Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

---

Query: UMLS:C0003864 (arthritis)
69,039 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The HLA-DRB1 gene was reported to be associated with anticitrullinated protein/peptide autoantibody (ACPA) production in rheumatoid arthritis (RA) patients. A new classification of HLA-DRB1 alleles, reshaping the shared epitope (SE) hypothesis, was recently found relevant in terms of RA susceptibility and structural severity. We investigated the relevance of this new classification of HLA-DRB1 SE+ alleles in terms of rheumatoid factor (RF) and ACPA production in a sample of French RA patients. We studied 160 early RA patients included in a prospective longitudinal cohort of French Caucasian patients with recent-onset arthritis. RF, anticyclic citrullinated peptide 2 (anti-CCP2) and antideiminated human fibrinogen autoantibodies (AhFibA) were assessed in all patients at inclusion. The HLA-DRB1 gene was typed by PCR-sequence specific oligonucleotides probes (PCR-SSOP), and SE+ alleles were classified into four groups (S1, S2, S3P, S3D) according to the new classification. The new classification of HLA-DRB1 SE+ alleles distinguishes predisposing and protective alleles for RF, anti-CCP2 or AhFibA production. The presence of S2 or S3P alleles is associated with both RF, anti-CCP2 or AhFibA positivity, whereas the presence of S3D or S1 alleles appears to be protective for RF, anti-CCP2 or AhFibA positivity. The new classification of HLA-DRB1 SE+ alleles is relevant in terms of autoantibody production in early RA patients by differentiating predisposing and protective alleles for RF or ACPA production.
Arthritis Res Ther 2007
PMID:A new classification of HLA-DRB1 alleles differentiates predisposing and protective alleles for autoantibody production in rheumatoid arthritis. 1732 18

Patients with rheumatoid arthritis (RA) are at risk of excess mortality, predominantly owing to cardiovascular (CV) events. The receptor for advanced glycation end products (RAGE) has been implicated in the perpetuation of the chronic inflammatory response in vascular disease. A Gly82-->Ser polymorphism in the RAGE gene, which is associated with enhanced RAGE signaling, is present more frequently in patients with RA than the general population. To investigate whether RAGE Gly82-->Ser polymorphism is associated with CV events in RA, we examined CV events, CV risk factors, features of RA and RAGE Gly82-->Ser polymorphism in 232 patients with RA attending a tertiary referral hospital. CV events, the duration and severity of RA, and risk factors for CV disease were determined using patient questionnaires, chart review, laboratory analysis and radiographs. DNA was typed for HLA-DRB1 genes and RAGE Gly82-->Ser polymorphism. The RAGE Ser82 allele, which is in linkage disequilibrium with the RA susceptibility allele HLA-DRB1*0401, was carried by 20% of patients. More than 20% of the cohort had suffered a vascular event; a shorter duration of RA, but not the RAGE genotype, was significantly associated with CV events. However, a history of statin use was protective. Thus, the RAGE Ser82 allele, associated with enhanced RAGE signaling, does not predispose to CV events in RA. However, treatment of hyperlipidemia with statins reduces the probability of a CV event.
Arthritis Res Ther 2007
PMID:Receptor for advanced glycation end products Glycine 82 Serine polymorphism and risk of cardiovascular events in rheumatoid arthritis. 1742 4

Gene-gene and gene-environment interactions are key features in the development of rheumatoid arthritis (RA) and other complex diseases. The aim of this study was to use and compare three different definitions of interaction between the two major genetic risk factors of RA--the HLA-DRB1 shared epitope (SE) alleles and the PTPN22 R620W allele--in three large case-control studies: the Swedish Epidemiological Investigation of Rheumatoid Arthritis (EIRA) study, the North American RA Consortium (NARAC) study, and the Dutch Leiden Early Arthritis Clinic study (in total, 1,977 cases and 2,405 controls). The EIRA study was also used to analyze interactions between smoking and the two genes. "Interaction" was defined either as a departure from additivity, as interaction in a multiplicative model, or in terms of linkage disequilibrium--for example, deviation from independence of penetrance of two unlinked loci. Consistent interaction, defined as departure from additivity, between HLA-DRB1 SE alleles and the A allele of PTPN22 R620W was seen in all three studies regarding anti-CCP-positive RA. Testing for multiplicative interactions demonstrated an interaction between the two genes only when the three studies were pooled. The linkage disequilibrium approach indicated a gene-gene interaction in EIRA and NARAC, as well as in the pooled analysis. No interaction was seen between smoking and PTPN22 R620W. A new pattern of interactions is described between the two major known genetic risk factors and the major environmental risk factor concerning the risk of developing anti-CCP-positive RA. The data extend the basis for a pathogenetic hypothesis for RA involving genetic and environmental factors. The study also raises and illustrates principal questions concerning ways to define interactions in complex diseases.
...
PMID:Gene-gene and gene-environment interactions involving HLA-DRB1, PTPN22, and smoking in two subsets of rheumatoid arthritis. 1743 41

Antibodies to citrullinated proteins (ACPA), i.e., to peptides posttranslationally modified by the conversion of arginine to citrulline, are specific serological markers for rheumatoid arthritis (RA). Studies on anticitrulline immunity, summarized in this review, demonstrate that the criterion-based syndrome RA should be subdivided into at least two distinct subsets (ACPA-positive and ACPA-negative disease). A new etiological model is proposed for ACPA-positive RA, built on MHC class II-dependent activation of adaptive immunity. Fundamentals of this model include the following: (a) ACPA antedate onset of arthritis; (b) ACPA may aggravate arthritis in rodents; (c) ACPA are triggered in the context of genes that confer susceptibility to RA (HLA-DRB1 SE) and by environmental agents triggering RA (smoking or bacterial stimuli); (d) ACPA may complex with citrullinated proteins present in target tissue as part of a multistep process for arthritis development. The model provides a new basis for molecular studies on the pathogenesis of ACPA-positive arthritis.
...
PMID:Immunity to citrullinated proteins in rheumatoid arthritis. 1817 73

In the past few years considerable advances have been made in the genetics of susceptibility to rheumatoid arthritis (RA). For decades the HLA-DRB1 alleles were the only extensively replicated genetic factor, but more genetic risk factors have now been identified that predispose to RA. Interestingly, several of the observed genetic variants conferred risk to anticitrulline-peptide antibody (ACPA)-positive RA and two variants may be restricted to ACPA-negative RA, pointing to the need for subclassification of RA. The current manuscript reviews recently identified genetic factors predisposing to ACPA-positive RA and ACPA-negative RA. Additionally, although being scarcely explored, genetic variants affecting the severity of disease course are discussed.
Arthritis Res Ther 2008
PMID:Advances in the genetics of rheumatoid arthritis point to subclassification into distinct disease subsets. 1839 79

The influence of certain alleles of the HLA-DRB1 locus on risk for rheumatoid arthritis has been well established through linkage and association studies. In addition, other loci in the HLA region on 6p21 may also affect an individual's risk profile. Here, we used a method to detect excess identity-by-descent sharing between affected sib pairs conditional on the observed genotypes at the hypothesized causal locus to test for the presence of additional arthritis risk loci in the linked region. We used affected sib pairs from two different studies. Because the test depends heavily on specifying accurate allele frequency estimates at the proposed causal locus, we used HLA-DRB1 allele frequency estimates from a large, population-based sample. We also discuss an alternate form of the test in which we could condition on parental genotypes, thereby eliminating the need for actual allele frequencies. The test showed no evidence for the presence of additional arthritis risk loci in the region in the British or North American samples made available for Genetic Analysis Workshop 15. Given the prior knowledge that there likely are arthritis risk loci other than HLA-DRB1 in the region, it appears the tests may have inadequate power to detect the presence of these loci in certain cases.
...
PMID:No evidence for multiple loci affecting rheumatoid arthritis risk on chromosome 6p21. 1846 41

Rheumatoid arthritis is a chronic inflammatory polyarthritis whose etiology remains uncertain. Recently we have learned that autoimmunity to citrullinated protein antigens has specificity for rheumatoid arthritis and defines a clinically and genetically distinct form of the disease. Multiple genes contribute to disease susceptibility, with the HLA locus accounting for 30% to 50% of overall genetic risk. Five risk loci have been identified and validated: HLA-DRB1, PTPN22, STAT4, a region in 6q23, and the TRAF1/C5 locus. Also, there is renewed interest in the contribution of T cells to ongoing inflammation in rheumatoid arthritis. Autoantibodies to citrullinated protein epitopes are specific for rheumatoid arthritis, are associated with a more aggressive disease course, and are pathogenic in an animal model of autoimmune arthritis. There is a strong association between shared-epitope-expressing HLA-DRB1 alleles and the development of rheumatoid arthritis associated with autoimmunity to citrullinated protein antigens.
...
PMID:The immunopathogenesis of rheumatoid arthritis. 1895 86

Anti-citrullinated protein/peptide antibodies (ACPA) have recently emerged as sensitive and specific serological markers of rheumatoid arthritis (RA), providing superior alternative of the rheumatoid factor (RF) test in the laboratory diagnostics of RA. Citrullination is a post-translational modification of arginine by deimination, physiologically occurring during apoptosis, inflammation or keratinization. The presence of several citrullinated proteins has been demonstrated in the RA synovium. The identification of citrullinated epitopes as targets led to the development of the first and later second-generation anti-cyclic citrullinated peptide (anti-CCP) antibody assays. The anti-Sa antibody has been identified a decade ago; however, recent studies confirmed that anti-Sa is directed against citrullinated vimentin. The determination of ACPA may have important prognostic significance, since ACPA production can precede the onset of clinical RA symptoms by years. ACPA(+) individuals with early, undifferentiated arthritis may have higher risk to develop RA. ACPA has important prognostic role during the progression of RA and it has also been associated with pronounced radiographic progression. ACPA production has been associated with several genetic predisposing factors, including HLA-DRB1 and PTPN22 1858T alleles, as well as with environmental and lifestyle-related factors, primarily smoking and possibly, the use of oral contraceptives and excessive caffeine intake. Thus, the assessment of ACPA, in addition to clinical, radiographic and genetic outcome measures may be important to assess disease prognosis and aids to design effective, early therapeutic strategies.
...
PMID:Anti-citrullinated protein/peptide autoantibodies in association with genetic and environmental factors as indicators of disease outcome in rheumatoid arthritis. 1942 13

Besides atherosclerosis and lung cancer, smoking is considered to play a major role in the pathogenesis of autoimmune diseases. It has long been known that there is a connection between rheumatoid factor-positive rheumatoid arthritis and cigarette smoking. Recently, an important gene-environment interaction has been revealed; that is, carrying specific HLA-DRB1 alleles encoding the shared epitope and smoking establish a significant risk for anti-citrullinated protein antibody-positive rheumatoid arthritis. We summarize how smoking-related alteration of the cytokine balance, the increased risk of infections (the possibility of cross-reactivity) and modifications of autoantigens by citrullination may contribute to the development of rheumatoid arthritis.
Arthritis Res Ther 2009
PMID:Rheumatoid arthritis and smoking: putting the pieces together. 1967 9

These days, rheumatoid arthritis (RA) is reported to be subclassified into two subsets by anti-citrullinated peptide antibody (ACPA) positivity. Clinically, ACPA positive RA tends to develop more severe arthritis than ACPA negative RA. In addition, a lot of reported susceptibility genes to RA (ie. HLA-DRB1(*)04, PTPN22, TRAF1/C5, CTLA4) are found to be associated only with ACPA positive RA but not with ACPA negative RA. It is getting clear that HLA-DRB1(*)04, which was believed to be primarily associated with RA, is not a primary risk factor but ACPA is. Then, a hypothesis for the disease mechanism of ACPA positive RA is set as follows; citrullination possibly due to smoking, etc, provokes ACPA production in individuals who have susceptibility alleles of genes including HLA, followed by joint inflammation in autoantibody-dependent manner. The search for susceptibility genes for ACPA negative RA is slowly progressing, but only a few genes are so far reported: HLA-DRB1(*)03 for Caucasian, HLA-DRB1(*)09 for Japanese, IRF5 and STAT4. When we investigate the disease mechanisms of RA, we should manage independently the two disease subsets : ACPA positive and ACPA negative RA.
...
PMID:[Is rheumatoid arthritis without anti-citrullinated peptide antibody a genetically distinct subset?]. 2004 16


<< Previous 1 2 3 4 5 6 Next >>

---