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)

From 11 studies, a total of 1,792 Caucasian probands with insulin-dependent diabetes mellitus (IDDM) are analyzed. Antigen genotype frequencies in patients, transmission from affected parents to affected children, and the relative frequencies of HLA-DR3 and -DR4 homozygous patients all indicate that DR3 predisposes in a "recessive"-like and DR4 in a "dominant"-like or "intermediate" fashion, after allowing for the DR3/DR4 synergistic effect. Removal of DR3 and DR4 reveals an overall protective effect of DR2, predisposing effects of DR1 and DRw8, and a slight protective effect of DR5 and a predisposing effect of DRw6. Analysis of affected-parent-to-affected-child data indicates that a subset of DR2 may predispose. The non-DR3, non-DR4 antigens are not independently associated with DR3 and DR4; the largest effect is a deficiency of DR2, followed by excesses of DR1, DRw8, and DRw6, in DR4 individuals, as compared with DR3 individuals. HLA-B locus distributions on patient haplotypes indicate that only subsets of both DR3 and DR4 are predisposing. The presence or absence of Asp at position 57 of the DQ beta gene, recently implicated in IDDM predisposition, is not by itself sufficient to explain the inheritance of IDDM. At a minimum, the distinguishing features of the DR3-associated and DR4-associated predisposition remain to be identified at the molecular level. Risk estimates for sibs of probands are calculated based on an overall sibling risk of 6%; estimates for those sharing two, one, or zero haplotypes are 12.9%, 4.5%, and 1.8%, respectively. Risk estimates subdivided by the DR type of the proband are also calculated, the highest being 19.2% for sibs sharing two haplotypes with a DR3/DR4 proband.
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PMID:Genetic heterogeneity, modes of inheritance, and risk estimates for a joint study of Caucasians with insulin-dependent diabetes mellitus. 305 85

1. Approximately 15% of kidney transplants each year were regrafts. 2. One-year survival of cadaveric second transplants was 66.1% vs 75.9% for first transplants. One-year survival of second transplants from living donors was 82.7% vs 89.4% for first transplants. 3. The major difference between first and second transplants was from graft loss within the first month (14.1% for second transplants vs 6.5% for first transplants). 4. Patients younger than age 10 and older than 60 were poor candidates for regrafts. One-year graft survival was 46.1% and 51.7%, respectively. Patients 31-40 years old had a 1-year graft survival rate of 68.9%. 5. HLA-matched regrafts functioned better than mismatched grafts. A 4-antigen HLA-B,DR mismatch was associated with a decreased 3-month graft survival of 11.6% (p = 0.001 vs 0 mismatches). PRA levels or flow cytometry crossmatches may be better predictors of second graft outcome. Patients with PRA levels of 10-100% prior to retransplantation had a 6-7% lower 1-year graft survival than patients who never developed antibodies. 6. Patients with end-stage renal disease from diabetes had similar graft survival rates to patients with other diseases. Diabetes, however, was associated with a 2.9% higher death rate at 1 year (p = 0.03). 7. Parous females responded similarly to nulliparous female or male recipients. 8. Female donor regrafts were associated with an 8% lower 1-year graft survival rate when compared to kidneys from male donors. 9. Black donor regrafts to nonblack recipients were associated with a 13.8% lower 1-year graft survival. Black recipients had a 7% lower 1-year graft survival rate compared to nonblack recipients. 10. Regrafted patients benefited from preoperative transfusions only if they had never received blood products previously. 11. First graft survival less than 6 months was associated with a 5-15% lower second graft survival rate at 1 year. Thereafter, the graft failure rate was higher in patients whose first graft survived more than 6 months. By 6 or 7 years responders and nonresponders had equivalent graft survival. 12. Long-term graft survival may be adversely affected by CsA. 13. The optimum interval between first graft failure and regrafting was 1-6 months.
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PMID:Renal regrafts. 315 89

By typing a large quantity of family-based material for HLA-B, HLA-DR, C4, C2 and factor B, we were able to derive four-gene complement haplotypes (C4A, C4B, C2, BF) and six-gene MHC haplotypes (HLA-B, complement, HLA-DR). Fourteen six-gene MHC haplotypes showed linkage disequilibrium but exact frequencies could not be determined because it was not always possible to assign null C4 alleles in families where null genes were not clearly seen to segregate. Comparison of unrelated type I diabetes, Graves' disease and Hashimoto's thyroiditis patients with healthy unrelated controls revealed the following MHC allele associations: C4B*3, HLA-DR3 and HLA-DR4 with type I diabetes; BF*F1 and HLA-DR3 with Graves' disease; HLA-DR4 with Hashimoto's thyroiditis. By typing families of type I diabetes and Graves' disease patients we were able to derive two high-risk DR3+ MHC haplotypes for both type I diabetes and Graves' disease. These are HLA-B8 C4A*Q0 C4B*1 BF*S HLA-DR3 and HLA-B18 C4A*3 C4B*Q0 BF*F1 HLA-DR3, and these haplotypes account for most of the associations between these diseases and HLA-DR3. The MHC haplotype HLA-B15 C4A*3 C4B*3 BF*S HLA-DR4 also carries high risk for type I diabetes in this group of patients. Our data suggest that other DR4+ haplotypes, probably containing C4A*3 C4B*1, carry increased risk for type I diabetes whereas haplotypes containing DR4 and C4 C4A*3 C4B*Q0 do not. Our phenotype data suggest that DR4 in Hashimoto's thyroiditis is frequently associated with HLA-B44, C4A*3, C4B*1 and BF*S.
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PMID:Class III alleles and high-risk MHC haplotypes in type I diabetes mellitus, Graves' disease and Hashimoto's thyroiditis. 346 Dec 34

In an effort to clarify the mode of inheritance of insulin-dependent diabetes mellitus (IDDM), a total of 230 nuclear families with pointers were analyzed using the computer program COMBIN. Each family was ascertained without deliberate selection for multiplex families, and most families were completely typed for HLA-B, HLA-DR, and properdin factor B (Bf). There were 186 families with normal parents, 44 families with one affected parent, and no families with two affected parents. The computer program COMBIN evaluates evidence for a major locus of disease susceptibility, linkage of the major locus to a known genetic marker locus, linkage disequilibrium between the marker haplotypes and disease susceptibility, pleiotropic effects, and presence of an unlinked modifier. The parameters of COMBIN are T, Q, and D, representing the displacement, gene frequency of the IDDM allele, and dominance, respectively, of the major locus--and TM, QM, and DM being the analogous parameters of the modifier. In addition, the recombination fraction, theta, between the IDDM locus and HLA as well as the coupling frequencies are estimated. Finally, COMBIN simultaneously performs segregation and linkage analysis, with the optimal model being adjusted by the fit to the haplotype sharing distribution of IDDM. The results of these analyses indicated that the best-fitting genetic model of diabetic susceptibility appears to be a single major locus with near recessivity on a scale of standardized genetic liability, with gene frequency of the IDDM susceptibility allele of approximately 14%. In addition, the recombination fraction between the major locus and HLA is zero in all models; that is, for the B-BF-DR haplotype, the IDDM locus is tightly linked, probably (according to data from previous studies) to HLA-DR. Information determined by magnitude of coupling frequencies indicated that there is significant positive linkage disequilibrium with the haplotypes B8-BfS-DR4 and B15-BfS-DR4, significant negative linkage disequilibrium with B7-BfS-DR2, and intermediate disequilibrium for B8-BfS-DR3, B18-BfF1-DR3, and B40-BfS-DR4. Significant evidence in favor of an unlinked (to HLA) modifier (either single major locus or polygenes) could not be demonstrated. In conclusion, genetic susceptibility to IDDM appears to be most consistent with a single major locus with near recessivity that is tightly linked to HLA.
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PMID:A combined segregation and linkage analysis of insulin-dependent diabetes mellitus. 357 73

Much debate has taken place over the mode(s) of inheritance of insulin-dependent diabetes mellitus (IDDM) and the possibility of etiological heterogeneity. We have analyzed the disease status (IDDM) and genetic marker (HLA-A/B haplotype) data from 61 multiple-case IDDM families ascertained through two registries in the Pittsburgh, Pennsylvania, area. Linkage analysis results were similar for five previously published simple models of transmission. No heterogeneity could be detected on the basis of the total sample or when the sample was categorized according to the proband's HLA-B or HLA-DR type. In contrast, categorizing the families by generation(s) of the affected individuals revealed differences in the linkage analysis results. Families with affected siblings only (N = 38) showed strong evidence for close linkage for all models. Families with a parent and siblings affected (N = 6) showed evidence against close linkage between HLA-B and IDDM for some models.
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PMID:Detection of genetic heterogeneity between families of insulin-dependent diabetes mellitus patients using linkage analysis. 385 83

The families of 41 probands with type I (insulin-dependent) diabetes mellitus (IDDM) were typed for HLA-A, HLA-B, and HLA-DR antigens in addition to the complement polymorphisms C2, C4A, C4B, and Bf. All of these loci are encoded on the short arm of human chromosome 6 in a narrow region. Alleles at HLA-B (8, 15, 18, and 40), HLA-DR (3 and 4), and Bf (F1) have been associated with increased relative risk (RR) for IDDM, while HLA-B7 and HLA-DR2 have been associated with decreased RR for IDDM. This study confirms those significant risks in addition to confirming increased risk for the null (silent) allele for C4A (C4AQ0) and a rare C4B variant (C4B2.9). The significantly associated antigens (alleles) and risks were: HLA-B8 (RR = 3.1), HLA-DR3 (RR = 5.2), HLA-DR4 (RR = 4.3), and BfF1 (RR = 7.1), in addition to C4AQ0 (RR = 2.8) and C4B2.9 (RR = 12.6). Significantly low risk was associated only with HLA-DR2 (RR = 0.1). In a recent study, we defined five high-risk haplotypes that were determined solely by HLA-B, Bf, and HLA-DR (B8-BfS-DR3, B8-BfS-DR4, B15-BfS-DR4, B18-BfF1-DR3, and B40-BfS-DR4). By inclusion of information from the complement polymorphism, we have defined in greater detail three of these five high-risk haplotypes. One previously identified haplotype (B40-BfS-DR4) showed no complement clustering, while the rare high-risk haplotype (B8-BfS-DR4) was seen only once in this smaller sample.(ABSTRACT TRUNCATED AT 250 WORDS)
Diabetes 1985 May
PMID:Complement and HLA. Further definition of high-risk haplotypes in insulin-dependent diabetes. 398 76

For a preliminary estimation of the prevalence and significance of HLA antigens, tests were carried out on the A and B loci in an unselected group of 107 patients with type 1 diabetes in Bucharest. Monospecific antisera furnished by NIH, Bethesda were used. For HLA-A the following data were obtained: A2 (20.3% of the total specificities); A1 (18.4%); A3 (14.0%); A28 (10.1%). Provisional estimations in the healthy population also indicated HLA-A2 as being more frequent than followed by A30/31, A1, A9, A3. For HLA-B: B7 (38.2%); B5, B12 and B14 (14.0% each); B8 (11.1%). In the healthy subjects, the order was B12, B35, B5, B8 the same as B18, then B7 (which did not exceed 11%). The most frequently encountered haplotypes in the diabetic patients were: A2/B7 (8.4% of the total haplotypes); A3/B7 (6.9%); A1/B7 (6.6%); A10/B7 (3.8%); A9/B7 and A11/B7 (3.6% each). An unexpectedly high frequency of the HLA-B7 antigen was found in group of diabetic patients investigated, contrasting with its assumed "protector" role in the Caucasian population. The frequency of antigen HLA-A3 and haplotype HLA-A3/B7 infringes their listing in the "resistance axis" to diabetes.
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PMID:Testing histocompatibility antigens (loci A and B) in a group of type 1 (insulin-dependent) diabetic patients in Bucharest. 404 1

Three groups of patients with insulin-dependent diabetes mellitus, ascertained by different procedures, were investigated for HLA-A, B, C and D antigens (n = 164), and a subset (n = 93) for HLA-DR. Both HLA-D/DR3 and D/DR4 were strongly positively associated and D/DR2 was negatively associated with insulin-dependent diabetes. HLA-DR+ was found to be a better marker for insulin-dependent diabetes than Dw4. The HLA-B associations (B8, B15 and B18) were clearly secondary to the increases of HLA-D/DR3 and D/DR 4. The HLA associations did not differ between familial and isolated cases indicating that these two groups may well have a common genetic background. Based on analysis of HLA-haplotype sharing in affected sibling pairs, a simple dominant model of inheritance could be ruled out, and a simple recessive model was found unlikely. The relative risks for the HLA-Dw3,4 and HLA-DR3,4 phenotype were 21.2 and 44.4 respectively and exceeded those of both the HLA-Dw3 and HLA-DR3 (5.6 and 4.3) as well as the HLA-Dw4 and DR4 (10.1 and 10.5) phenotypes. This argues against an intermediate genetic model but further studies are needed to clarify whether there is more than one susceptibility gene for insulin-dependent diabetes mellitus within the HLA-system.
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PMID:HLA-D and -DR antigens in genetic analysis of insulin dependent diabetes mellitus. 616 81

The literature of the past ten years shows that the introduction of highly purified heterologous and, lastly, homologous insulins has notably lowered the production of IgG and IgE specific insulin antibodies, but has not succeeded in completely eliminating clinical manifestations of the immune or hyper-immune response to insulin therapy. In particular, insulin allergy with or without lipodystrophy is still seen. Among the factors of insulin immunogenicity, there is a possible genetic control of the immune response in type I diabetes: determining HLA halloantigens (A, B, C, D) might identify specific immune response genes (Ir genes). Initial researches, performed until now almost exclusively upon diabetics treated with conventional heterologous insulin, seem to indicate a positive relationship between haplotype HLA - B15 - DR4 and an elevated immune response, whereas haplotypes HLA - B8 - DR3 and HLA - B18 - DR3 might protect against the formation of anti-insulin antibodies. Antigens D/DR3 and D/DR4 are known to be primitively associated to susceptibility for type I diabetes, whereas antigens B8, B15, B18 are secondarily associated to the rise in frequency of DR3 and DR4 for the "linkage disequilibrium" existing between alleles of B and D loci. The results of HLA typing are presented in 2 groups of insulin-dependent diabetics (ID) followed from an immunological viewpoint during therapy with monocomponent heterologous insulin for over 5 years. The first group is composed of 50 patients with low IgG anti-insulin antibody titers (less than 1 mU/ml, Christiansen: low responders); the second group is made up of 23 patients with high IgG anti-insulin antibody titers (greater than 2.5 mU/ml, Christiansen: high responders) and includes 5 subjects with insulin allergy (associated or not with insulin lipoatrophy) and high levels of insulin specific IgE antibodies. A study of the frequencies of various HLA-B antigens in both groups of patients, in regard to a control group of piemontese population, in relation to the intensity of association (relative risk) and to the statistical importance of frequencies, shows only a possible protective effect of the HLA-B18 phenotype (linkage disequilibrium with HLA - DR3) towards the production of anti-insulin antibodies and hyperimmune clinical manifestations, such as allergy. Reliable conclusions are not possible between low and high responders for the other phenotypes (HLA - B7, B8, B15) commonly implicated. HLA-B12 was noted in 3 of 5 patients with allergy, in 2 cases associated with B8.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:[HLA typing and insulin antibody production in insulin-dependent diabetics]. 644 4

Two hundred subjects with insulin-dependent (type I) diabetes mellitus (IDDM) were typed for HLA-B, HLA-DR, and properdin factor B (Bf). HLA and Bf antigen and haplotype frequencies in subjects were compared with control frequencies derived from the 8th HLA Workshop. Frequencies of extended haplotypes (defined by B-Bf-DR alleles on a chromosome) were also contrasted with control frequencies. Significant positive associations between IDDM and HLA-B8, DR3, DR4, BfS, and BfF1 were confirmed, as were significant negative associations between IDDM and HLA-B7, DR2, DR5, DR7, and BfF. One haplotype (B7-BfS-DR2) exhibited significant negative association, while five haplotypes (B8-BfS-DR3, B8-BfS-DR4, B15-BfS-DR4, B18-BfF1-DR3, and B40-BfS-DR4) exhibited significant positive associations with IDDM. In this sample, 64% of all probands carried at least one of the high-risk haplotypes. In conclusion, the occurrence of five "high-risk" haplotypes associated with IDDM provides evidence for previously undocumented genetic heterogeneity and suggests that possibly more than two HLA-region genes may be involved in IDDM susceptibility.
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PMID:Genetic heterogeneity of insulin-dependent (type I) diabetes mellitus: evidence from a study of extended haplotypes. 659 40


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