Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

---

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

The human leukocyte antigen (HLA) complex, encompassing 3.5 Mb of DNA from the centromeric HLA-DPB2 locus to the telomeric HLA-F locus on chromosome 6p21, encodes a major part of the genetic predisposition to develop type 1 diabetes, designated "IDDM1." A primary role for allelic variation of the class II HLA-DRB1, HLA-DQA1, and HLA-DQB1 loci has been established. However, studies of animals and humans have indicated that other, unmapped, major histocompatibility complex (MHC)-linked genes are participating in IDDM1. The strong linkage disequilibrium between genes in this complex makes mapping a difficult task. In the present paper, we report on the approach we have devised to circumvent the confounding effects of disequilibrium between class II alleles and alleles at other MHC loci. We have scanned 12 Mb of the MHC and flanking chromosome regions with microsatellite polymorphisms and analyzed the transmission of these marker alleles to diabetic probands from parents who were homozygous for the alleles of the HLA-DRB1, HLA-DQA1, and HLA-DQB1 genes. Our analysis, using three independent family sets, suggests the presence of an additional type I diabetes gene (or genes). This approach is useful for the analysis of other loci linked to common diseases, to verify if a candidate polymorphism can explain all of the association of a region or if the association is due to two or more loci in linkage disequilibrium with each other.
...
PMID:The predisposition to type 1 diabetes linked to the human leukocyte antigen complex includes at least one non-class II gene. 1073 75

The TNF-alpha gene is located in the HLA region and has been implicated in the pathogenesis of Type I (insulin-dependent) diabetes mellitus (IDDM). We investigated the frequency of TNFa microsatellite alleles in 76 young-onset IDDM patients, 65 adult-onset IDDM patients, and 90 control subjects. We also examined the association of these TNFa alleles with HLA-DRB1 alleles, HLA-class I alleles, and TNF-alpha production. The frequency of the TNFa2 and TNFa9 alleles was increased in the young-onset IDDM patients compared to control subjects, but the increased frequency of TNFa2 was not significant after the correction for the number of comparisons was made. We did not find any association of TNFa2 or TNFa9 with any of the HLA-DRB1 alleles. In contrast, the frequency of the TNFa13 allele was decreased in both the young-onset and the adult-onset IDDM patients compared to the control subjects, but the difference lost significance after the correction was made in the adult-onset IDDM. The TNFa13 allele was strongly associated with DRB1*1502. Patients with TNFa2 or TNFa9 had greater TNF-alpha production, while those positive for TNFa13 had lower TNF-alpha production than patients with non-TNFa2, a9, and a13 alleles. These results suggest that TNFa polymorphisms are associated with age-at-onset of IDDM and influence the inflammatory process of pancreatic beta cell destruction in the development of IDDM.
...
PMID:Influence of TNF microsatellite polymorphisms (TNFa) on age-at-onset of insulin-dependent diabetes mellitus. 1056 98

Recently, a novel gene for a putative transmembrane protein (WFS1/wolframin) was found to be mutated in patients with Wolfram syndrome or DI-DM-OA-D (diabetes insipidus, diabetes mellitus, optic atrophy, and deafness) syndrome. It is suggested that the WFS1 protein is important in the survival of islet beta-cells. We studied the WFS1 gene in a Japanese population to assess its possible role in common type 1 diabetes. Mutation screening revealed four missense mutations; R456H, G576S, H611R, and I720V. By genetic association studies of 185 type 1 diabetes patients and 380 control subjects, we found that R456H was significantly increased in the type 1 diabetes group compared to the control group (P = 0.0005); H611R and I720V were also significantly increased with weaker significance. Furthermore, in patients with the R456H mutation, type 1 diabetes-resistant HLA-DRB1 alleles (DRB1*0406, 1501, and 1502) were significantly increased compared to mutation-negative patients while susceptible DRB1*0901 was significantly decreased. Frequencies of autoimmunity characteristics (ICA or GAD-Ab positiveness and combination of autoimmune thyroid disease) were decreased in the R456H-positive patients compared to the R456H-negative patients. These data suggest that the WFS1 gene may have a role in the development of common type 1 diabetes as a nonautoimmune genetic basis.
...
PMID:Missense variations of the gene responsible for Wolfram syndrome (WFS1/wolframin) in Japanese: possible contribution of the Arg456His mutation to type 1 diabetes as a nonautoimmune genetic basis. 1067 52

Type 1 diabetes mellitus (IDDM) results from a chronic process of autoimmune destruction of beta cells of the Langerhans islets. The presence of autoantibodies (ICA, GADA, anti-IA2, IAA) in serum precedes the clinical onset of the disease. Genetic predisposition for IDDM is connected with HLA, CTLA-4 and insulin gene region. The aim of the study was the genetic and immunological analysis of a triplet. One of them developed Type 1 diabetes mellitus. We analysed HLA class II, CTLA-4 and insulin gene polymorphisms in the whole family. Besides, we investigated immunological status of three brothers. All patients present identical genotype for VNTR loci: D1S80, D17S5 and Apo B, as well as for HLA-DRB1, -DQA1, -DQB1, CTLA-4 gene and all studied insulin gene polymorphisms. That proves their monozigosity. The triplet presents strong genetic predisposition for IDDM. The two patients without overt diabetes have increased levels of ICA, GADA, IA2 and IAA.
...
PMID:Type 1 diabetes and prediabetic state in a monozygotic triplet. 1091 59

The BAT2 gene lies within the class III region of the major histocompatibility complex. We investigated the frequency of the BAT2 microsatellite alleles (BAT2) in 74 young-onset insulin-dependent diabetes mellitus (IDDM) patients, 51 adult-onset IDDM patients, and 85 normal control subjects, and assessed the associations among these BAT2 alleles, TNFa microsatellite alleles (TNFa), and HLA-DRB1 alleles. The frequency of the BAT2.9 allele was significantly increased in the young-onset IDDM patients (12.8 vs 4.1%, Pc=0.04896), whereas the frequency of BAT2.12 allele was significantly decreased in young-onset IDDM patients (0.0 vs 11.8%, Pc=0.00002) compared with control subjects. The BAT2.9 allele was strongly associated with TNFa9 in the young-onset IDDM patients, although no association was found between the BAT2.9 and HLA-DRB1 alleles. The BAT2.12 allele was strongly associated with TNFa13, and with DRB1*1502 in control subjects. These results suggest that the BAT2 microsatellite polymorphism is associated with the age-at-onset of IDDM and possibly with the inflammatory process of pancreatic beta-cell destruction during the development of IDDM. However, this association is not independent of TNFa polymorphisms.
...
PMID:Genetic contribution of the BAT2 gene microsatellite polymorphism to the age-at-onset of insulin-dependent diabetes mellitus. 1098 45

Insulin-dependent neonatal diabetes mellitus (NDM) is a rare form of diabetes with a heterogeneous genetic background. The HLA-DRB1 and DQB1 genotypes were determined for 13 patients with NDM, from 9 unrelated families. Four patients had permanent NDM (PNDM) and 9 patients had transient NDM (TNDM). No excess of HLA susceptibility markers for type 1 diabetes (IDDM) was observed in this series of patients, whatever the forms of diabetes PNDM or TNDM. Paternal isodisomy of chromosome 6 was observed in two TNDM cases. These observations are consistent with the current hypothesis that there is a recessive susceptibility gene, at least in the transient form of the disease, unlinked to the MHC locus on chromosome 6. Although established in a short series, our results do not support an additive role of IDDM1 in the progression of the disease.
...
PMID:HLA-DRB1 and DQB1 genotypes in patients with insulin-dependent neonatal diabetes mellitus. A study of 13 cases. 1103 57

From 1991 to 1998 we vaccinated 4835 neonates against hepatitis B virus (HBV) and monitored their humoral response to the recombinant vaccine. In a sample of 184 of these babies we studied the association between HLA class I and II genomic polymorphisms and humoral response to the vaccine and the association between the response and immune-mediated diseases. A subgroup of 96 babies also underwent HLA class III (C4A and C4B) typing. Four levels of humoral response were identified, each with a peculiar MHC restriction. Different HLA products seem to act as agonists (C4AQ0 and HLA-DQB1(*)02) or antagonists (C4AQ0, HLA-DQB1(*)02, and HLA-DRB1(*)11, DQB1(*)0301) in lowering humoral response to HBV vaccine. The group of responders was characterized more for lacking "nonresponder" alleles than for having specific "responder" ones. Tolerance to HBV peptides may have clinical implications, possibly being a marker for babies with a genetic risk of immunopathologies. In fact, many of the poor responders carried from two to four HLA-DQ alpha beta heterodimers predisposing to insulin-dependent diabetes mellitus and celiac disease. Two true nonresponders suffered from allergies and two slow responders had transient episodes of hyperglycemia.
...
PMID:Humoral response to recombinant hepatitis B virus vaccine at birth: role of HLA and beyond. 1111 62

Type 1 diabetes mellitus is a common disease with a complex mode of inheritance. Its aetiology is underpinned by a major locus, insulin-dependent diabetes mellitus 1 (IDDM1) in the human leukocyte antigen (HLA) region of chromosome 6p21, and an unknown number of loci of lesser individual effect. In linkage analyses IDDM1 is a single peak, but it is evident that the linkage is caused by allelic variation of three adjacent genes in a 75 kb region, namely the class II genes, HLA-DRB1, -DQA1 and -DQB1. However, even these three genes may not explain all of the HLA association. We investigated, in the founder population of Sardinia, whether non-DQ/DR polymorphic markers within a 9.452 Mb region encompassing the whole HLA complex further influence the disease risk, after taking into account linkage disequilibrium with the disease loci HLA-DQB1, -DQA1 and -DRB1. We generalized the conditional association test, the haplotype method, to detect marker associations that are independent of the main DR/DQ disease associations. Three regions were identified as risk modifiers. These associations were not only independent of the polymorphic exon 2 sequences of HLA-DQB1, -DQA1 and -DRB1, but also independent of each other. The individual contributions of these risk modifiers were relatively modest but their combined impact was highly significant. Together, alleles of single nucleotide polymorphisms at the DMB and DOB genes, and the microsatellite locus TNFc, identified approximately 40% of Sardinian DR3 haplotypes as non-predisposing. This conditional analysis approach can be applied to any chromosome region involved in the predisposition to complex traits.
...
PMID:Conditional linkage disequilibrium analysis of a complex disease superlocus, IDDM1 in the HLA region, reveals the presence of independent modifying gene effects influencing the type 1 diabetes risk encoded by the major HLA-DQB1, -DRB1 disease loci. 1128 54

It has been postulated that variation in the distribution of human leukocyte antigen (HLA)-encoded susceptibility alleles for insulin-dependent diabetes mellitus (IDDM) is the genetic basis for variation in the incidence of the disease between populations. The aim of this study was to characterize HLA-encoded susceptibility to IDDM in Hungary and to identify whether HLA-DRB1/DQ-encoded susceptibility could account for the five times lower incidence of disease in Hungary compared with Finland. The haplotypes DRB1*03-DQA1*05-DQB1*02 (DRB1*03-DQ2) and DRB1*04-DQA1*0301-DQB1*0302 (DRB1*04-DQ8) were significantly associated with disease in both populations. Three genotypes incorporating either or both of these haplotypes accounted for over 70% of the diabetic population in both races. The combined background frequency and the degree of risk as measured by odds ratios of these HLA-DRB1-DQ genotypes were not significantly different in the two countries. Comparison of the DRB1*0401-DQ8 haplotype between the two races suggested a role for HLA-B alleles in susceptibility. These data indicate that the susceptibility associated with high risk DRB1-DQ genotypes alone is insufficient to account for the fivefold variation in incidence of IDDM between Hungary and Finland. Other genetic and/or environmental influences must be involved.
...
PMID:HLA alleles and IDDM in children in Hungary: a comparison with Finland. 1129 72

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


<< Previous 1 2 3 4 5 6 7 8 Next >>

---