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

Progress has been made in investigating the genetic factors involved in type 1 diabetes (T1D) development for the past few years. While Linkage disequilibrium (LD) mapping has been useful for both the confirmation and fine-mapping of susceptibility intervals, as well as identification of etiological mutations, identification of specific disease genes has been a challenge and limited to known candidate genes. The overall risk for T1D from the HLA DR and DQ molecules (IDDM1) is determined by combinations of polymorphic alleles. Functional studies indicate that the susceptible and protective HLA-DR and -DQ bind and present non-overlapping peptides. Although consistent linkage evidence was reported for the susceptibility intervals IDDM2, IDDM5 and IDDM12, evidence for most other intervals varies in different data sets. The variable number of tandem repeats at the 5' end of the insulin gene (IDDM2) regulates insulin expression in the thymus. Studies on IDDM5 have led to the discovery of a novel polymorphism 163 A-->G (M55V) in SUMO4 gene, which was found to be associated with T1D patients with Asian origin. Functionally SUMO4 conjugates to IkBalpha and negatively regulates NFkB transcriptional pathway. The M55V substitution reduces the sumoylation activity of the V55 variant, which resulted in higher NFkB dependent transcriptional activity. The polymorphisms of the cytotoxic T lymphocyte antigen 4 gene (CTLA4, IDDM12) encoding a regulatory molecule in the immune system associate with T1D and autoimmune thyroid diseases (ATD). The 3' untranslated region of this gene determines the level of soluble CTLA-4. Genetic mapping of variants conferring a small disease risk can identify pathways in complex disorders, as evidenced by quantitative alterations of candidate genes contributing to autoimmune tissue destruction. Moreover, the identification of two transcription factors that, when mutated, are responsible for severe autoimmune disease is leading to a better understanding of T cell tolerance. Both AIRE and Foxp3, identified initially via their association with genetically manipulated mice, are involved in tolerance induction in humans. Although mutations in these genes may cause rare but serious diseases, it is likely that other transcription factors will contribute to the genetic load that predisposes certain individuals to disease.
 ...
PMID:Functional evaluation of the type 1 diabetes (T1D) susceptibility candidate genes. 1744 64

Two loci, Idd5.1 and Idd5.2, that determine susceptibility to type 1 diabetes (T1D) in the NOD mouse are on chromosome 1. Idd5.1 is likely accounted for by a synonymous single nucleotide polymorphism in exon 2 of Ctla4: the B10-derived T1D-resistant allele increases the expression of the ligand-independent isoform of CTLA-4 (liCTLA-4), a molecule that mediates negative signaling in T cells. Idd5.2 is probably Nramp1 (Slc11a1), which encodes a phagosomal membrane protein that is a metal efflux pump and is important for host defense and Ag presentation. In this study, two additional loci, Idd5.3 and Idd5.4, have been defined to 3.553 and 78 Mb regions, respectively, on linked regions of chromosome 1. The most striking findings, however, concern the evidence we have obtained for strong interactions between these four disease loci that help explain the association of human CTLA4 with T1D. In the presence of a susceptibility allele at Idd5.4, the CTLA-4 resistance allele causes an 80% reduction in T1D, whereas in the presence of a protective allele at Idd5.4, the effects of the resistance allele at Ctla4 are modest or, as in the case in which resistance alleles at Idd5.2 and Idd5.3 are present, completely masked. This masking of CTLA-4 alleles by different genetic backgrounds provides an explanation for our observation that the human CTLA-4 gene is only associated with T1D in the subgroup of human T1D patients with anti-thyroid autoimmunity.
 ...
PMID:Interactions between Idd5.1/Ctla4 and other type 1 diabetes genes. 1805 79

The identification of genes placing individuals at an increased risk for the development of autoimmune thyroid disease (AITD) has been a slow process. However, over the last 20 years or so real progress has been made with the mapping of novel loci, via a number of different approaches. First, through the use of traditional immunological methods, Human Leucocyte Antigen (HLA)/Major Histocompatibility Complex (MHC) was the first gene region to be associated with AITD and consistent replications have been reported. Second, the CTLA-4 gene region on 2q33 was the first non-MHC replicated locus to be primarily identified using the candidate gene method. Third, family-based linkage studies led to the mapping of a new type 1 diabetes locus, the PTPN22 gene, which has subsequently been independently replicated as a susceptibility gene for Graves' disease (GD). Fourth, despite many unsuccessful attempts at implicating the TSHR gene as a susceptibility locus for GD, a recent approach of 'tagging' all the common variation within the gene has led to its identification as the first GD specific locus. Moreover, the use of tag single nucleotide polymorphisms (SNPs) has also been used to implicate the recently identified type 1 diabetes locus, CD25 as a susceptibility gene for GD. Finally, large scale, ongoing genome-wide association studies in multiple autoimmune diseases (AID) states, including AITD seem likely to lead to the identification of additional MHC and non-MHC susceptibility loci.
 ...
PMID:Genetic developments in autoimmune thyroid disease: an evolutionary process. 1808 80

Type 1 A diabetes mellitus (T1AD) results from the autoimmune destruction of the insulin producing pancreatic beta-cells. The largest contribution to genetic susceptibility comes from several genes located in the major histocompatibility complex on chromosome 6p21.3 (IDDM1 locus), accounting for at least 40% of the family aggregation of this disease. The highest-risk human leukocyte antigen HLA genotype for T1AD is DR3-DQA1*0501-DQB1*0201/DR4-DQA1*0301-DQB1*0302, whereas -DR15-DQA1*0102-DQB1*0602 haplotype is associated with dominant protection. Three other T1D loci associated with predisposition are the Variable Number for Tandem Repeats (VNTR) near the insulin gene (IDDM2), which accounts to 10% of genetic susceptibility, the Cytotoxic T-Lymphocyte-associated Antigen (CTLA-4)(IDDM 12) and the Protein Tyrosine Phosphatasis Nonreceptor-type 22 (PTPN22). Many other gene suspected to predispose to autoimmunity have been investigated. T1AD is frequently associated with autoimmune thyroid disease, celiac disase, Addison s disease and many other autoimmune diseases, characterized by organ-specific autoantibodies and related to the same genetic background. Using these autoantibodies, organ specific autoimmunity may be detected before the development of clinical disease preventing significant morbidity.
 ...
PMID:[Genetic and humoral autoimmunity markers of type 1 diabetes: from theory to practice]. 1843 27

Pancreatic islet endothelial cells (ECs) form the barrier across which autoreactive T cells transmigrate during the development of islet inflammation in type 1 diabetes. Little is known about the immune phenotype of islet ECs that might shape their molecular interaction with autoreactive T cells before and during the development of islet inflammation. In this study we examined the expression and functional significance of costimulatory molecules by human islet ECs. Freshly isolated human islet ECs constitutively expressed CD86 (B7-2) and ICOS ligand but not CD80 (B7-1) or CD40 costimulatory molecules. The functional activity of islet EC-expressed CD86 was examined by coculture of resting islet ECs with CD4 T cells stimulated by CD3 ligation alone. Marked T cell proliferation in the coculture was completely abrogated by mAb blockade of CD86, confirming that costimulatory properties are conferred on ECs by CD86 expression. In view of its location on the vasculature, we hypothesized a role for CD86 in T cell adhesion/transmigration. In keeping with this, adhesion/transmigration of activated (CD3 ligated) memory (CD45R0(+)) CD4 T cells across islet ECs was completely inhibited in the presence of CD86 blocking mAb. Identical results were obtained for T cell adhesion using either CTLA-4 blocking mAb or CTLA-4Ig (abatacept), indicating CTLA-4 as the T cell ligand for these CD86-mediated effects. These data suggest a novel role for CD86 expression on the microvasculature, whereby ligation of CTLA-4 on CD4 T cells by CD86 on islet ECs is key to the adhesion of recently activated T cells.
 ...
PMID:Expression of CD86 on human islet endothelial cells facilitates T cell adhesion and migration. 1894 Dec

The MHC region (6p21) aggregates the major genes that contribute to susceptibility to type 1 diabetes (T1D). Three additional relevant susceptibility regions mapped on chromosomes 1p13 (PTPN22), 2q33 (CTLA-4), and 11p15 (insulin) have also been described by linkage studies. To evaluate the contribution of these susceptibility regions and the chromosomes that house these regions, we performed a large-scale differential gene expression on lymphomononuclear cells of recently diagnosed T1D patients, pinpointing relevant modulated genes clustered in these regions and their respective chromosomes. A total of 4608 cDNAs from the IMAGE library were spotted onto glass slides using robotic technology. Statistical analysis was carried out using the SAM program, and data regarding gene location and biological function were obtained at the SOURCE, NCBI, and FATIGO programs. Three induced genes were observed spanning around the MHC region (6p21-6p23), and seven modulated genes (5 repressed and 2 repressed) were seen spanning around the 6q21-24 region. Additional modulated genes were observed in and around the 1p13, 2q33, and 11p15 regions. Overall, modulated genes in these regions were primarily associated with cellular metabolism, transcription factors and signaling transduction. The differential gene expression characterization may identify new genes potentially involved with diabetes pathogenesis.
 ...
PMID:Gene expression profiles stratified according to type 1 diabetes mellitus susceptibility regions. 1912 Mar 14

CTLA-4 is a homeostatic regulator of T cell activation and is believed to play a critical role in immune tolerance. Polymorphisms in the CTLA-4 promoter (-318C/T) and in exon 1 (+49 A/G) were analyzed in 300 Chilean patients with type 1 diabetes mellitus (T1D) and 310 healthy children by polymerase chain reaction-restriction fragment length polymorphism. The effect of CTLA-4 allele and haplotype frequencies on the interferon-gamma, tumor necrosis factor-alpha, and transforming growth factor-beta(1) levels and the presence in serum of GAD65 and IA-2 autoantibodies at the onset of T1D was evaluated. The distribution of the CTLA-4 allele and genotype frequencies was found to be similar in patients and control children. However, among the T1D patients' carriers of GG genotype on CTLA-4 gene a higher frequency of anti-GAD65 autoantibodies (87.2%) was observed. On the other hand, higher ketoacidosis at onset, younger age at onset, and higher levels of tumor necrosis factor-alpha and interferon-gamma were observed in T1D patients carriers of G allele in comparison with the carriers of AA genotype. In conclusion, the result of this study showed that CTLA-4 +49 A/G and -318 C/T polymorphisms were not linked with a higher genetic risk for T1D. However, the presence of a GG genotype or G allele dosage was associated with a younger age of onset, higher prevalence of ketoacidosis at the moment of diagnosis and positive anti-GAD65 serum autoantibodies.
 ...
PMID:Association of CTLA-4 polymorphisms and clinical-immunologic characteristics at onset of type 1 diabetes mellitus in children. 1913 37

Patients with type 1 diabetes (a TH1 disease) have been reported to be at a lower risk of developing asthma (a TH2 disease). Both diseases are affected by environmental and genetic factors. Our objective is to examine this relationship in Lebanon, a Middle-Eastern country, where no previous similar studies are available. This is a cross-sectional observational study conducted at the Chronic Care Center, a referral medical center for type 1 diabetics. Patients with type 1 diabetes aged 6-39 years old, their unaffected siblings and age-matched control completed the International Primary Care Airways Group asthma screening questionnaire. The prevalence of asthma symptoms was compared among the three groups and separately within a subgroup of diabetics in relation to their carrier state of previously collected genetic data. Among 305 diabetics, 776 siblings and 187 controls, diabetics were at lower risk of having any asthma symptoms than controls; OR 0.48 (95% CI 0.32-0.72, p < 0.001) and siblings were at lower risk than diabetics and controls; OR 0.64 (95% CI 0.45-0.91, p = 0.01) and 0.28 (95% CI 0.19-0.42, p < 0.001), respectively. Among 66 diabetics, carriers of the HLA-DQB1*0201 allele were at lower risk of having any asthma symptoms than non-carriers (25.5 vs. 53.3%, p = 0.04). Only a statistically non-significant trend of higher risk was observed in carriers of HLA-DQB1*0301 and G allele at the 49 (A/G) nucleotide of CTLA-4 gene. The TH1-TH2 paradigm might partially explain these findings, since siblings were the least to report asthma symptoms. Future research is needed with diagnostic tests for asthma and extensive genetic testing.
 ...
PMID:Prevalence of asthmatic symptoms in Lebanese patients with type 1 diabetes and their unaffected siblings compared to age-matched controls. 1931 67

The concept of susceptibility genes common to different autoimmune diseases is now firmly established with previous studies demonstrating overlap of loci conferring susceptibility to type 1 diabetes (T1D) with both Coeliac disease and multiple sclerosis. Rheumatoid arthritis (RA) is an archetypal autoimmune disease and we, therefore, targeted putative T1D susceptibility loci for genotyping in UK RA cases and unrelated controls. A novel RA susceptibility locus at AFF3 was identified with convincing evidence for association in a combined sample cohort of 6819 RA cases and 12 650 controls [OR 1.12 95% confidence intervals (CI) 1.07-1.17, P = 2.8 x 10(-7)]. Association of two previously described loci (CTLA-4 and 4q27) with RA was also replicated (OR 0.87, 95% CI 0.82-0.94, P = 1.1 x 10(-4) and OR 0.86, 95% CI 0.79-0.94, P = 5.4 x 10(-4), respectively). These findings take the number of established RA susceptibility loci to 13, only one of which has not been associated with other autoimmune diseases.
 ...
PMID:Identification of AF4/FMR2 family, member 3 (AFF3) as a novel rheumatoid arthritis susceptibility locus and confirmation of two further pan-autoimmune susceptibility genes. 1935 76

Genetic heterogeneity may affect the analysis of risk factors associated with type 1 diabetes (T1D). We studied the effect of the INS -23A/T, PTPN22 1858C/T, and CTLA-4 +49A/G polymorphisms on the emergence of T1D-associated autoimmunity in children exposed to cow's milk (CM) based formula during early or late infancy. The study comprised of 156 children from the Finnish DIPP cohort who had developed >or= 2 types of autoantibodies (ICA, IAA, GADA or IA-2A) or clinical T1D and 563 control children. The PTPN22 1858T allele was associated with the appearance of the autoantibodies and clinical T1D among children exposed to CM formula before the age of 6 months (PTPN22: for all P <or= 0.001, Log Rank test), but not among children exposed later on. Cox regression analysis showed an interaction between early CM exposure and 1858T allele and enhanced appearance of ICA, IAA and IA-2A (for all P <or= 0.04). Our results imply that the PTPN22 polymorphism affects the development of T1D-associated autoimmunity only if children are exposed to CM formula during early infancy suggesting an interplay between genetic and environmental factors. This may provide an explanation for the contradictory findings on the significance of CM formula exposure in T1D.
 ...
PMID:Interplay between PTPN22 C1858T polymorphism and cow's milk formula exposure in type 1 diabetes. 1947 15


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