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)

The HLA complex, located on the short arm of chromosome 6, is the strongest genetic marker for type 1 diabetes (T1DM). In previous study we demonstrated association between genes HLA-DRB1 and HLA-DQB1 and T1DM in the Polish population. There is a strong-independent association of alleles HLA-DRB1*0401 and DQB1*302, despite population linkage disequilibrium among alleles of these genes. The aim of the current study was to verify a hypothesis that some alleles or haplotypes of HLA-DRB1, DQA1 and DQB1 genes increase the risk for familiar aggregation of T1DM. We analysed 507 patients with IDDM derived from 80 multiplex and 325 patients from simplex families. PCR and hybridisation with SSO probes performed HLA typing for DRB1, DQA1 and DQB1 alleles. Genetic analysis demonstrated strong association of allele HLA-DQB1*0302 with T1DM in the Polish population in families with single (DM1) and more numerous cases (DM2) cases, compared with healthy cases (n=103). The HLA-DQB1*302 allele frequencies were 27.8% vs 8.7%; Pc<10(-5); OR(95%CI)=4,03(3.80-4.25) and 16.3% vs 8.7%; Pc<0.04; OR(95%CI)=2.04(1.79-2.89), respectively. The presence of allele HLA-DQB1*0602 has a strong protective effect from T1DM in both studied groups (1.46% vs. 13.6%; Pc<10(-5); OR(95%CI)=0.09(-0.25-0.44) and 0.98% vs. 13.6%; Pc<10(-5); OR(95%CI)=0.06(-0.46-0.58), respectively. Interestingly, HLA-DRB1*04 allele more often co-segregated with DM2 families as comparing the DM1 group (31.0% vs. 15.8%, respectively; Pc<10(-5)). However in both cases differences remain significant as compared to controls: Pc<10(-5), OR (95%CI)=3.52(3.33-3.70) and Pc<10(-5) OR(95%CI)=6.17(5.97-6.37), for DM1 and DM2 respectively. Subtyping of HLA-DRB1*04 alleles demonstrated that the strongest predisposing effect has been identified with DRB1*0401. Moreover, difference in frequencies of the protective allele HLA-DQB1*0301 among DM1 and DM2 group was revealed (8.8% vs. 13.7%, respectively; Pc<10(-5)) and the protective effect of this allele remained only significant in DM1 group: 8.8% vs. 19.9%; Pc<10(-5); OR(95%CI)=0.39(0.19-0.58). The results suggest that it is likely that familial aggregation of T1DM is associated with lower frequency of protective alleles of HLA-DQB1 gene.
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PMID:[Alleles of HLA-DQB1 and familial aggregation of type 1 diabetes]. 1287 86

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

Type 1 diabetes results from an autoimmune insulitis, associated with HLA class II alleles. The evidence about HLA allele association is not clear in patients diagnosed after 35 years of age. In this study we have analyzed HLA alleles of DQB1 and DRB1 genes by sequence specific primer (SSP)-PCR technique in adult patients with disease onset after 35 years of age. Two hundred and eighty-one patients were divided into three groups according to the insulin therapy, the level of C peptide (CP), and GAD antibodies (anti-GAD). Group 1 (type 1 diabetes in adults) was characterized by CP less than 200 pmol/L and anti-GAD more or less than 50 ng/mL (n = 80). All of them had insulin therapy within 6 months after diagnosis. Group 2 latent autoimmune diabetes mellitus in adults (LADA) was defined by a minimum 6-month-long phase after diagnosis without insulin therapy, and was characterized by CP more than 200 pmol/L and anti-GAD more than 50 ng/mL (n = 70). Group 3 (type 2 diabetes) was characterized by CP more than 200 pmol/L and anti-GAD less than 50 ng/mL (n = 131). None ever had insulin therapy. In group 1, there was increased frequency of DRB1*04 (45.0% vs. controls 14.1%, OR = 5.0, P < 0.0005) and DQB1*0302 alleles (43.3% vs. controls 11.1%, OR = 6.1, P < 0.00005). There was increased frequency of DRB1*03 and DQB1*0201, and decreased frequency of DQB1*0602 (3.3% vs. controls 20.2%), but it was not significant. In group 2, there was a significantly increased frequency of DRB1*03 only (50.0% vs. controls 21.2%, OR = 3.7, P < 0.05). Compared with children with type 1 diabetes and adults with type 2 diabetes (group 3), we conclude that the presence of predisposing DQB1 alleles in adults with type 1 diabetes decreases with the age, probably due to environmental factors. Only the DRB1*03, but not the DQB1 gene, becomes the main predisposing allele in LADA patients. These findings suggest that the presence of HLA-DQB1*0302 identifies patients at high risk of requiring insulin treatment. Type 1 diabetes mellitus (DM) in children or adults may have partly different immunogenetic etiopathogenesis than LADA.
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PMID:HLA in Czech adult patients with autoimmune diabetes mellitus: comparison with Czech children with type 1 diabetes and patients with type 2 diabetes. 1467 93

The study aimed to compare the HLA specificities of AAb-positive healthy schoolchildren with those of patients with type 1 diabetes (T1D). HLA-DRB1 and DQB1 alleles were determined in 178 AAb-positive and 339 AAb-negative schoolchildren aged 6-17 years without first-degree relatives with T1D and in 274 patients with T1D. AAbs against glutamic acid decarboxylase (GADA), protein tyrosine phosphatase (IA-2A), and insulin (IAA) were determined by (125)I-antigen binding, and islet cell cytoplasmic antibodies (ICAs) immunohistochemically. Here, 82.6% (147/178) of AAb-positive schoolchildren had single AAbs and 17.4% (31/178) had multiple AAbs. In both groups, GADA occurred with highest and IAA with lowest frequency. In children with single AAbs at levels between the 99th and 99.9th percentile, frequencies of the diabetes-associated DRB1 (*03, *04) and DQB1 (*02, *0302) alleles and the protective DRB1 (*15) and DQB1 (*0602) alleles did not differ from those of controls. In patients, the positive associations were confirmed for DRB1*04 (OR = 5.39) and DQB1*0302 (OR = 9.05), whereas DRB1*15 (OR = 0.05) and DQB1*0602 (OR = 0.06) were negative-associated (p < 0.001). The same association was found in schoolchildren with multiple AAbs for DRB1*04 (OR = 3.84), DQB1*0302 (OR = 4.95), and DRB1*15 (OR = 0.1; p < 0.001-0.014), and with high-titer single AAbs (>/=99.9th percentile), but none of them had DQB1*0602. The highest risk genotype DQB1*02/*0302 occurred in 36.5% of patients (OR = 21.07) and in 19.3% of children with multiple AAbs (OR = 8.8; p<0.001). It is concluded that probands with multiple and high-titer single AAbs in the general population have the same genetic predisposition for T1D as patients and are therefore at highest risk for the disease.
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PMID:Multiple and high-titer single autoantibodies in schoolchildren reflecting the genetic predisposition for type 1 diabetes. 1467 44

Type 1 diabetes mellitus (DM) is caused by genetic and environmental factors. Twice as many fathers as mothers of children with type 1 DM have the disease. The reason for the differences remains unclear. We looked at the transmission rates of diabetes-related alleles from parents to children with diabetes. All children with newly diagnosed type 1 DM from August 1, 1996 to August 1, 2000, aged 0 to 15 years, in Lithuania were invited to participate. Blood samples for full genetic analysis were available from 125 families. HLA DQA1, DQB1, and DRB1 typing was done on DNA extracted from peripheral blood, by polymerase chain reaction amplification, manual dot-blotting onto nylon membranes, synthetic sequence-specific oligonucleotide probe 3'-end labeling with (32)P-dCTP, and hybridization, followed by stringency washes, autoradiography, and allele calling. Frequency of diabetes risk-related alleles DQB1*0302, DQA1*0201, DR4, and DR3 was less prevalent among Lithuanian than among Swedish children with type 1 DM. Transmission rates of DR4-DQB1*0302-DQA1*0301 and DR3-DQB1*0201-DQA1*0501 haplotypes from parents were higher than expected: chi(2) (TDT) 30.56, p < 0.0001, and chi(2) (TDT) 11.26, p = 0.0008, respectively. DQB1*0302 and DR4 were significantly more frequently transmitted from both parents, but DR3 was transmitted more frequently only from mothers. Any of these alleles had similar frequencies among female and male offspring. We conclude that, besides DR4-DQB1*0302-DQA1*0301 and DR3-DQB1*0201-DQA1*0501, there are other inherited alleles that determine risk for type 1 DM among children in Lithuania. Fathers might transfer other alleles of disease susceptibility in higher frequency or mothers might provide a protective environment during pregnancy, which results in higher risk to offspring of fathers than mothers to develop diabetes.
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PMID:Inheritance of MHC class II genes in Lithuanian families with type 1 diabetes. 1467 79

Autoimmune disorders such as type 1 diabetes (T1DM), celiac disease (CD), and Addison's disease (ADD) develop in individuals with genetic susceptibility that are exposed to environmental triggering factors not completely defined. Patients with an autoimmune disease (and their relatives) are at increased risk of developing another disorder, and this might be caused by a common genetic origin of autoimmunity; for example, HLA class II region in 6p21 shows a very strong association with most diseases. The aim of this study was to determine whether shared susceptibility markers extend from the central (DRB1) through the telomeric (MICA) HLA region. We analyzed three independent sets of families with one autoimmune disease, T1DM, CD, or ADD, and genotyped them for HLA-DRB1 and for the exon 5 GCT polymorphism of MICA. For HLA-DRB1, allele DRB1*0301 was the only one associated with risk for all three diseases; in the case of MICA, allele A9 was found to be the common protective allele. Haplotype analysis shows that haplotype A5.1-DRB1*0301 confers risk to autoimmunity. Our results show that there are common risk and protection alleles in both loci, suggesting a core of genetic association with autoimmunity (HLA-DRB1*0301 risk; A9 protection) that could be modulated by other alleles/loci or environmental factors toward one or another disease. Some alleles are part of conserved haplotypes (A5.1-DR3, A5.1-DR2), whereas others seem to have independent effect (A9) and support the idea of two independent loci in this region.
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PMID:HLA-DRB1 and MICA in autoimmunity: common associated alleles in autoimmune disorders. 1467 82

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

As part of a longitudinal study aimed at defining the natural history of prediabetic autoimmunity and predicting the risk of future cases of type 1 diabetes, 3607 newborns from three regions of continental Italy (Lombardia, Liguria, and Lazio) were subjected to genetic testing to determine human leukocyte antigen-DRB1 (HLA-DRB1) and -DQB1 allele and phenotype frequencies. Polymerase chain reaction and immobilized sequence-specific oligonucleotide probe assays were used to identify ten DRB1 allele lineages and three DQB1 alleles. No major inter-regional differences emerged in the allelic distribution indicating homogeneous distribution of the HLA DRB1-DQB1 alleles among the three regions analyzed. Comparison of our data with those published for other Caucasian populations reveals that these three regions are characterized by a very low frequency of DRB1*04 (8%) and a high frequency of DRB1*11 (25%). The phenotype frequencies of HLA-DQB1*0302 and DQB1*0602 observed are also lower than those reported for other populations. Furthermore, the DRB1*04-DQB1*0302 haplotype was relatively infrequent in our population (5.3% of the newborns tested). These findings furnish a genetic "portrait" of the populations of the analyzed regions that will be useful not only for investigation of the genetic risk of type 1 diabetes mellitus in Italy but also for studies of other autoimmune diseases related to HLA genotypes.
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PMID:HLA class II typing in newborns reveals a low frequency of the DRB1*04 allele and a high frequency of DRB1*11 allele in three regions of continental Italy. 1512 Jan 92

Alleles of HLA class II genes DQB1, DQA1, and DRB1 in the MHC region are major determinants of genetic predisposition to type 1 diabetes (T1D). Several alleles of each of these three loci are associated with susceptibility or protection from disease. In addition, relative risks for some DR-DQ genotypes are not simply the sum or product of the single haplotype relative risks. For example, the risk of the DRB1*03-DQB1*02/DRB1*0401-DQB1*0302 genotype is often found to be higher than for the individual DRB1*03-DQB1*02 and DRB1*0401-DQB1*0302 homozygous genotypes. It has been hypothesized that this synergy or epistasis occurs through formation of highly susceptible trans-encoded HLA-DQ(alpha 1, beta 1) heterodimers. Here, we evaluated this hypothesis by estimating the disease associations of the range of DR-DQ genotypes and their inferred dimers in a large collection of nuclear families. We determined whether the risk of haplotypes in DRB1*0401-DQB1*0302-positive genotypes relative to the DRB1*03-DQB1*02-positive genotypes is different from that of DRB1*01-DQB1*0501, which we used as a baseline reference. Several haplotypes showed a different risk compared to DRB1*01-DQB1*0501, which correlated with their ability to form certain trans-encoded DQ dimers. This result provides new evidence for the potential importance of trans-encoded HLA DQ molecules in the determination of HLA-associated risk in T1D.
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PMID:Genotype effects and epistasis in type 1 diabetes and HLA-DQ trans dimer associations with disease. 1516 2

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.
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PMID:Molecular basis of predisposition to develop type 1 diabetes mellitus in North Indians. 1524 69


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