patients and 181 control subjects were stratified, and 241 patients and 354 controls were stratified for the DR3/4(0401) genotype. Ten microsatellite markers in the HLA class III and I regions (D6S273, TNFa, C12A, STR MICA, MIB, C125, C143, C245, C3211, and MOGc) and selected alleles of the HLA-A and HLA-B genes were studied. In the DR3/4(0404)-stratified group, we found that markers located between C12A and C143 near the HLA-B gene confer a strong additional diabetes association. This was confirmed by the population differentiation test in both DR3/4(0404)- and DR3/4(0401)-stratified groups. Our data indicate that an additional gene associated with type 1 diabetes is located in the 240-kb region near HLA-B. We excluded STR MICA polymorphism as a mutation responsible for diabetes association.
Diabetes 2000 Dec
PMID:Non-class II HLA gene associated with type 1 diabetes maps to the 240-kb region near HLA-B. 1111 29

The aim of this study was to compare the frequencies of HFE mutations in African-American women with non-insulin-dependent diabetes mellitus (NIDDM) to that of controls and to determine whether these mutations are associated with NIDDM and iron overload. We studied 167 African-American women with NIDDM. The 71 non-diabetic controls were African-American female controls. HLA-A and -B typing and HFE mutation analysis for C282Y and H63D alleles were performed using standard molecular genetic techniques. The frequencies of C282Y and H63D were not significantly different in NIDDM patients and controls. C282Y was observed in 0.59% of patients and 1.41% of controls. H63D was observed in 2.99% of patients and 3.08% of controls. All of the NIDDM patients who possessed either C282Y or H63D mutations had normal values of serum ferritin, serum iron and transferrin saturation. A woman who inherited C282Y also possessed HLA-A3, -B7 which is considered part of the ancestral haplotype containing the gene predisposing to hemochromatosis in Caucasians. The frequencies of C282Y and H63D vary in African Americans from different geographic regions of the United States; this variance can be explained by Caucasian admixture. Although most iron overload cases in African Americans bear more resemblance to cases of African iron overload than to those of Caucasian hemochromatosis, rare cases resembling Caucasian hemochromatosis have been observed in African Americans.
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PMID:HFE mutations in African-American women with non-insulin-dependent diabetes mellitus. 1176 82

A total of 21,000 general population newborns (NECs) and 693 young siblings-offspring of patients with type 1A diabetes (SOCs) were class II genotyped and 293 NECs and 72 SOCs with the high-risk genotype, DR3/4, DQB1*0302 have been prospectively evaluated. Seventeen individuals who converted to persistent autoantibody positivity and two autoantibody-negative control groups (35 SOCs and 24 NECs) were typed for HLA-A class I alleles. The A1, A2 genotype was significantly increased among the autoantibody-positive subjects (47%) compared to autoantibody-negative SOCs (14%, P = 0.01) and NECs (13%, P = 0.02). Life-table analysis of DR3/4, DQB1*0302 siblings revealed a risk of 75% for development of islet autoantibodies by the age of 2 years for those with A1, A2. The HLA-A2 phenotype frequency was increased among an independent DR3/4, DQB1*0302 young diabetes cohort (64% versus 33% for autoantibody-negative NECs). These results suggest that a high incidence and early appearance of islet autoantibodies for siblings of patients with type 1A diabetes are associated with DR3/4, DQB1*0302 and potentially increased with HLA-A genotype A1, A2.
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PMID:Millennium award recipient contribution. Identification of children with early onset and high incidence of anti-islet autoantibodies. 1189 Jul 8

Diabetic nephropathy (DN) is the leading cause of end-stage renal failure and a major risk factor for cardiovascular mortality in diabetic patients. To evaluate the multiple pathogenetic factors implicated in DN, unbiased mRNA expression screening of tubulointerstitial compartments of human renal biopsies was combined with hypothesis-driven pathway analysis. Expression fingerprints obtained from biopsies with histological diagnosis of DN (n = 13) and from control subjects (pretransplant kidney donors [n = 7] and minimal change disease [n = 4]) allowed us to segregate the biopsies by disease state and stage by the specific expression signatures. Functional categorization showed regulation of genes linked to inflammation in progressive DN. Pathway mapping of nuclear factor-kappaB (NF-kappaB), a master transcriptional switch in inflammation, segregated progressive from mild DN and control subjects by showing upregulation of 54 of 138 known NF-kappaB targets. The promoter regions of regulated NF-kappaB targets were analyzed using ModelInspector, and the NF-kappaB module NFKB_IRFF_01 was found to be specifically enriched in progressive disease. Using this module, the induction of eight NFKB_IRFF_01-dependant genes was correctly predicted in progressive DN (B2M, CCL5/RANTES, CXCL10/IP10, EDN1, HLA-A, HLA-B, IFNB1, and VCAM1). The identification of a specific NF-kappaB promoter module activated in the inflammatory stress response of progressive DN has helped to characterize upstream pathways as potential targets for the treatment of progressive renal diseases such as DN.
Diabetes 2006 Nov
PMID:Modular activation of nuclear factor-kappaB transcriptional programs in human diabetic nephropathy. 1706 35

Between March 1976 and December 2004, 1690 consecutive allogenic living donor renal transplants were carried out at Mansoura, Egypt. We herewith report on 1600 transplants that had a minimum follow-up period of one year. The overall graft survival rates were 76% and 52% at five and 10-years respectively. The corresponding patient survival rates were respectively 86% and 71%. The projected half-life was 10.7 years for grafts and 18.2 years for patients. Predictors for graft outcome were classified as pre-transplant variables, technical factors or post-transplant predictors. Among the long list of these variables, factors that had a significant impact on outcome by univariate analysis included donor's and recipient's age, donor-recipient consanguinity, HLA-A, cytomegalovirus (CMV) and hepatitis C virus (HCV) markers, ischemia time, primary immunosuppression, ad juvant therapy, total steroid dose within the first three months, number of acute rejection episodes, time to onset of diuresis, hypertension post-transplant, serum creatinine at one year and at last follow-up besides chronic rejection. Only five factors sustained their significance by multivariate analysis: they included recipient's age, primary immunosuppression, post-transplant hypertension and serum creatinine at one year and last follow-up. Some specific complications encountered among the recipients such as hemolytic anemia, post-transplant diabetes mellitus, bone complications, malignancy, erectile dysfunction and surgical complications are discussed. In conclusion, we hope to start the cadaveric donor transplant program soon in our unit. Also, the ambition concerning the transplantation field in the new millennium is to overcome xenotransplantation barriers and to induce immunologic tolerance with neither rejection nor immunosuppression.
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PMID:Living donor renal transplantation, 1976 - 2003: the mansoura experience. 1820 12

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