Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0011854 (type 1 diabetes)
 20,749 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

There is strong evidence that DQB1, DQA1, and DRB1 alleles are not the only contributors to the human leukocyte antigen (HLA) linked type 1 diabetes (T1D) predisposition. Although the HLA complex is much studied for disease association, little is known about the neighboring centromeric region. We have previously found suggestive association on DQ2-DR3 haplotypes for marker D6S291, located 3.6-Mb centromeric of HLA-DQB1. This region on human chromosome 6 is syntenic to a part of the region adjacent to the mouse major histocompatibility complex (MHC) on chromosome 17, which has been suggested to harbor a susceptibility gene in mouse (Idd16). To evaluate a possible role of the region centromeric of HLA-DQB1 in human T1D, we have scanned the region with nine microsatellite markers in 267 T1D families from five different populations. Our results indicate that the characteristic strong linkage disequilibrium in the HLA complex does not extend into this region. Furthermore, we did not detect any consistent T1D association for the markers analyzed in the study. In conclusion, our data argue against the presence of any strong genetic susceptibility factors for T1D in the region centromeric of the HLA complex.
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PMID:No evidence of type 1 diabetes susceptibility genes in the region centromeric of the HLA complex. 1452 92

Autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED) is caused by mutations in the autoimmune regulator (AIRE) gene, which has a central function in maintaining immunological tolerance. A number of conditions with proven or likely autoimmune pathogenesis occur in APECED: hypoparathyroidism, adrenocortical insufficency, candidiasis, hypogonadism, type 1 diabetes, hypothyroidism, hypophysitis, hepatitis, malabsorption, nail dystrophy, enamel hypoplasia and keratopathy. It is not clear which factors are responsible for variation in clinical picture of APECED, but human leukocyte antigen (HLA) genotype may be important. The authors report the first description of a case of primary pulmonary hypertension (PPH) in patient with APECED, caused by R257X mutation in AIRE. The HLA genotype of the patient (DRB1*01/DRB1*11, DQB1*0301/DQB1*0501) has been previously reported as a predisposing factor to PPH. The findings from this study, provided that other similar cases are reported, suggest that immune deregulation plays a role in the pathogenesis of primary pulmonary hypertension.
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PMID:Fatal primary pulmonary hypertension in a 30-yr-old female with APECED syndrome. 1458 26

Ketosis-prone diabetes is heterogeneous. Its causes could include novel beta-cell functional defects. To characterize such defects, 103 patients with diabetic ketoacidosis were evaluated for beta-cell autoimmunity and human leukocyte antigen (HLA) class II alleles, with longitudinal measurements of beta-cell function and biochemical and clinical parameters. They were classified into four A beta groups, based on the presence of glutamic acid decarboxylase (GAD)65, GAD67, or IA-2 autoantibodies (A+ or A-) and beta-cell functional reserve (beta+ or beta-). The group distribution was: 18 A+beta-, 23 A-beta-, 11 A+beta+, and 51 A-beta+. Collectively, the two beta- groups differed from the two beta+ groups in earlier onset and longer duration of diabetes, lower body mass index, less glycemic improvement, and persistent insulin requirement. HLA class II genotyping showed that the A-beta- group differed from the A+beta- group in having lower frequencies of two alleles strongly associated with autoimmune type 1 diabetes susceptibility: DQA*03 and DQB1*02. Similarly, the A-beta+ group differed from the A+beta+ group in having a lower frequency of DQB1*02. Ketosis-prone diabetes comprises at least four etiologically distinct syndromes separable by autoantibody status, HLA genotype, and beta-cell functional reserve. Novel, nonautoimmune causes of beta-cell dysfunction are likely to underlie the A-beta+ and A-beta- syndromes.
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PMID:Ketosis-prone diabetes: dissection of a heterogeneous syndrome using an immunogenetic and beta-cell functional classification, prospective analysis, and clinical outcomes. 1460 30

In addition to the known human leukocyte antigen (HLA)-associated risk, polymorphisms of insulin gene region show association with type 1 diabetes. We analyzed possible interactions between the HLA class II genotypes and -2221 MspI (insulin) INS gene polymorphism in Finnish population, using a series of 1331 diabetic children and 2222 healthy newborns. C/C genotype was increased among diabetic children compared to the controls (83.2 vs 70.1%). This genotype was slightly more common in diabetic children with low or moderate HLA-associated risk than in those with high risk, but INS gene effect was clear in all major HLA-risk genotypes and, thus, can be used as an additional risk prediction marker, irrespective of HLA genotypes.
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PMID:The human leukocyte antigen genotype has a modest effect on the insulin gene polymorphism-associated susceptibility to type 1 diabetes in the Finnish population. 1465 26

Type 1 diabetes is a multifactorial disease in which the genes of the major histocompatibility complex (MHC) play a key role. Recently, non-human leukocyte antigen (non-HLA) genes in the class III region of this complex have been presumed to be associated with type 1 diabetes by linkage analyses. We investigated the possibility of the inhibitor of kappaB-like (IKBL, also known as 'NFKBIL1') gene as one of these candidates. We carried out a case-control study of 124 patients with type 1 diabetes and 330 healthy control subjects. The haplotypes of the IKBL promoter, i.e., PA (-263A, -63T), PB (-263A, -63A), PC (-263G, -63T), were assigned by the single-nucleotide polymorphisms at positions -263 and -63 from the transcription start site. The frequency of the wild-type haplotype, PA, was elevated, while that of the variant-type haplotype, PC, was lower in patients than controls. In two-locus analyses with HLA-DRB1 alleles, the PA haplotype showed linkage disequilibrium with the DRB1*0405 allele and the PC haplotype with the DRB1*1502 allele. A notable observation was that the PC haplotype was significantly associated with protection in the DRB1*1502-negative population. Our study indicates the first evidence of a possible independent association between type 1 diabetes and polymorphisms in the promoter of the IKBL gene.
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PMID:IKBL promoter polymorphism is strongly associated with resistance to type 1 diabetes in Japanese. 1498 11

In cord blood banking, substantial amounts of data on infants and cord blood are gathered at high cost, including birth weights and human leukocyte antigen (HLA) genotypes. As certain HLA alleles have been associated with protective host responses, it is possible that an HLA allele, or another factor linked to it, might even affect normal intrauterine growth. We explored cord blood bank data (n = 1381 infants) to elucidate whether there is an association between birth weight and HLA class II (DRB1) alleles. HLA DRB1 data were available from 1263 infants. We observed an association between birth weight and HLA DRB1*13, which was over-represented among full-term infants with the highest birth weights. The association remained when the birth weight was corrected for varying gestational age (relative birth weight) according to gender (P = 0.015). After correction of the P-value for multiple comparisons, the association was not statistically significant. However, when the birth weights of all infants were analysed for the effect of DRB1*13, infants positive for HLA DRB1*13 (n = 319) were found to have higher birth weights than infants negative for this allele (n = 944; median 3690 g vs. 3650 g, respectively; P = 0.044). Although the difference in median birth weight was only 40 g, it may be considered significant because it appeared after segregation of the infants into two groups according to the single HLA class II allele group earlier associated with protection against, for example, childhood type 1 diabetes and certain infectious diseases. The present finding may thus suggest identification of a new factor affecting normal intrauterine growth.
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PMID:High birth weight is associated with human leukocyte antigen (HLA) DRB1*13 in full-term infants. 1500 77

The need for blood samples in genetic epidemiologic studies often leads to low response rate among non-diseased individuals, and the collection of blood samples is costly and labor-intensive. We tested the feasibility of extracting DNA for human leukocyte antigen (HLA) typing from buccal cells collected with mailed, self-administered mouth brushes. A random sample of 1474 Norwegian children aged 0-17 yr was contacted by mail and received information about the study and mouth brushes for buccal cell samples. Brushes were returned by mail, DNA was extracted and the HLA-DQA1 and -DQB1 allelic polymorphisms were determined using polymerase chain reaction (PCR) and sequence-specific oligonucleotide probes. Mouth swabs were returned from 1068 (72.5%). Of these, DNA was extracted and HLA typing successfully completed for 1056 individuals (98.9%). In conclusion, we have described an efficient and safe set of methods for application in genetic epidemiologic studies of type 1 diabetes and other HLA-related diseases. A large proportion of randomly selected children returned self-administered mouth swabs with DNA of sufficient quality and quantity for HLA genotyping.
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PMID:DNA extraction and HLA genotyping using mailed mouth brushes from children. 1501 62

To examine human leukocyte antigen (HLA) class II association of type 1 diabetes mellitus (DM) in Czech children, we performed a case-control study of 261 patients diagnosed before the age of 15 and 289 non-diabetic control children. Complete HLA-DQA1, DQB1 genotyping and DRB1*04 subtyping were carried out by polymerase chain reactions with sequence-specific primers. The effect of the DRB1*04 subtypes was studied in DRB1*04 alleles carried on DQB1*0302-DQA1*03 haplotypes. The risk was statistically evaluated by testing 2 x 2 tables, considering corrected p-values < 0.05 significant. The DQB1*0302 (odds ratio, OR = 9.0), DQB1*0201 (OR = 3.4) and DQA1*03 (OR = 7.5) alleles were significantly associated with diabetes risk, while the DQB1*0602 (OR = 0.02), DQB1*0301 (OR = 0.08), DQB1*0503 (OR = 0.13), DQB1*0603 (OR = 0.20), DQA1*01 (OR = 0.28) and DQA1*02 (OR = 0.26) alleles were significantly protective. Of the DQA1-DQB1 genotypes, we point out the extremely high risk of OR = 116 conferred by HLA-DQA1*05-DQB1*0201/DQA1*03-DQB1*0302. Among DRB1*04 subtypes, DRB1*0403 was significantly protective (OR = 0.05, CI 95% 0.01-0.45). Since none of the remaining DRB1*04 subtypes was associated with type 1 DM, our study may present another piece of evidence that the DRB1*0401 and DRB1*0404 alleles do not modify type 1 diabetes risk generally in European populations.
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PMID:HLA class II genetic association of type 1 diabetes mellitus in Czech children. 1501 91

Circulating antibodies to pancreatic beta-cell antigens are markers of islet autoimmunity. In first-degree relatives of persons with type 1 diabetes, the levels and range of antigen specificities of these islet antibodies reflect the risk for clinical diabetes. However, in the general population, in which the disease prevalence is up to 30-fold lower, the predictive value of islet antibodies is correspondingly less. Islet antibody assays are primarily research tools to identify 'prediabetic' individuals for secondary prevention trials, but can also discriminate type 1 diabetes in several clinical situations. Loss of first-phase insulin response (FPIR) to intravenous glucose signifies imminent diabetes, but FPIR is normal in most islet-antibody-positive individuals. The contribution of a single FPIR measurement to risk assessment is therefore limited, but rate of fall of FPIR may be a useful predictor. Although beta cells are destroyed by autoreactive T cells, the assay of islet antigen-reactive T cells is not routine. Genetically, the major histocompatibility complex encoding human leukocyte antigen (HLA) alleles accounts for about 50% of familial clustering of type 1 diabetes. HLA typing is not diagnostic, but can be used to differentiate high- from low-risk individuals, e.g. at birth. While 'preclinical' diagnosis raises important medical and ethical questions, an optimized screening strategy provides a basis for counselling and follow-up. Recent knowledge of disease mechanisms and 'proof-of-principle' in the non-obese diabetic (NOD) mouse model justify expectations that type 1 diabetes is preventable, and even intervention that only delays onset of clinical diabetes is likely to be cost-effective.
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PMID:Risk assessment, prediction and prevention of type 1 diabetes. 1501 1

Environmental agents are proposed to play a role in triggering or exacerbating pancreatic islet autoimmunity in people genetically predisposed to type 1 diabetes. However, with few exceptions, these agents remain enigmatic. Clues to environmental agents may be found by investigating population/geographic clusters or 'hotspots' of high disease incidence. We were alerted to a small community where the incidence of type 1 diabetes appeared to be five-fold higher than expected. Because type 1 diabetes is now recognized to have a subclinical phase during which anti-islet antibodies can be detected, we aimed to identify and characterize a reservoir of children with subclinical disease in this community. Venous blood samples were collected from 1906/2347 (81%) local school children during one week. Islet cell antibodies (ICAs) were detected in 122 (6.4%) children, 18 (0.9%) being high titer (> or = 20 Juvenile Diabetes Foundation units (JDFu)). On retest, 15 months later, the majority of low titer ICAs were undetectable, whereas high-titer ICAs persisted. The latter were found in two distinct age-related, ethnically similar groups. The younger group, aged 6-9 yr, had antibodies to insulin (IAAs), glutamic acid decarboxylase (GAD) and tyrosine phosphatase IA2 in addition to ICA, human leukocyte antigen (HLA) genes associated with susceptibility to type 1 diabetes, and lower first-phase insulin responses (FPIRs) to intravenous glucose. The older group, aged 13-16 yr, the age cohort of the index clinical cases, had few antibodies other than ICA, non-susceptibility HLA genes and normal FPIRs. During follow-up, three children, all from the younger group with multiple antibodies and FPIRs less than the first percentile, developed diabetes 4, 6 and 7 yr after screening. The finding of two age groups of subclinical disease suggests that if environmental agents triggered islet autoimmunity they did not act constantly on the community. Furthermore, the absence of multiple autoantibodies and/or HLA susceptibility genes in the older group, the source of index clinical cases, implies they are a residual subgroup with slow or absent progressive beta-cell destruction. This study illustrates that the natural history of type 1 diabetes may be elucidated by analyzing age-related subclinical disease in the general population.
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PMID:Screening for preclinical type 1 diabetes in a discrete population with an apparent increased disease incidence. 1501 15


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