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)

Geographical variations in the HLA-DQ genotypes associated with risk for type 1 diabetes were evaluated in Finland. Samples of 280 diabetic children diagnosed in Turku (south-west of the country) and 405 in Oulu (north of the country) were studied as well as a series of 14 096 and 10 016 newborns collected from the same hospitals. There were no major differences in the risk or protection conferred by various HLA-DQB1 genotypes between south-western and northern parts of the country when genotypes of children with type 1 diabetes from these two centres were compared with those of newborns, representing the background populations. However, the distribution of various genotypes was different, both in diabetic children and in newborns, when compared between the two regions (P < 0.0001, chi2 test). These differences reflected the allele frequencies in newborn cohorts in which HLA-DQB1*02 and DQB1*0301 were found more often in Turku and DQB1*0302 more often in Oulu (P < 0.0001 for all differences). Similar types of differences were detected when children who were diagnosed as having diabetes during the national 'Childhood Diabetes in Finland' (DiMe) study between the years 1986-1989 were compared according to their residence. The observed differences in genotype and allele frequencies demonstrate the heterogeneity for HLA alleles even in a population that is generally regarded as highly homogeneous. These differences also affect the sensitivity and efficiency of the screening programme used for identifying infants with genetic susceptibility to IDDM in the ongoing Finnish Diabetes Prediction and Prevention Study.
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PMID:Geographical differences within Finland in the frequency of HLA-DQ genotypes associated with type 1 diabetes susceptibility. The Childhood Diabetes in Finland Study Group. 1099 87

Several studies provide evidence that in addition to the DQ-DR genes, HLA contains another uncharacterized gene or genes associated with type 1 diabetes. Our aim was to investigate the effect of this gene independently of the DQ-DR genes and to localize it with a matched case-control study. More than 1,400 patients and 30,000 control individuals from Finland were studied. They were first genotyped for the selected alleles of the HLA-DQB1, -DQA1, and -DRB1 genes. For the DR3/4(0404) genotype, 75 patients and 181 control subjects were stratified, and 241 patients and 354 controls were stratified for the DR3/4(0401) genotype. Ten microsatellite markers in the HLA class III and I regions (D6S273, TNFa, C12A, STR MICA, MIB, C125, C143, C245, C3211, and MOGc) and selected alleles of the HLA-A and HLA-B genes were studied. In the DR3/4(0404)-stratified group, we found that markers located between C12A and C143 near the HLA-B gene confer a strong additional diabetes association. This was confirmed by the population differentiation test in both DR3/4(0404)- and DR3/4(0401)-stratified groups. Our data indicate that an additional gene associated with type 1 diabetes is located in the 240-kb region near HLA-B. We excluded STR MICA polymorphism as a mutation responsible for diabetes association.
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PMID:Non-class II HLA gene associated with type 1 diabetes maps to the 240-kb region near HLA-B. 1111 29

Several studies have indicated that additional genes in the major histocompatibility complex (MHC) region, other than the class II genes HLA-DQB1 and -DRB1 (the IDDM1 locus), may contribute to susceptibility and resistance to type 1 diabetes. The relative magnitude of these non- DR/DQ effects is uncertain and their map location is unknown owing to the extraordinary linkage disequilibrium that extends over the 3.5 Mb of the MHC. The homozygous parent test has been proposed as a method for detection of additional risk factors conditional on HLA-DQB1 and -DRB1. However, this method is inefficient since it uses only parents homozygous for the primary disease locus, the DQB1-DRB1 haplotype. To overcome this limitation, Conditional ETDT was used in the present report to test for association conditional on the DQB1-DRB1 haplotype, thereby allowing all parents to be included in the analysis. First, we confirm in UK and Sardinian type 1 diabetic families that allelic variation at HLA-DRB1 has a very significant effect on the association of DQB1 and vice versa. The Conditional ETDT was then applied to the HLA TNF (tumour necrosis factor) region and microsatellite marker D6S273 region, both of which have been reported to contribute to IDDM1 independent of the HLA-DQB1-DRB1 genes. We found no evidence for a major role for either of these two regions in IDDM1.
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PMID:Conditional ETDT analysis of the human leukocyte antigen region in type 1 diabetes. 1124 73

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.
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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

The human leukocyte antigen (HLA) system plays a crucial role in the autoimmune process leading to childhood diabetes. The purpose of this study was to evaluate the association between type 1 diabetes and the polymorphism encoded by the HLA-DQB1 gene by using case-parents trios. The study area was the metropolitan region of Santiago, Chile, and cases were ascertained from March 1997 to August 1998. Genotyping was performed in 94 trios comprising incident cases less than 17 years of age at the time of diagnosis and their parents. The transmission/disequilibrium test was used to detect differential transmission in the HLA-DQB1 locus. The authors found that alleles DQB1(*)0302 and DQB1(*)0201 were strongly associated with the disease. By using 1:3 matched sets of cases-pseudosibs and conditional logistic regression models, allelic relative risks were estimated for DQB1(*)0302 (r = 7.2, 95% confidence interval: 2.8, 18.5) and DQB1(*)0201 (r = 4.7, 95% confidence interval: 1.9, 11.6); DQB1(*)0301 was considered the baseline allele. When case-parents trios were used, alleles DQB1(*)0302 and DQB1(*)0201 were strongly associated with a higher risk of type 1 diabetes in the population of SANTIAGO:
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PMID:Association between HLA-DQB1 alleles and type 1 diabetes in a case-parents study conducted in Santiago, Chile. 1129 53

Enterovirus infections are a potential environmental trigger of the autoimmune process leading to clinical type 1 diabetes. It has been suggested that the risk of virus-induced beta-cell damage might be connected with a defect in humoral immune responsiveness to enteroviruses. In the present study we assessed whether such a defect in IgG responsiveness to coxsackievirus B4 antigen existed in young children who developed diabetes-associated autoantibodies during prospective observation from birth until the age of 18 months. IgG levels and maturation of antibody avidity were analysed in 21 children with autoantibodies and 41 control children who had experienced an equal number of enterovirus infections and were additionally matched for age, sex and HLA-DQB1 risk alleles for type 1 diabetes but had not produced diabetes-associated autoantibodies. IgG levels to coxsackievirus B4 were high in cord serum reflecting the presence of maternal antibodies. Mean IgG levels gradually decreased but began to increase after the age of 6 months, showing no significant difference between autoantibody positive and control children. The avidity of antibodies was strong in cord serum and decreased gradually during the first year of life when maternal antibodies disappeared. The avidity indices, which varied considerably from child to child, did not differ between the autoantibody-positive and -negative subjects. In conclusion, our data suggest that children affected by a beta-cell damaging autoimmune process show normal responses to coxsackievirus B4 antigens.
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PMID:No evidence of abnormal regulation of antibody response to coxsackievirus B4 antigen in prediabetic children. 1173 58

Timing of onset of autoimmunity is a prerequisite for unmasking triggers and pathogenesis of type 1 diabetes. We followed 4,590 consecutive newborns with 8 or 3% HLA-DQB1 conferred risk for type 1 diabetes at 3-, 6-, or 12-month intervals up to 5.5 years of age. Islet cell autoantibodies (ICAs) and, in the 137 children with ICAs, insulin autoantibodies (IAAs), GAD65 autoantibodies (GADAs), and IA-2 protein autoantibodies (IA-2As) were measured. Children with high genetic risk developed ICAs more often than those with moderate risk (log-rank P = 0.0015); 85 and 91% remained ICA negative by 5 years of age, respectively. The time of appearance of biochemical autoantibodies was then compared with the appearance of ICAs. IAAs and GADAs emerged usually before ICAs (means -1.8 and -1.5 months, respectively) and IA-2As after ICAs (mean 2.0 months). Ninety-five percent of all IAAs, GADAs, and IA-2As seroconversions occurred in a cluster (-12 to 8 months) around the ICA seroconversion. We conclude that diabetes-associated autoantibodies emerged in children with predisposing HLA-DQB1 alleles after 3 months of age at a constant tempo, determined by the genetic risk level, usually in the order of IAA, GADA, ICA, and IA-2A. Seroconversion to multiple autoantibody positivity usually occurred tightly clustered in time.
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PMID:Genetic risk determines the emergence of diabetes-associated autoantibodies in young children. 1187 62

Rotavirus, the most common cause of childhood gastroenteritis, has been implicated as one of the viral triggers of diabetes-associated autoimmunity. To study the possible association between rotavirus infections and the development of diabetes-associated autoantibodies, we measured the prevalence of rotavirus antibodies in serum samples collected at 3-6-month intervals up to the age of 2 years from 177 children selected from consecutive newborns because they carried HLA-DQB1 alleles associated with increased risk for type 1 diabetes. Twenty-nine of the children developed at least two of four diabetes-associated autoantibodies (ICA, IAA, GADA or IA-2A) during the first 2 years of life (the cases), whereas 148 children remained autoantibody-negative matched with the cases for date of birth, gender, living region and HLA-DQB1 alleles. The temporal association between the development of the first-appearing diabetes-associated autoantibody and rotavirus infections was studied by analysing whether the cases had a diagnostic increase in rotavirus antibody titre more often during the 6-month period that preceded seroconversion to autoantibody positivity than the controls. By the age of 12 months one of the 13 case children (7%), who had a serum sample drawn at that age and who had developed at least one type of diabetes-associated autoantibodies, had experienced a rotavirus infection, while 12 of the 61 (20%) autoantibody-negative control children had had a rotavirus infection. By 18 months, four of the 22 autoantibody-positive cases (18%) and 18 of the 89 controls (20%) had rotavirus antibodies, and by the age of 24 months the respective numbers were five of the 27 cases (19%) and 32 of the 113 (28%) controls. A rotavirus infection occurred during the 6 months preceding the sample which was positive for an autoantibody in four of the 25 periods (16%) for which both necessary samples were available, while the controls had a rotavirus infection during 55 of the 370-such periods (15%). Accordingly, our data suggest that rotavirus infections are unlikely triggers of beta-cell autoimmunity in young children with genetic susceptibility to type 1 diabetes.
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PMID:Rotavirus infections and development of diabetes-associated autoantibodies during the first 2 years of life. 1206 6

The most important gene loci defining risk of type 1 diabetes mellitus (T1DM) are located within the HLA gene region. HLA-DQ molecules are of primary importance but HLA-DR gene products modify the risk conferred by HLA-DQ. The risk associated with an HLA genotype is defined by the particular combination of susceptible and protective alleles. The highest risk is associated with a combination of two different risk haplotypes (7% risk to develop T1DM in Finland) whereas protective genotypes covering 69% of population have a risk of less than 0.2%). The complicated analysis of HLA genotypes is simplified by strong linkage disequilibrium between HLA-DRB1, -DQA1 and -DQB1 loci. In many cases one can deduce the alleles of other loci based on determination of the alleles in one locus. Differences between various populations in the frequency of marker alleles and in the linkages between them has to be taken into account. We have developed PCR based typing methods that utilize blood spot samples, microtiter plate format and lanthanide labeled oligonucleotide probes to define HLA-DQ and -DR alleles relevant for T1DM risk. Typing is run stepwise so that after initial HLA-DQB1 typing only those samples will be further analyzed in which -DQA1 or -DRB1 typing is informative and expected to contribute to the risk estimation. This method has been used to screen more than 50,000 newborn infants in Finland over a time period of 6 years, and it has been able to identify most children who have developed T1D during the follow-up period. The efficiency of the procedure has also been tested in Finnish and Greek populations.
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PMID:Estimation of genetic risk for type 1 diabetes. 1211 74

Enterovirus infections have been associated with the manifestation of clinical type 1 diabetes in a number of reports, and recent prospective studies have suggested that enterovirus infections may initiate the autoimmune process, leading to the disease. In the present study, we analyzed the role of enterovirus infections in a Finnish birth cohort study, Diabetes Prediction and Prevention (DIPP), in which all newborn infants are screened for diabetes-associated HLA-DQB1 alleles, and those with an increased genetic risk are invited for prospective follow-up. Enterovirus infections were diagnosed by serology and reverse transcriptase-polymerase chain reaction (RT-PCR) from serum samples taken from birth every 3-6 months. Case children included 41 infants who became positive for diabetes-associated autoantibodies during the observation. Control children comprised altogether 196 infants who remained autoantibody negative and were matched for the time of birth, sex, and HLA-DQB1 alleles. Enterovirus infections were more frequent in case children than in control children (P = 0.004), and the average enterovirus antibody levels were also higher in the case children (P = 0.003). Enterovirus infections were particularly frequent during the 6-month period preceding the first detection of autoantibodies: 51% of the case children compared with 28% of the control children had an infection in that time interval (P = 0.003). There was no difference in the frequency of adenovirus infections between the groups (P = 0.9). The present results imply that enterovirus infections are associated with the appearance of beta-cell autoantibodies. A possible causal relationship is supported by the clustering of infections to the time when autoantibodies appeared.
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PMID:Enterovirus infections are associated with the induction of beta-cell autoimmunity in a prospective birth cohort study. 1243 83


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