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)

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

Despite early obstacles impacting the success of pancreatic transplantation, the introduction of new procedures and new immunosuppressive therapies during the past 2 decades has improved outcomes for pancreatic transplant recipients. For example, the use of bladder drainage and better human leukocyte antigen matching has helped overcome some of the early obstacles of pancreatic transplantation. In addition, the introduction of tacrolimus in 1994 and mycophenolate mofetil in 1996 has helped lower rates of acute rejection and increase graft survival, with less nephrotoxicity than treatment with cyclosporine. Regimens allowing the tapering of corticosteroids have also helped reduce the rates of acute pancreas rejection. To further improve therapeutic options for patients with type 1 diabetes or end-stage renal disease, pancreatic islet transplantation and organ and islet xenotransplantation should be further explored.
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PMID:Advances in pancreas transplantation. 1520 88

The objective of this study was to test whether maternal age at delivery, child's birth order, cesarean section, complicated delivery, maternal smoking during pregnancy, or neonatal jaundice predict islet autoimmunity in children at genetically increased risk of type 1 diabetes in a birth cohort with blood draws at ages 9, 15, and 24 months and yearly thereafter. Newborns with diabetes-associated human leukocyte antigen genotypes (n = 938) and offspring or siblings of persons with type 1 diabetes (n = 428) from the Denver, Colorado, metropolitan area were examined from January 1994 to February 2003. Information on perinatal factors was collected by using questionnaires soon after the birth. Islet autoimmunity was defined as positivity for > or = 1 autoantibody to glutamic acid decarboxylase65, insulin, or protein tyrosine phosphatase-2/ICA512 at > or = 2 consecutive visits (n = 52; mean follow-up, 3.9 years). Complicated delivery (breech, forceps, vacuum extraction) predicted a higher risk of islet autoimmunity (hazard ratio = 2.10, 95% confidence interval: 1.09, 4.05). Increasing maternal age was related to risk of islet autoimmunity among first-degree relatives of persons with type 1 diabetes (hazard ratios = 3.96 and 8.88 for maternal ages 25-34 and > or = 35 years, respectively, compared with < 25 years; p for trend = 0.008. Other factors evaluated were not related to risk of islet autoimmunity. In conclusion, influences in utero or during delivery may affect the fetal immune system.
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PMID:Perinatal factors and development of islet autoimmunity in early childhood: the diabetes autoimmunity study in the young. 1522 11

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

Diabetes Autoimmunity Study in the Young (DAISY) has followed 1972 children for islet autoimmunity and diabetes: 837 first-degree relatives of persons with type 1 diabetes and 1135 general population newborns identified through human leukocyte antigen (HLA) screening. During follow-up of 4.06 yr (range, 0.17-9 yr), serial determination of autoantibodies to glutamic acid decarboxylase, protein tyrosine phosphatase IA2, and insulin has generated approximately 20,000 results. Among 162 children with at least one positive autoantibody, in 31% the test was false positive (autoantibodies were negative twice on blinded duplicate aliquots), in 31% it was transiently positive (confirmed on blinded duplicate aliquots but negative on follow-up), and in 36% it was persistently positive. Using proportional hazards modeling, the HLA-DR3/4 DQ8 genotype, another positive autoantibody at the first positive visit, and level of autoantibody were predictive of persistent positivity. Only HLA-DR3/4 DQ8 genotype was predictive of progression to diabetes in proportional hazards modeling. This prospective study reveals that cross-sectional determination of islet autoantibodies in a population with relatively low previous probability of autoimmunity identifies as "positive" a large number of individuals who are either false or transiently positive. Predictive value of autoantibodies increases with blinded duplicate and independent sample retesting and incorporation of the level of autoantibody in the predictive algorithm.
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PMID:Prediction of autoantibody positivity and progression to type 1 diabetes: Diabetes Autoimmunity Study in the Young (DAISY). 1529 24

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.
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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 region spanning the tumor necrosis factor (TNF) cluster in the human major histocompatibility complex (MHC) has been implicated in susceptibility to numerous immunopathological diseases, including type 1 diabetes mellitus and rheumatoid arthritis. However, strong linkage disequilibrium across the MHC has hampered the identification of the precise genes involved. In addition, the observation of "blocks" of DNA in the MHC within which recombination is very rare, limits the resolution that may be obtained by genotyping individual SNPs. Hence a greater understanding of the haplotypes of the block spanning the TNF cluster is necessary. To this end, we genotyped 32 human leukocyte antigen (HLA)-homozygous workshop cell lines and 300 healthy control samples for 19 coding and promoter region SNPs spanning 45 kb in the central MHC near the TNF genes. The workshop cell lines defined 11 SNP haplotypes that account for approximately 80% of the haplotypes observed in the 300 control individuals. Using the control individuals, we defined a further six haplotypes that account for an additional 10% of donors. We show that the 17 haplotypes of the "TNF block" can be identified using 15 SNPs.
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PMID:High-Density SNP genotyping defines 17 distinct haplotypes of the TNF block in the Caucasian population: implications for haplotype tagging. 1552 49

The genetic susceptibility for gestational diabetes (GDM) was estimated by comparisons of genotypes within human leukocyte antigen (HLA) and major histocompatibility complex class I chain-related gene A (MICA) in 199 women with GDM and 213 healthy women. At least one of ICA, glutamic acid decarboxylase antibodies, or islet cell antigen-2 antibodies/tyrosine phosphatase antibodies was found in 6.0% (12/199) of women with GDM and were considered as autoimmune GDM, whereas the remaining 187 were considered as nonautoimmune GDM. HLA genotyping was done with polymerase chain reaction and sequence-specific oligonucleotides. MICA polymorphism was determined with polymerase chain reaction and fragment size determination. HLA-DR3-DQ2/x or DR4-DQ8/x and MICA5.0/5.1 were more frequent in autoimmune GDM compared with controls; 92% versus 46% and 42% versus 13% and conferred increased risk (odds ratio [OR] = 13; 95% confidence interval [CI] 1.7-104) and (OR = 4.7; 95%CI 1.4-16). Four other genotypes were more frequent in nonautoimmune GDM compared with controls: HLA-DR7-DQ2/y, 24% versus 14%; DR9-DQ9/y, 9.6% versus 1.9%; DR14-DQ5/y, 7.5% versus 0.94%; and MICA5.0/z, 24% versus 13% and gave increased risk: OR = 2.0; 95%CI 1.2-3.4, OR = 5.6; 95%CI 1.8-17, OR = 8.5; 95%CI 1.9-38, and OR = 2.0; 95%CI 1.2-3.4, respectively. We concluded that autoimmune diabetes with onset during pregnancy is associated with the type 1 diabetes-associated genotypes and also with MICA5.0/5.1, whereas DR7-DQ2/y, DR9-DQ9/y, DR14-DQ5/y, and MICA5.0/z are risk factors for nonautoimmune GDM.
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PMID:Different HLA-DR-DQ and MHC class I chain-related gene A (MICA) genotypes in autoimmune and nonautoimmune gestational diabetes in a Swedish population. 1560 71

The interrelationship between human leukocyte antigen immunogenetics and environmental factors and their contribution to the emergence of type 1 diabetes (T1D) were studied in Jewish immigrants from Ethiopia in Israel. This community displays high incidence of T1D, and is unique both by its ethnic segregation and its rapid exposure to a new environment after the immigration. The study population consisted of 152 Ethiopian Jews living in Israel, 33 with T1D and 119 unrelated controls. Human leukocyte antigen class II susceptible and protective alleles in the Jewish Ethiopian patients were similar to those in patients of other ethnic groups in Israel and in non-Jewish Ethiopian patients, with a few exceptions. Three haplotypes were markedly associated with diabetes in Jewish Ethiopian patients: DRB1*0301 DQA1*05 DQB1*02 (OR 4.4, p < 0.001); DRB1*0404 DQA1 03 DQB1*0302 (OR 19.2, p = 0.006), and DRB1*0405 DQA1*03 DQB1*0302 (OR 87.8, p < 0.001). The highly susceptible allele DRB1*0301 was more common in the general Ethiopian population (25.2%) than in all other ethnic groups in Israel, which may render this community prone to the disease. The age at onset of disease in patients with two susceptible haplotypes was negatively correlated with the duration of living in Israel (r = -0.621, p = 0.04). We concluded that ongoing exposure of genetically predisposed immigrants from Ethiopia to diabetogenic environmental factors eventually leads to a high incidence of overt diabetes in this ethnic group.
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PMID:Type 1 diabetes in Jewish Ethiopian immigrants in Israel: HLA class II immunogenetics and contribution of new environment. 1560 74

The PTPN22 (protein tyrosine phosphatase N22) gene encodes the protein tyrosine phosphatase Lyp. One function of Lyp is downregulation of T-cell signaling through its interaction with the negative regulatory kinase C-terminal Src tyrosine kinase (Csk). A single nucleotide polymorphism in the PTPN22 gene, C1858T, encodes products with different Csk binding affinities. Disease association of the PTPN22 1858T allele has been reported in case-control studies of three different autoimmune disorders: type 1 diabetes (T1D), rheumatoid arthritis, and systemic lupus erythematosus. In this study, a set of 341 white, multiplex T1D families were genotyped for the C1858T single nucleotide polymorphism of PTPN22, and transmission disequilibrium test analysis revealed significant association (p = 0.005) of the T allele with T1D. No effects of parent of origin, sex of patient, or human leukocyte antigen genotype (high-risk human leukocyte antigen DR3/DR4 vs non-DR3/DR4) were observed. However, transmission of the T allele was significantly increased in the subset of patients who also carried at least one copy of the TCF7 883A allele, another allele that is important in regulating T-cell responses and that is associated with T1D. These results are consistent with the hypothesis that individuals lacking the C allele of PTPN22 may have reduced capacity to downregulate T-cell responses and may therefore be more susceptible to autoimmunity.
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PMID:Association of the single nucleotide polymorphism C1858T of the PTPN22 gene with type 1 diabetes. 1562 Apr 63


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