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)

The aim of this study was to test the hypothesis that HLA-DRB1, -DQA1, and -DQB1 subgroups or angiotensin-converting enzyme (ACE) gene polymorphisms are associated with severe retinopathy in younger Type 1 diabetic patients. Twenty-four Type 1 diabetic patients who had received panretinal photocoagulation for severe nonproliferative or proliferative diabetic retinopathy were compared with 24 Type 1 diabetic patients (participating in a photographic screening program with regular fundus examinations) with no or minimal retinopathy, matched for age at onset and duration of diabetes. The HLA-DRB1-DQA1-B1 haplotype 04-03-0302 represented 22/48 (46%) in the severe and 21/48 (44%) in the no/minimal retinopathy group, respectively (n.s.). The most common genotype, 03-0501-0201/04-03-0302, occurred in 8/24 (33%) with severe and 10/24 (42%) with no/minimal retinopathy, respectively (n.s.). There were no statistical differences between patients with severe and no/minimal retinopathy whether DRB1, DQA1, or DQB1 alleles, haplotypes, or genotypes were analysed. The ACE gene polymorphism was almost identical between patients with severe and no/minimal retinopathy, and serum ACE levels did not differ. Thus, in the present study on a small group with carefully characterised diabetic retinopathy phenotypes, there was no indication that HLA-DRB1, -DQA1, and -DQB1 subtypes or ACE gene polymorphisms were associated with severe retinopathy in younger Type 1 diabetic patients.
J Diabetes Complications
PMID:HLA-DRB1, -DQA1, and -DQB1 subtypes or ACE gene polymorphisms do not seem to be risk markers for severe retinopathy in younger Type 1 diabetic patients. 1501 97

Type 1 diabetes (T1D) mellitus is a multifactorial autoimmune disease where more than 90% of insulin-producing pancreatic beta cells are destroyed before the clinical manifestations, warranting a need to identify the children predisposed to get the disease. Of the 20 genomic intervals implicated for the risk to develop T1D, the major histocompatibility complex (MHC) region on chromosome 6p21.31 (IDDM1) has been the major contributor, followed by 5' regulatory region of the insulin (INS) gene on chromosome 11p15.5 (IDDM2). MHC has a role in antigen presentation and IDDM2 has been shown to have a role in transcription of insulin in the thymus. Hence, alleles of human leukocyte antigen (HLA)-DRB1, DQB1, and insulin-linked variable number of tandem repeats (INS-VNTR) were studied in 110 T1D patients and 112 healthy controls using polymerase chain reaction and hybridization with sequence-specific oligonucleotide probes (PCR-SSOP) and PCR restriction fragment length polymorphism (PCR-RFLP), respectively. HLA-DRB1*0301 was significantly increased in the T1D patients along with associated DQB1*0201 followed by DRB1*0401 and DRB1*0405. DRB1*0701 was observed to be the most protective allele followed by DRB1*0403 and DRB1*0404. Although DQB1*0302 which is associated with both the protective and susceptible DR4 alleles was not significantly increased, heterozygous DQB1*0201, *0302 was significantly increased in the TID patients. Because INS-VNTR class I homozygosity was also significantly increased in the patients, simultaneous presence of DRB1*0301 along with homozygous INS-VNTR class I, gave a relative risk (RR) of 70.81. However, a similar analysis of DQB1*0201 and *0302 along with INS-VNTR alleles did not give such high RRs. Thus, the two independently assorting alleles at two loci i.e., DRB1*0301 and INS-VNTR class I, on two different chromosomes may have the potential to predict a prediabetic in North India.
 ...
PMID:Molecular basis of predisposition to develop type 1 diabetes mellitus in North Indians. 1524 69

Genetic associations between type 1 diabetes and alleles at the HLA class II locus DPB1 have been previously reported. Observed associations could be due to variation in the DPB1 locus itself or to linkage disequilibrium (LD) between DPB1 alleles and other susceptibility loci. One measure of whether the association of an allele with a disease reflects a true effect of the locus or is simply due to LD is the observation of that association in multiple ethnic groups. Previous type 1 diabetes associations have been reported for DPB1*0301 and DPB1*0202 (predisposing) and for DPB1*0402 (protective). In this study, results are reported from testing these associations in three different sample sets: 1) Puerto Rican case and control subjects, 2) Mexican-American simplex families, and 3) high-risk (DR3/DR4) individuals with and without an affected relative. DPB1*0301 was associated in all three groups, even after accounting for LD with DRB1-DQB1. DPB1*0202 and DPB1*0402 were positively and negatively associated, respectively, in two of the three populations. These results suggest that the observed DPB1 associations, especially that of the DPB1*0301 allele, with type 1 diabetes are likely to be true associations. This supports the concept that multiple genes in the HLA region can affect type 1 diabetes susceptibility.
Diabetes 2004 Aug
PMID:DPB1 alleles are associated with type 1 diabetes susceptibility in multiple ethnic groups. 1527 1

The autoimmune disease process leading to childhood-onset type 1 diabetes appears to start in infancy, and decisions on treatment to prevent initiation of autoimmunity will need to be based on genetic susceptibility alone. We set out to quantify the absolute risk associated with human leukocyte antigen (HLA) DRB1-DQA1-DQB1 class II genotypes and to develop strategies for recruitment into primary prevention trials. HLA class II haplotype- and genotype-specific risks were derived from 753 United Kingdom families from the Bart's-Oxford population-based study of type 1 diabetes and combined with incidence data from the region to calculate the absolute risk of development of diabetes. A hierarchy of susceptibility was established for both HLA class II haplotypes and genotypes, and the sensitivity and specificity of each genotype was established relative to age at disease onset. Highest risk was conferred by the genotype DRB1*03-DQA1*0501-DQB1*0201/DRB1*0401-DQA1*0301-DQB1*0302 (5% absolute risk of diabetes by age 15 yr), although sensitivity was only 22.6%. Combining the six highest risk genotypes conferred similar risk but increased sensitivity to 36.6% and was most sensitive for diagnosis of diabetes before age 5 yr (48.4%), whereas inclusion of 11 genotypes achieved the same sensitivity for diagnosis for ages 10-14 yr. Analysis of genotype-specific risk should form the basis for design of future primary prevention trials in the general population.
 ...
PMID:Absolute risk of childhood-onset type 1 diabetes defined by human leukocyte antigen class II genotype: a population-based study in the United Kingdom. 1529 46

The heterozygous combination of DQA1*03-DQB1*0302 (DQ8) and DQA1*05-DQB1*0201 (DQ2) confers the highest known HLA-DQ-linked risk for type 1 diabetes, suggesting a role for transcomplementation. The trans-heterodimer encoded by DQA1*03 and DQB1*02 is also rarely observed in cis in whites. Islet antibody-positive diabetic patients (P; n = 2,238) and control subjects (C; n = 2,223) of white descent were genotyped by a HLA-DQA1-DQB1 dot-blot method. The presence of the DQA1*03-DQB1*02 haplotype was observed in 22 patients (1%) versus 6 controls (0.3%) (odds ratio [OR] = 3.7, p = 0.005). It was more prevalent in whites of Northern African descent, but both in European (n = 3,813) and in Northern African whites (n = 648), the DQA1*03-DQB1*02 haplotype tended to be associated with diabetes (respectively, P 0.3% vs. C 0.03%, OR = 12.2, p = 0.005; and P 2.1% vs. C 0.6%, OR = 3.8, p = 0.03). DRB1 typing revealed that DQA1*03-DQB1*02 is usually associated with the DRB1*0405 risk allele in European patients and with DRB1*0405, DRB1*07 and DRB1*09 in Northern African whites. Like in DQ2/DQ8-positive patients, the presence of DQA1*03-DQB1*02 is preferentially associated with younger age at clinical onset than in other genotypes, but unlike in subjects carrying DQ2/DQ8, earlier clinical manifestation was mostly restricted to male subjects, often carrying DR3 and/or DQB1*02 on the other chromosome. These results are compatible with an effect of cis-encoded heterodimers or with previously suggested interactions of X-linked genetic factors with (DR3-)DQB1*02 haplotypes.
 ...
PMID:The rare HLA-DQA1*03-DQB1*02 haplotype confers susceptibility to type 1 diabetes in whites and is preferentially associated with early clinical disease onset in male subjects. 1530 63

DRB1*030101 is a major genetic risk factor for type 1 diabetes mellitus (T1DM) and is the only DRB1*03 allele usually seen in T1DM probands. Approximately 16% of parental DRB1*030101 alleles were not transmitted to T1DM probands in our Genetics of Kidneys and Diabetes study trio families. We performed a polymorphism screen to determine whether variations exist in DRB1*030101 alleles outside of exon 2 that may modify risk for developing T1DM. A combination of long-range and sequence-specific priming polymerase chain reaction was used to amplify a hemizygous template from both transmitted and nontransmitted parental DRB1*030101 chromosomes. Exon 2 DRB1*030101-specific and flanking DRB1-specific primers amplified the entire genomic locus as a 10.6-kb 5' fragment and a 5.3-kb 3' fragment, respectively. All exons and intron/exon borders of introns 1 and 2, all of introns 3-5, and flanking regulatory regions of 32 transmitted and 31 nontransmitted alleles (99% power to detect a 5% minimal allele frequency) were analyzed through fluorescent DNA sequencing. The only polymorphic sites detected, a previously described intron 2 complex dinucleotide repeat and an additional complex repeat approximately 1.8 kb downstream of exon 6, do not significantly differ between T1DM patients and controls in this small data set.
 ...
PMID:Polymorphism scan for differences between transmitted and nontransmitted DRB1*030101 alleles outside of exon 2 for type 1 diabetes: the frequency of polymorphisms is similar. 1530 64

In this study, we have investigated the frequencies of TAP1 and TAP2 alleles in a group of 226 persons, living in La Reunion Island, consisting of 70 patients with insulin-dependent diabetes mellitus (IDDM) and most of their first degree relatives (i.e., 156 parents and full sibling subjects) and previously HLA DQB1, DQA1, and DRB1 genotyped. The population of this island is constituted by a particular structure of highly crossbreeding people. Interestingly, the new TAP2*0104 allele, previously discovered by our team in Reunion Island, was found to be increased in the IDDM population and the calculated HRR was relatively high (HRR = 3.3). This result seems to be due to a positive linkage disequilibrium between TAP2*0104 allele and the highly diabetogenous DQB1* 0201-DQA1* 0501-DRB1 0301 haplotype (HRR = 9), which suggests that TAP2*0104 cannot be considered as an additional predispositional factor, but more as a genetic susceptibility marker of IDDM. In addition, we show that minor alleles (TAP2D, *0102, *0103, *0104) are associated with a restricted number of HLA DQ-DR haplotypes and each of them exhibits a preferential linkage with one particular haplotype. In contrast with other alleles, and despite a HRR value close to 1, we show that TAP2*0102 allele contributes significantly to a drastic reduction of the diabetogenic effect of DQB1*0201-DQA1*0301.1-DRB*0701 haplotype. Indeed, this haplotype, which is usually preferentially transmitted to affected children, is dominantly transmitted to healthy children when it is associated with TAP2*0102. Therefore, this allele seems to contribute to genetic protection to IDDM.
 ...
PMID:Is TAP2*0102 allele involved in insulin-dependent diabetes mellitus (type 1) protection? 1533 79

There is still uncertainty concerning the joint action of the two established type 1 diabetes susceptibility loci, the HLA class II DQB1 and DRB1 genes (IDDM1) and the insulin gene (INS) promoter (IDDM2). Some previous studies reported independence, whereas others suggested heterogeneity in the relative effects of the genotypes at these disease loci. In this study, we have assessed the combined effects of the HLA-DQB1/DRB1 and INS genotypes in 944 type 1 diabetic patients and 1,023 control subjects, all from Sardinia. Genotype variation at INS significantly influenced disease susceptibility in all HLA genotype risk categories. However, there was a significant heterogeneity (P = 2.4 x 10(-4)) in the distribution of the INS genotypes in patients with different HLA genotypes. The INS predisposing genotype was less frequent (74.9%) in high-risk HLA genotype-positive patients than in those with HLA intermediate-risk (86.1%) and low-risk (84.8%) categories. Gene-gene interaction modeling led to rejection of the additive model, whereas a multiplicative model showed a better, albeit still partial, fit to the observed data. These genetic results are consistent with an interaction between the protein products of the HLA and INS alleles, in which both the affinity of the various HLA class II molecules for a preproinsulin-derived peptide and the levels of this peptide in the thymus act jointly as key regulators of type 1 diabetes autoimmunity.
Diabetes 2004 Dec
PMID:Heterogeneity in the magnitude of the insulin gene effect on HLA risk in type 1 diabetes. 1556 61

Type 1 diabetes (T1D) is frequently associated with other autoimmune diseases. The occurrence of common features of autoimmune diseases and the coassociation of multiple autoimmune diseases in the same individual or family support the notion that there may be common genetic factors. We previously reported that immunogenetic markers of T1D were similar in Korean and U.S. families. We hypothesized that nonislet autoimmunity might be expressed in a similar manner in Korean as well as in Caucasian patients and correlated with the DRB1-DQB1 haplotypes. Twenty-five percent of Korean patients with T1D (32/128) had antithyroid autoantibodies (ATA+), whereas eight percent of age-matched controls were ATA+ [OR = 3.7 (95% CI:1.0-12.0), P < 0.05]. Twenty-three percent (84/369) of age-matched T1D patients from the U.S. had ATA (not statistically different from that in Koreans). None of the Korean patients nor the family members were positive for 21-hydroxylase (21OH) or transglutaminase autoantibodies (TG). In contrast, in U.S. patients, nine T1D patients (2.4%) were 21OH+ (not statistically different from that in Koreans) and 39 T1D patients (10.6%) were TG+ [OR = 30.7 (95% CI: 4.6-111), P < 10(-4) vs. Korean patients]. Nonislet autoimmunity is prevalent in Korean and U.S. patients with T1D and their family members, but specific forms of autoimmunity differ even after matching for their HLA haplotypes. Individuals with T1D and their relatives frequently develop a panel of autoantibodies, perhaps due to other common susceptibility genes that are shared among first-degree relatives.
 ...
PMID:Differential expression of nonislet autoimmunity: comparison of Korean and U.S. patients with type 1 diabetes. 1569 95

Mechanisms for observed associations within the major histocompatibility complex (MHC) and autoimmune diseases including multiple sclerosis (MS) remain uncertain. Genotyping of the HLA Class II DRB1 locus in 4347 individuals from 873 multiplex families with MS highlights the genetic complexity of this locus. Excess allele sharing in sibling pair families lacking DRB1*15 and DRB1*17 (58.5% sharing; P=0.012) was comparable to that seen where parents were DRB1*15 positive (62%, P=0.0006). DRB1*17 (P=0.00027) was clearly established as an MS susceptibility allele in addition to DRB1*15 (P<10(-14)). DRB1*14 showed striking under-transmission (P=0.000032) to affected offspring newly establishing this allele as a broadly acting resistance factor. Trans interactions were seen in both DRB1*15 and non-DRB1*15 bearing genotype combinations. DRB1*08 was transmitted preferentially with DRB1*15 (P=0.0114) and, in the presence of DRB1*08, the transmission of DRB1*15 was almost invariable (37 transmissions to one non-transmission). DRB1*01 was under-transmitted to offspring in the presence of DRB1*15 (P=0.019). Both DRB1*01 and DRB1*14 haplotypes carry DQA1*01-DQB1*05 alleles, suggesting a common DQ-related mechanism for the protection mediated by these haplotypes. These studies demonstrate that it is the Class II genotype that determines susceptibility and resistance to MS. By analogy with celiac disease and type I diabetes, the pattern of susceptibility strongly supports an autoimmune aetiology.
 ...
PMID:Complex interactions among MHC haplotypes in multiple sclerosis: susceptibility and resistance. 1593 13


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