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 humoral immune response to endothelium has a pivotal role in the development of atherosclerosis. Using a molecular method, we sought to identify endothelial autoantigens in carotid atherosclerosis. Immunoscreening of a HUAEC expression library with IgG from a pool of two sera from patients with carotid atherosclerosis identified a clone specific to actin. We evaluated actin-specific IgG reactivity in patients with carotid atherosclerosis and compared responses with those in patients with systemic lupus erythematosus and type 1 diabetes mellitus and in healthy subjects. Enzyme-linked immunoassay detected actin-specific IgG in a significantly higher percentage of sera from patients with atherosclerosis and systemic lupus erythematosus than from healthy subjects (16/61, 26% and 13/33, 39%versus 2/41, 5%, P = 0.012 and P < 10(-4), by chi2 test). Mean optical density values were significantly higher in patients than in healthy subjects (P < 10(-4) by Student's t-test). Patients with atherosclerosis and uncomplicated plaques had significantly higher serum anti-actin IgG reactivity than those with complicated plaques (P = 0.048 by Student's t-test). Our findings suggest that actin is an autoantigenic molecule of potential clinical interest in carotid atherosclerosis.
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PMID:Screening of a HUAEC cDNA library identifies actin as a candidate autoantigen associated with carotid atherosclerosis. 1519 64

We genotyped 525 independent North American white individuals with systemic lupus erythematosus (SLE) for the PTPN22 R620W polymorphism and compared the results with data generated from 1,961 white control individuals. The R620W SNP was associated with SLE (genotypic P=.00009), with estimated minor (T) allele frequencies of 12.67% in SLE cases and 8.64% in controls. A single copy of the T allele (W620) increases risk of SLE (odds ratio [OR]=1.37; 95% confidence interval [CI] 1.07-1.75), and two copies of the allele more than double this risk (OR=4.37; 95% CI 1.98-9.65). Together with recent evidence showing association of this SNP with type 1 diabetes and rheumatoid arthritis, these data provide compelling evidence that PTPN22 plays a fundamental role in regulating the immune system and the development of autoimmunity.
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PMID:Genetic association of the R620W polymorphism of protein tyrosine phosphatase PTPN22 with human SLE. 1527 34

1. The numbers of CGN patients have decreased, with a corresponding increase in transplants into IDDM. HTN and MHT have also increased in recent years. 2. Waiting time on dialysis has increased, with an increase in patient age. 3. Transfusions have decreased for all diseases, although less so for SLE. 4. Disease recurrence was highest in FGS, IgA, SLE and CGN. The incidence of recurrence has decreased in recent years. 5. Tacrolimus-MMF and Neoral-MMF were superior to CsA-AZ for all diseases with respect to 5-year graft survival. 6. Systemic diseases such as SLE and IDDM had lower graft survival rates than IgA, PC and ALP. Exclusion of deaths made functional graft survival of all diseases quite similar. 7. Blacks had lower graft survival rates than Whites, Hispanics, and Asians for all diseases. 8. SPK had higher graft survivals than KA in Blacks and Whites. 9. PC patients with HLA-DR1 had a statistically significant higher graft survival than those without DR1 in Whites and Hispanics. 10. IDDM patients with HLA-DR4 had a statistically significantly higher graft survival rates than those without DR4 in Blacks, Whites, Hispanics, and Asians. 11. PC, IgA, and ALP patients had a lower incidence of rejection before discharge than other patients. HTN and IDDM patients had the highest rate of first day non-function and need for dialysis. 12. Need for dialysis and rejection before discharge led to 20 percentage points lower 5-year graft survival compared with those patients who were free of these complications. 13. First day anuria led to 10 percentage point lower 5-year graft survival compared with those with first day diuresis.
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PMID:Effect of primary diseases. 1538 26

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

We reported previously the autoantibodies directed to caspase-8 among patients with silicosis, systemic sclerosis (SSc) and systemic lupus erythematosus (SLE) , and in healthy individuals. In this study, we analyzed the correlation between anti-caspase-8 autoantibody responses and HLA class II alleles in silicosis patients. The frequencies of HLA-DRB1*0406 were significantly higher in antibody positive patients (16.67%) than in control individuals (3.03%, p=0.0006). The lysine (K) at position 71 as in DRB1*0406 has been reported to be associated with rheumatoid arthritis (RA) and insulin dependent diabetes mellitus (IDDM). The haplotype HLA-DR4; DQB1*0302 was detected in 4 of 12 antibody positive patients. RA, IDDM, or pemphygus vulgaris link to the haplotype. The frequencies of DQB1*0401 were significantly lower in antibody positive patients (0%) than that in controls (13.33%, p=0.0390). The aspartic acid at position 57 in the DQB1 molecule as in DQB1*0401 is reported to play a role in the resistance to IDDM. The frequency of DPB1*0601 in antibody positive patients (5.88%) was significantly higher than that in controls (0.56%, p=0.0003). DPB1*0601 is reported to be a risk factor among RA patients, and glutamate at position 69 of the DPB1 molecule may be involved. Repeated and continuous screening of autoantibodies seems to be necessary among workers in contact with Si-related substances for the detection of immunological disorders in the early stage.
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PMID:Anti-caspase-8 autoantibody response in silicosis patients is associated with HLA-DRB1, DQB1 and DPB1 alleles. 1570 53

Autoimmune disorders constitute a diverse group of phenotypes with overlapping features and a tendency toward familial aggregation. It is likely that common underlying genes are involved in these disorders. Until very recently, no specific alleles--aside from a few common human leukocyte antigen class II genes--had been identified that clearly associate with multiple different autoimmune diseases. In this study, we describe a unique collection of 265 multiplex families assembled by the Multiple Autoimmune Disease Genetics Consortium (MADGC). At least two of nine "core" autoimmune diseases are present in each of these families. These core diseases include rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), type 1 diabetes (T1D), multiple sclerosis (MS), autoimmune thyroid disease (Hashimoto thyroiditis or Graves disease), juvenile RA, inflammatory bowel disease (Crohn disease or ulcerative colitis), psoriasis, and primary Sjogren syndrome. We report that a recently described functional single-nucleotide polymorphism (rs2476601, encoding R620W) in the intracellular tyrosine phosphatase (PTPN22) confers risk of four separate autoimmune phenotypes in these families: T1D, RA, SLE, and Hashimoto thyroiditis. MS did not show association with the PTPN22 risk allele. These findings suggest a common underlying etiologic pathway for some, but not all, autoimmune disorders, and they suggest that MS may have a pathogenesis that is distinct from RA, SLE, and T1D. DNA and clinical data for the MADGC families are available to the scientific community; these data will provide a valuable resource for the dissection of the complex genetic factors that underlie the various autoimmune phenotypes.
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PMID:Analysis of families in the multiple autoimmune disease genetics consortium (MADGC) collection: the PTPN22 620W allele associates with multiple autoimmune phenotypes. 1571 22

The lymphoid-specific phosphatase (LYP) encoded by PTPN22 is involved in preventing spontaneous T-cell activation by dephosphorylating and inactivating T-cell receptor-associated Csk kinase. We have genotyped 396 type 1 diabetic patients and 1,178 control subjects of Caucasian descent from north central Florida and report a strong association between type 1 diabetes and a polymorphism (R620W) in the PTPN22 gene. The homozygous genotype for the T allele encoding the 620W residue is associated with an increased risk for developing type 1 diabetes (odds ratio [OR] = 3.4, P < 0.008), and the heterozygous genotype C/T had an OR of 1.7 (P = 6 x 10(-6)). The C/C homozygous genotype is protective against type 1 diabetes (OR = 0.5, P = 6 x 10(-6)). Furthermore, transmission disequilibrium analysis of 410 affected sibpair and simplex families of Caucasian descent indicated that the type 1 diabetes-associated T allele is transmitted more often (57.2%) than randomly expected (P < 0.003). Together with previous reports of the association between PTPN22 and type 1 diabetes, as well as rheumatoid arthritis and systemic lupus erythematosus, these results provide compelling evidence that LYP is a critical player in multiple autoimmune disorders.
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PMID:Genetic association between a lymphoid tyrosine phosphatase (PTPN22) and type 1 diabetes. 1573 72

Inflammatory diseases encompass a variety of medical conditions. In this chapter, autoimmune diseases and allergic disorders will be our focus. The autoimmune diseases include organ-specific autoimmunities, such as type I diabetes mellitus and autoimmune thyroiditis (AITD), and organ non-specific disorders such as systemic lupus erythematosus (SLE). All of them seem to share aspects of aberrant immunologic tolerance toward self-antigens. Asthma and atopic diathesis are among the allergies. Crohn disease and SLE are relatively rare with a prevalence of 10-50 per 100,000, and rheumatoid arthritis (RA), psoriasis, AITD and asthma are commoner with a prevalence of 500 per 100,000 or much higher. The difference among ethnic groups is not prominent for rheumatoid arthritis, psoriasis, AITD or asthma, but Crohn disease and SLE affect some ethnic populations more than others. Although all of these disorders have some environmental component, asthma and atopy seem most affected by environmental factors, as is suggested by the significant increase in their incidence over the last several decades with changes in various environmental factors, especially in developed countries. Over the last 10 years, multiple linkage studies revealed many disease-linked loci throughout the genome with various consistencies. As implicated by some pathophysiological studies of inflammatory immune system related disorders, certain loci are involved in multiple disorders. In the following sections, reports on the identification of disease-associated genes or markers will be summarized for individual diseases (cytotoxic T lymphocyte-associated 4 (CTLA4), CARD15, DLG5, SLC22A4/A5, programmed cell death 1 (PDCD1), RUNX1, SLC9A3R1/NAT9, PADI4, ADAM33, DPP10, PHF11 and GPRA), followed by a discussion of the genes that have been implicated in multiple disorders.
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PMID:Recent findings on genes associated with inflammatory disease. 1582 43

Several multiple, large-scale, genetic studies on autoimmune-disease-associated SNPs have been reported recently: peptidylarginine deiminase type 4 (PADI4) in rheumatoid arthritis (RA); solute carrier family 22 members 4 and 5 (SLC22A4 and 5) in RA and Crohn's disease (CD); programmed cell death 1 (PDCD1) in systemic lupus erythematosus (SLE), type 1 diabetes mellitus (T1D), and RA; and protein tyrosine phosphatase nonreceptor type 22 (PTPN22) in T1D, RA, and SLE. Because these reports on association were not always evaluated in multiple ethnic groups and because ethnic difference in allele frequency of the variants has been also reported, we investigated allele frequencies of nine SNPs in four autoimmune-disease-associated loci in Caucasian, African-descent, and Japanese populations. Although SNPs in PADI4 had similar allele frequency among three groups [maximal difference 11%; (P >0.05)], the other three loci revealed statistically significant allele frequency differences (maximal difference 39% (P <0.00001), 13% (P <0.00001), and 8% (P <0.00001) in SLC22A4, PDCD1, and PTPN22, respectively). Of note, three SNPs in the three loci that had allele frequency more than 8% in the Caucasian population were either not polymorphic at all or extremely rare in the Japanese population. Our data suggest that ethnic variations of polymorphisms should be evaluated in detail, and differences should be incorporated into investigations of susceptibility variants for common diseases.
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PMID:Ethnic differences in allele frequency of autoimmune-disease-associated SNPs. 1588 54

Excess levels of tumor necrosis factor-alpha (TNF-alpha) have been associated with certain autoimmune diseases. Under the rationale that elevated TNF-alpha levels are deleterious, several anti-TNF-alpha therapies are now available to block the action of TNF-alpha in patients with autoimmune diseases with a chronic inflammatory component to the destructive process. TNF-alpha antagonists have provided clinical benefit to many patients, but their use also is accompanied by new or aggravated forms of autoimmunity. Here we propose a mechanistically based hypothesis for the adverse events observed with TNF-alpha antagonists, and argue for the opposite therapeutic strategy: to boost or restore TNF-alpha activity as a treatment for some forms of autoimmunity. Activation defects in the transcription factor nuclear factor kappaB leave autoreactive T cells sensitive to TNF-alpha-induced apoptosis. Treatment with TNF-alpha, by destroying autoreactive T cells, appears to be a highly targeted strategy to interrupt the pathogenesis of type 1 diabetes, lupus and certain forms of autoimmunity.
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PMID:The therapeutic potential of tumor necrosis factor for autoimmune disease: a mechanistically based hypothesis. 1596 69


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