Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0003873 (rheumatoid arthritis)
 53,068 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Rheumatoid arthritis (RA) is a chronic disease of unknown pathogenesis. To identify abnormally expressed genes in synovium from RA patients, we performed column gel electrophoresis-coupled subtractive hybridization (CGESH). CGESH is a newly developed subtractive hybridization technique to achieve sufficient enrichment of DNA sequences. CGESH was performed using restricted enzyme digested cDNA synthesized from mRNA of synovial tissues from one RA patient and one osteoarthritis (OA) patient. The obtained subtraction libraries (RA-OA) were screened by dot blot hybridization. The clones showing higher hybridization with the RA-OA probe were identified by sequence analysis and homology search. Their DNA sequencing revealed that the genes of HLA-DRB1, sequestosome 1, elongation factor 1alpha were included. Furthermore, a functionally unknown gene (FLJ00133) was also identified. It is reported that sequestosome 1 is a scaffold in the signal transduction of TNFalpha and interleukin 1, which are the important cytokines involved in the pathogenesis of RA. It is possible that other genes identified by the CGESH technique would be associated with the pathogenesis of RA, although there is no direct evidence yet. Our results imply that the CGESH technique is a useful tool to detect genes involved in the pathogenesis of RA. Further investigation of the functional roles of candidate genes should shed light on the pathogenesis of RA.
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PMID:Analysis of abnormally expressed genes in synovium from patients with rheumatoid arthritis using a column gel electrophoresis-coupled subtractive hybridization technique. 1570 37

It has been known that rheumatoid arthritis (RA)-associated antigenic peptides CII263-272 are coupled with human leucocyte antigen (HLA)-DRB1 and recognized by T-cell receptor (TCR), which in turn induced T-cell proliferation and pathogenesis of RA. Non-T-cell-stimulating type II collagen (CII) peptides might be generated by removing the amino acids responsible for TCR contact and keeping the HLA-DR-binding residues intact. In this study, a panel of altered CII peptides (APs) with consecutive or single substitutions of the TCR-contacting residues were synthesized. Through peptide binding and T-cell activation assays, we demonstrated that altered CII263-272 peptides with substitution of the TCR-contacting residues did not or barely induced T-cell activation; one of the best non-T-cell-stimulating peptide AP268-270 inhibited the binding of wild-type CII263-272 to HLA-DR1 and T-cell activation triggered by wild-type CII263-272 and HA306-318 in a dose-response manner. These data suggest that removal of the TCR-contacting residues of CII263-272 leads to HLA-DRB1 binding and low T-cell-stimulating peptides, which could potentially inhibit the T-cell response induced by HLA-DRB1-binding antigenic peptides.
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PMID:The inhibitory effect of altered collagen II peptide on HLA-DRB1-restricted T-cell activation. 1578 43

We studied HLA-DRB1 alleles in 101 patients with rheumatoid arthritis (RA) and 229 normal subjects by polymerase chain reaction and sequence-specific oligonuclotide hybridization. We observed a statistically significant association between HLA-DR4 and RA (p = 0,0088). This association was not observed for the DR1 status. No particular DR4 suballeles were preferentially expressed in patients. Allele *0102 was more frequent in RA patients (p = 0.0084), while *0103 in controls (p = 0.000047). No difference was observed for the presence of early erosions and extra-articular features in patients with no, one or two RA associated alleles and among share epitope positive and negative patients.
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PMID:[HLA-DRB1 alleles and rheumatoid arthritis in northern Italy: lack of correlation with disease severity and extra-articular manifestations]. 1592 13

Anti-cyclic citrullinated peptide antibodies (anti-CCP) are a new diagnostic marker for rheumatoid arthritis (RA), which shows a specificity of 97% and a sensitivity of 81% in the second generation assay. About 61% of RA patients express HLA-DRB1*0401. In a cohort of patients with RA we investigated whether the expression of anti-CCP correlates with the carriage of certain genes on the HLA-DRB1 locus. Our data reveal a highly significant association between anti-CCP and HLA-DR4, and a weaker but still significant association with HLA-DR1. HLA-DRB1*0401 is not a prerequisite for anti-CCP production, but if HLA-DRB1*0401 was present, 90% of our RA patients were anti-CCP positive.
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PMID:HLA-DRB1 and anti-cyclic citrullinated peptide antibody production in rheumatoid arthritis. 1597 Jun 40

A major goal of current human genome-wide studies is to identify the genetic basis of complex disorders. However, the availability of an unbiased, reliable, cost efficient and comprehensive methodology to analyze the entire genome for complex disease association is still largely lacking or problematic. Therefore, we have developed a practical and efficient strategy for whole genome association studies of complex diseases by charting the human genome at 100 kb intervals using a collection of 27,039 microsatellites and the DNA pooling method in three successive genomic screens of independent case-control populations. The final step in our methodology consists of fine mapping of the candidate susceptible DNA regions by single nucleotide polymorphisms (SNPs) analysis. This approach was validated upon application to rheumatoid arthritis, a destructive joint disease affecting up to 1% of the population. A total of 47 candidate regions were identified. The top seven loci, withstanding the most stringent statistical tests, were dissected down to individual genes and/or SNPs on four chromosomes, including the previously known 6p21.3-encoded Major Histocompatibility Complex gene, HLA-DRB1. Hence, microsatellite-based genome-wide association analysis complemented by end stage SNP typing provides a new tool for genetic dissection of multifactorial pathologies including common diseases.
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PMID:Whole genome association study of rheumatoid arthritis using 27 039 microsatellites. 1600 Mar 23

Leukocyte immunoglobulin-like receptor subfamily B member 1 (LILRB1/LIR1/ILT2) is an inhibitory receptor broadly expressed on leukocytes and recognizes HLA-class I and human cytomegalovirus UL18. LILRB1 is encoded within the leukocyte receptor complex on 19q13.4, previously implicated to be a susceptibility region to systemic lupus erythematosus (SLE). In this study, we screened for polymorphisms of LILRB1 and examined their association with SLE and rheumatoid arthritis (RA). In the 5' portion of LILRB1, three haplotypes containing four non-synonymous substitutions within the ligand-binding domains and two single nucleotide polymorphisms within the promoter region were identified and designated as PE01-03. In the 3' portion, two haplotypes (CY01, 02) containing a non-synonymous substitution of the cytoplasmic region were identified. CY01 and 02 did not co-segregate with PE01-03. Significant association with susceptibility to SLE or RA was not observed; however, among the subjects not carrying RA-associated HLA-DRB1 shared epitope (SE), LILRB1.PE01/01 diplotype was significantly associated with RA (odds ratio 2.05, P = 0.019 and Pc = 0.038). Gross difference was not observed in the crystal structures, thermostabilities and binding affinities to HLA-class I ligands among LILRB1.PE01-03 haplotype products; however, surface expression of LILRB1 was significantly decreased in lymphocytes and monocytes from the carriers of PE01 haplotype. These findings demonstrated that LILRB1 is highly polymorphic and is associated with susceptibility to RA in HLA-DRB1 SE negative subjects, possibly by insufficient inhibitory signaling in leukocytes. In addition, these observations suggested that the polymorphisms of LILR family members may be substantially involved in the diversity of human immune responses.
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PMID:Extensive polymorphisms of LILRB1 (ILT2, LIR1) and their association with HLA-DRB1 shared epitope negative rheumatoid arthritis. 1601 35

Susceptibility to and outcome for rheumatoid arthritis (RA) have been associated with particular HLA-DR alleles, but these alleles vary among ethnic groups and geographic areas. The frequency of HLA-DR1 (HLA-DRB1*0101, DRB1*0102) and HLA-DR4 (DRB1*0401, DRB1*0404) alleles is elevated among Caucasian patients with RA. We studied a northeastern Hungarian population of RA patients to determine the frequency of HLA-DR1 and HLA-DR4 phenotypes in this population and to compare it with healthy control subjects, as well as to investigate whether the presence of these alleles could be a marker for RA. We performed HLA-DRB1 genotyping (DRB1*01-DRB1*16) in 83 RA patients and 55 healthy controls using polymerase chain reaction with sequence-specific primers (PCR-SSP). In the case of HLA-DR1- or HLA-DR4-positive patients, the DR1 and DR4 subtypes were also determined. The frequency of HLA-DR4 alleles was significantly higher in RA patients than in controls (31.3 vs. 10.9%; P <.05). HLA-DR1, in particular, tended to be more frequent in patients than in controls (32.5 vs. 18.1%). Among the HLA-DR4 subtypes, DRB1*0401 and DRB1*0404 were the most common alleles found in both groups. However, no significant differences were seen in the frequency of HLA-DRB1*0401 and HLA-DRB1*0404 between RA patients and controls. In contrast, HLA-DRB1*0405 and HLA-DRB1*0408 were significantly more common in RA patients than in control subjects. Among HLA-DR1 subtypes, the DRB1*0101 allele was most commonly detected, but HLA-DRB1*0101 as well as DRB1*0102 and DRB1*0105 were similarly frequent in RA patients and controls. HLA-DR12 was more common among controls than in RA patients (18.1 vs. 0%; P <.05). Our results generally agree with the findings in other Caucasian populations. Nonetheless, we found differences in the frequency of HLA-DR1 and HLA-DR4 subtypes among Hungarian patients compared with reports from other geographic regions (e.g., Finland and Asia). Our data suggest that in northeastern Hungary, HLA-DR4 as well as its subtypes DRB1*0405 and DRB1*0408 may be involved in susceptibility to RA, but HLA-DR1 may not. In addition, the presence of HLA-DR12, at least in Hungary, may protect from this disease.
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PMID:Association of rheumatoid arthritis with HLA-DR1 and HLA-DR4 in Hungary. 1612 67

The development or radiographic progression of rheumatoid arthritis (RA) is associated with HLA-DRB1 alleles encoding a conserved amino acid sequence commonly called the shared epitope(SE). Besides HLA-DRB1, however, other genes may be implicated in the progression of RA. On the other hand, osteoclasts play an important role in the joint destruction in patients with RA. Thus, it is speculated that polymorphisms in genes of cytokines which stimulate or inhibit osteoclastogenesis are associated with severity of RA. In fact, it has been reported that polymorphisms in genes of osteoclastogenesis-related cytokines are associated with the severity or radiographic progression of RA. In this article, we review recent findings, including ours, indicating that polymorphisms in genes of osteoclastogenesis-related cytokines may account for the severity of RA.
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PMID:[Association of polymorphisms in genes of osteoclastogenesis-related cytokines with severity in patients with rheumatoid arthritis]. 1616 14

Rheumatoid Arthritis (RA) is the most common chronic inflammatory joint disease. The overall prevalence is 1% and in people older than 60 it is more than 2%. RA has auto-immune features: auto-antibodies against the Fc part of IgG, so-called Rheumatoid Factor (RF) are found more often in RA patients and more recently RA-specific auto-antibodies directed against Cyclic Citrunilated Peptides (CCP) have been discovered. Based on twin studies the contribution of genetic factors to the pathogenesis has been estimated to be about 60%. The main genetic contribution (about 40%) comes from the HLA complex. An association between HLA-DR4 and RA was already documented almost 30 years ago. This association was more prominent for severe forms of the disease. Because more HLA-DRB1 alleles appeared to be associated with RA and the products of these alleles shared a 5AA sequence in a peptide-binding pocket the so-called Shared Epitope (SE) hypothesis was formulated, the prediction being that these DRB1 molecules would bind an RA inducing peptide(s). Thus far however such (a) peptides remain elusive. Because the risk for RA associated with different but SE-identical DRB1 alleles varies considerably this SE can also not be the whole explanation for the HLA contribution to RA susceptibility/severity. A modified SE has been postulated and a role for DQ has been postulated. There is also evidence for a contribution of non-class II genes to susceptibility. About 5 years ago we have reported that certain HLA-DRB1 alleles are associated with protection from (severe) RA. The products of these alleles carry instead of the SE sequence another peptide anchor region consisting of the amino acid DERAA. In a large prospective cohort study we showed recently that these alleles indeed confer (dominant) protection both against developing RA and a severe course of the disease. This protection was observed both in the presence and the absence of SE susceptibility alleles. We are presently exploring the hypothesis that this protection is mediated by regulatory T cells reactive with the DERAA epitope. An obvious way to unravel the apparently complex association between HLA and RA is to reduce the heterogeneity of this multifactorial disease. Recently, we have discovered that SE positive DRB1 alleles are exclusively associated with CCP positive RA. The previously reported association with RF positive RA appeared to be secondary to the association with anti-CCP pos. RA. This was the case both for the association found for susceptibility and severity. Interestingly, DRB1*03 was exclusively associated with anti-CCP neg. RA. Because recent evidence puts the immune response against citrunilated proteins (CCP) as prime suspect for disease induction and progression in this subgroup of RA these observations are a big leap forwards in solving the HLA-RA puzzle.
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PMID:Redefining the HLA and RA association: to be or not to be anti-CCP positive. 1625 78

The objective of this study was to examine HLA-DRB1 and HLA-DQB1 genotypes in patients with severe extra-articular rheumatoid arthritis (ExRA) and to compare them with the genotypes of rheumatoid arthritis (RA) patients without extra-articular manifestations. Patients with severe ExRA were recruited from a large research database of patients with RA, from two cohorts of prevalent RA cases, and from a regional multicenter early RA cohort. Cases with ExRA manifestations (n = 159) were classified according to predefined criteria. Controls (n = 178) with RA but no ExRA were selected from the same sources. Cases and controls were matched for duration of RA and for clinical center. PCR based HLA-DRB1 and HLA-DQB1 genotyping was performed using the Biotest SSP kit, with additional sequencing in order to distinguish DRB1*04 subtypes. Associations between alleles and disease phenotypes were tested using multiple simulations of random distributions of alleles. There was no difference in global distribution of HLA-DRB1 and HLA-DQB1 alleles between patients with ExRA and controls. DRB1*0401 (P = 0.003) and 0401/0401 homozygosity (P = 0.002) were more frequent in Felty's syndrome than in controls. The presence of two HLA-DRB1*04 alleles encoding the shared epitope (SE) was associated with ExRA (overall odds ratio 1.79, 95% confidence interval 1.04-3.08) and with rheumatoid vasculitis (odds ratio 2.44, 95% confidence interval 1.22-4.89). In this large sample of patients with ExRA, Felty's syndrome was the only manifestation that was clearly associated with HLA-DRB1*0401. Other ExRA manifestations were not associated with individual alleles but with DRB1*04 SE double dose genotypes. This confirms that SE genes contribute to RA disease severity and ExRA. Other genetic and environmental factors may have a more specific impact on individual ExRA manifestations.
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PMID:The impact of HLA-DRB1 genes on extra-articular disease manifestations in rheumatoid arthritis. 1654 68


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