Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0011849 (diabetes)
 277,896 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

There is evidence that certain alleles at the HLA-DQ locus are correlated with susceptibility to insulin-dependent diabetes mellitus (IDDM) and in particular that DQ beta-chain alleles containing aspartic acid at position 57 are protective. The availability of a large group of patients with IDDM enabled us to assess the role of HLA-DQ alleles in susceptibility to the disease in order to confirm and extend recent observations derived from studies of smaller numbers of patients. Using allele-specific oligonucleotide probes and the polymerase chain reaction, we studied 266 unrelated patients with IDDM and 203 unrelated normal subjects for eight HLA-DQ beta-chain alleles. Two major findings emerged from these studies. First, the presence of an HLA-DQw1.2 allele was protective. Only 6 of the 266 patients with IDDM (2.3 percent) were positive for HLA-DQw1.2, as compared with 74 of the 203 normal subjects (36.4 percent; P less than 0.001). Thus, persons with the HLA-DQw1.2 allele, which is one of the polymorphic forms of the beta chain of the HLA-DQ molecule, rarely had IDDM, no matter which other HLA-DQ beta-chain allele they inherited ("dominant protection"). Second, the presence of the HLA-DQw8 allele increased the risk of IDDM. The relative risk of IDDM was 5.6 in persons homozygous for HLA-DQw8, and it was similar in persons with the HLA-DQw1.1/DQw8 or HLA-DQw2/DQw8 haplotype ("dominant susceptibility"). However, the relative risk of IDDM in persons who had the HLA-DQw1.2/DQw8 haplotype was 0.37, demonstrating that the protective effect of HLA-DQw1.2 predominated over the effect of HLA-DQw8. We conclude that the presence of the HLA Class II antigen DQw1.2 is strongly protective against the development of IDDM, and that complete HLA-DQ typing is necessary for accurate assessment of susceptibility to IDDM.
 ...
PMID:Analysis of HLA-DQ genotypes and susceptibility in insulin-dependent diabetes mellitus. 234 40

HLA DQ beta chain, in particular amino acid at position 57, has been reported to contribute to susceptibility and resistance to Type 1 (insulin-dependent) diabetes mellitus in Caucasians. Resistance has been proposed to be conferred by aspartic acid at this position. To ascertain the association of HLA DQ beta and DR beta genes with Type 1 diabetes in Japanese subjects, ten Japanese Type 1 diabetic patients were investigated at DNA level. Genomic DNA was amplified by polymerase chain reaction, and dot blot analysis was carried out using the amplified DNA with allele specific oligonucleotide probes. All patients had aspartic acid at position 57 of at least one of their two DQ beta chains, and there was no significant difference of amino acids at the same position of DR beta chain in patients compared to control subjects. These data indicate that the protective role of aspartic acid at position 57 of DQ beta chain is less significant in Japanese compared with Caucasian subjects.
 ...
PMID:Aspartic acid at position 57 of DQ beta chain does not protect against type 1 (insulin-dependent) diabetes mellitus in Japanese subjects. 251 91

Type 1 (insulin-dependent) diabetes mellitus, like some other autoimmune diseases, is linked to certain alleles coded by genes in the HLA-D region. Sequence analysis of DQ beta chains indicates that aspartic acid at codon 57 confers resistance to the development of Type 1 diabetes. However, a full explanation for the HLA-association of Type 1 diabetes, particularly the increased susceptibility of DR3/4 heterozygotes is still awaited. The localisation of tumour necrosis factor genes on the short arm of chromosome 6 between HLA-B and the complement genes (Class III) prompted us to investigate a possible polymorphism of TNF-alpha at the genomic level in relation to Type 1 diabetes susceptibility. A dialleleic TNF-alpha restriction fragment length polymorphism was found with Ncol and its segregation with HLA-haplotypes analysed in diabetic families. We describe here a strong linkage of TNF-alpha alleles with certain DR haplotypes. For example, the common extended haplotype HLA A1-B8-DR3 was almost exclusively associated with the 5.5 kb TNF-alpha allele whereas Bw62-DR4 with the 10.5 kb allele. Thus both alleles segregate to diabetic patients. DR matched haplotypes of affected family members differed significantly from those of the non-affected at the TNF alpha locus. All affected sibling pairs in 11 multiplex affected families were identical for TNF-alpha alleles, even if they were only haploidentical for HLA-B-DR haplotypes. In addition, heterozygosity for the TNF-alpha alleles was significantly more frequent in the patients. This tight linkage of TNF-alpha alleles with some extended haplotypes could help to explain the HLA-association of Type 1 diabetes as well as some other autoimmune diseases.
 ...
PMID:TNF-alpha gene polymorphisms in type 1 (insulin-dependent) diabetes mellitus. 257 98

In Caucasoids HLA-DQB1 genes encoding amino acids other than aspartic acid at position 57 of the DQ beta chain (non-Asp-57) are associated with susceptibility to develop insulin-dependent diabetes mellitus (IDDM), while resistance is associated with aspartic acid at this residue (Asp-57). Following amplification of genomic DNA by the polymerase chain reaction, the DQB1 alleles of 87 random Norwegian IDDM patients and 187 healthy controls were investigated with 11 different sequence-specific oligonucleotide probes. Of these patients 82% carried DQB1 alleles encoding non-Asp-57 at both of their DQ beta chains, compared to 27% of the controls (relative risk = 12.2, p less than 0.0001). Sixteen percent of the patients (versus 51% of the controls) were heterozygous Asp-57/non-Asp-57. Two percent of the patients (22% of the controls) were apparently Asp-57 homozygous. The results demonstrate that non-Asp-57 DQ beta chains are associated with susceptibility to develop IDDM but also indicate that the protection associated with DQ beta Asp-57 may not be as dominant as reported by others.
 ...
PMID:The amino acid at position 57 of the HLA-DQ beta chain and susceptibility to develop insulin-dependent diabetes mellitus. 260 46

A patient with type II diabetes associated with hyperproinsulinemia has been shown to have a point mutation in one insulin gene allele, resulting in replacement of histidine with aspartic acid at position 10 of the B-chain. To investigate the basis of the proinsulin processing defect, we introduced an identical mutation in the rat insulin II gene and expressed both the normal and the mutant genes in the AtT-20 pituitary corticotroph cell line. Cells expressing the mutant gene showed increased secretion of proinsulin relative to insulin and rapid release of newly synthesized proinsulin. Moreover, the mutant cell lines did not store the prohormone nor did they release it upon stimulation with secretagogues. These data indicate that a significant fraction of the mutant prohormone is released via the constitutive secretory pathway rather than the regulated pathway, thereby bypassing granule-related processing and regulated release.
 ...
PMID:Partial diversion of a mutant proinsulin (B10 aspartic acid) from the regulated to the constitutive secretory pathway in transfected AtT-20 cells. 265 40

The present knowledge of the HLA system and its biological function is summarized as a basis for the subsequent discussion of the associations between this system and insulin-dependent diabetes (IDDM) and some mechanisms that may explain them. Although the serologically detectable DR determinants are still the most handy markers, there is now increasing evidence from studies of restriction enzyme fragment length polymorphism (RFLP) in IDDM that DQ determinants may play a primary role in causing susceptibility and/or resistance to this disease. Thus, it is now evident that about 90% of DR4-positive diabetics carry the DQw8 determinant present in only about 65% of DR4-positive controls. Most recently, it has been claimed that an aspartic acid in position 57 of the DQB1 (DQ-beta-1) chain confers resistance to IDDM. Although this may be true, it does not explain the disproportionate decrease of DR2 or the particularly high risk of DR3/4 heterozygotes, which is still good evidence that several HLA genes are involved. Because Class II antigens show the strongest associations, the most plausible hypothesis about the mechanism(s) involves specific presentation of as yet unknown antigenic peptides to T-helper lymphocytes, which may induced the formation of both anti-islet cell antibodies and T-cytotoxic lymphocytes capable of destroying beta cells. However, T-suppressor lymphocytes also may be involved. If this hypothesis is correct, the most urgent task is to define the antigenic peptides in question, whether they are environmental (e.g., viral) or autologous.
 ...
PMID:HLA and insulin-dependent diabetes: an overview. 265 26

The HLA-DQ beta-chain gene shows a close association with susceptibility or resistance to autoimmune insulin-dependent diabetes mellitus (IDDM) and it has been suggested that the amino acid in position 57 may be of pathogenetic importance. To study the expression of the IDDM associated HLA-DQ beta-chain alleles, we immunized rabbits with 12 to 13 amino acid long peptides representing HLA-DQw7 and -DQw8 allelic sequences, differing only by one amino acid in position 57 being aspartic acid (Asp) and alanine (Ala), respectively. Immunoblot analysis of lymphoblastoid cells showed that several antisera recognized a 29-kDa protein, equivalent to the expected molecular size of the HLA-DQ beta-chain to yield two antisera specific for HLA-DQw7 (pos. 57Asp) and three antisera for HLA-DQw8 (pos. 57Ala) positive cells. Analysis of HLA-DR 3/4 positive IDDM patients (n = 24) and controls (n = 19) showed that all (100%) patients were positive for pos. 57Ala antiserum compared to 13 of 19 (68%) of the controls. The remaining six controls reacted with the pos. 57Asp antisera, whereas none of the patients did. We have therefore successfully been able to generate site-specific antibodies that distinguish single amino acid substitutions in predetermined positions of allelic HLA-DQ beta-chain gene products. Such sera should become useful to detect and investigate HLA associated susceptibility to autoimmune diseases in man.
 ...
PMID:Site-specific antibodies distinguish single amino acid substitutions in position 57 in HLA-DQ beta-chain alleles associated with insulin-dependent diabetes. 273 2

One hundred seventy-two members from 27 randomly selected multiple case Caucasian families of patients with insulin-dependent diabetes mellitus (IDDM) were studied at the DNA level to ascertain the reliability of codon 57 of the HLA-DQ beta-chain gene as a disease protection/susceptibility marker. The analysis was carried out by polymerase chain reaction amplification of DNA encoding the first domain of the DQ beta chain and by dot blot analysis of the amplified material with allele-specific oligonucleotide probes. One hundred twenty-three randomly selected healthy Caucasian donors were also tested. The results demonstrated that haplotypes carrying an aspartic acid in position 57 (Asp-57) of their DQ beta chain were significantly increased in frequency among nondiabetic haplotypes (23/38), while non-Asp-57 haplotypes were significantly increased in frequency among diabetic haplotypes (65/69). Ninety-six percent of the diabetic probands in our study were homozygous non-Asp/non-Asp as compared to 19.5% of healthy unrelated controls. This conferred a relative risk of 107 (chi 2 = 54.97; P = 0.00003) for non-Asp-57 homozygous individuals. Even though the inheritance and genetic features of IDDM are complex and are not necessarily fully explained by DQ beta chain polymorphism, this approach is much more sensitive than HLA serolog in assessing risk for IDDM.
 ...
PMID:Aspartic acid at position 57 of the HLA-DQ beta chain protects against type I diabetes: a family study. 318 14

Gruppuso et al. [Gruppuso, P.A., Gordon, P., Kahn, C. R., Cornblath, M., Zeller, W. P. & Schwartz, R. (1984) N. Engl. J. Med. 311, 629-634] have recently described a family in which hyperproinsulinemia is inherited in an autosomal dominant pattern, suggesting a structural abnormality in the proinsulin molecule as the basis for this disorder. However, unlike two previous kindreds with a similar syndrome, the serum proinsulin-like material in this family did not appear to be an intermediate conversion product but instead behaved like normal human proinsulin by several criteria. To further characterize this disorder we isolated and sequenced the insulin gene of the propositus. Leukocyte DNA was cloned into lambda-WES and recombinants containing the two insulin alleles, lambda MD41 and lambda MD51, were isolated by plaque hybridization. DNA sequencing of lambda MD51 showed that it contained the normal coding sequence for human preproinsulin. Sequence analysis of lambda MD41, however, revealed a single nucleotide substitution in the codon for residue 10 of proinsulin (CAC----GAC) that predicts the exchange of aspartic acid for histidine in the insulin B chain region. This mutation was also found in an insulin allele cloned from a second affected family member (propositus's father). These results, along with the linkage analysis of Elbein et al. [Elbein, S.C., Gruppuso, P., Schwartz, R., Skolnick, M. & Permutt, M.A. (1985) Diabetes 34, 821-824], strongly implicate this mutation as the cause of the hyperproinsulinemia in this family. Inhibition of the conversion of proinsulin to insulin may be related to altered folding and/or self-association properties of the [Asp10]proinsulin.
 ...
PMID:A mutation in the B chain coding region is associated with impaired proinsulin conversion in a family with hyperproinsulinemia. 347 Jul 84

An alpha-amylase inhibitor isolated from Streptomyces tendae, strain 4158 was re-purified by chromatography on CM- and DEAE-cellulose column. Two inhibitors could be characterized: alpha-amylase inhibitor Hoe-467 A (with aspartic acid as N-terminal residue), and alpha-amylase inhibitor Hoe-467 S (with serine as N-terminal residue). The primary structure was determined by automatic Edman-degradation procedures of the aziranized inhibitor and tryptic peptides, derived from digestions of the performic oxidized, aziranized and maleylated inhibitor, respectively. The alpha-amylase inhibitor Hoe-467 A consists of 74 residues and has a calculated molecular weight of 7958. It is composed of all common amino acids except methionine and phenylalanine. Digestion with pepsin was carried out to determine the disulfide bonds. Two fractions could be isolated, containing one cystine each giving information about the positions of the disulfide bridges. The possible clinical application of the inactivator (diabetes mellitus) is pointed out.
 ...
PMID:[The sequence of the alpha-amylase inhibitor Hoe-467 A (alpha-amylase inactivator Hoe-467 A) from Streptomyces tendae 4158]. 616 65


<< Previous 1 2 3 4 5 6 7 8 9 10 Next >>