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)

Genomic typing of in vitro amplified DNA with sequence-specific oligonucleotide (SSO) probes was performed for DRB1, DQA1, DQB1, DPA1 and DPB1 alleles in 54 random Norwegian rheumatoid arthritis (RA) patients and 181 healthy controls. DRB1 alleles encoding the serological specificity DR4 were found in 80% of the patients, compared to 34% of the controls (relative risk = 7.9, p less than 0.0001). All DR4-positive RA patients carried either DRB1*0401 (Dw4), 0404 (Dw14), or 0405 (Dw15), while no patients were found to carry DRB1*0402 (Dw10) or 0403 (Dw13). The frequency of the DRB1*0101 allele encoding DR1 was not increased, even among DR4-negative RA patients, and we were unable to detect any sharing of other class II alleles among DR4-negative patients. No contribution of any DQA1, DQB1, DPA1 or DPB1 alleles to RA susceptibility could be detected. The results suggest that in the Norwegian population RA is primarily associated with a shared sequence at residues 67-74 of the DR beta 1 chain, but only when this sequence is expressed on DR4 molecules.
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PMID:Rheumatoid arthritis may be primarily associated with HLA-DR4 molecules sharing a particular sequence at residues 67-74. 209 4

To determine the HLA-DR4 subtypes associated with rheumatoid arthritis (RA), we performed amplification of DR4 DRB1 genes by the polymerase chain reaction and dot-blots with oligonucleotide probes. In 52 HLA-DR4+ RA patients, Dw4 was the predominant subtype. This subtype was found in 45 of 52 patients (86.5%) compared with 33 of 59 DR4+ controls (55.9%; P less than 0.001). In the whole population, Dw4 also gave the highest relative risk for RA (RR = 5.31). Relative risk was also associated with DR1.1, the common white DR1 (Dw1) type, which has a third hypervariable region amino acid sequence similar to some forms of DR4 and has glycine at position 86. Variants of DR1 (DR1.2) or DR4 (Dw13.1, Dw14.1) with valine at position 86 appeared less able to confer risk for RA. Substitution of residues in the third hypervariable region of the first domain of DRB1 appeared to correlate with relative risk for RA. Among subjects having 0-1 amino acid substitutions, RA developed in 53%, whereas in subjects with 2-4 amino acid changes, RA was present in only 17.4% (P less than 0.00001). DQw7 (formerly DQw3.1) was slightly increased in DR4+ RA patients compared with controls, but a striking excess of Dw4,DQw7 homozygous patients was observed. The results suggest that DQw7 may have an additional effect, possibly with a recessive mechanism, since it was observed only in DR4 homozygous patients.
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PMID:HLA-DR alleles with naturally occurring amino acid substitutions and risk for development of rheumatoid arthritis. 205 43

Susceptibility to rheumatoid arthritis (RA) may be due to the presence of shared functional epitopes common to the HLA-DR beta chains of several RA-associated haplotypes. We have obtained direct evidence for this hypothesis by using the polymerase chain reaction and sequencing the DRB1 and DQB1 genes from RA patients. A highly conserved epitope present on DR beta chains of DR4 and DR1 haplotypes was found in 83% of 149 patients with classical or definite RA but was found in only 46% of 100 control individuals (P less than 0.0001). Two Dw subtypes of DR4 (Dw4 and Dw14) were associated with disease susceptibility but two other subtypes (Dw10 and Dw13) were not. Sequence differences between these subtypes implicate those residues around the putative antigen binding site of the DR beta molecule in the pathogenesis of RA. These data provide a basis for understanding host susceptibility to RA at a molecular level.
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PMID:HLA-DR4 subtype frequencies in rheumatoid arthritis indicate that DRB1 is the major susceptibility locus within the HLA class II region. 248 9

61 patients suffering from classic erosive rheumatoid arthritis (RA) with a condition persisting for more than 5 years, were examined together with 69 healthy control subjects with regard to associations to "supertypic" HLA-D specificities. We found a significant increase of HLA-DRw53 in patients with seropositive RA (SPRA) (31/42 patients = 73.8%, Chi 2 = 18.4, p less than 0.01, RR = 7.3). Our results confirm the hypothesis, that the HLA-DRB4 gene is closer related to the disease susceptibility genes of SPRA than of DR4 (DRB1).
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PMID:[The effect of HLA-DRB4 on the clinical picture of chronic polyarthritis]. 278 57

Extensive studies in different ethnic groups have associated the susceptibility to development of rheumatoid arthritis (RA) with the third hypervariable region of the major histocompatibility complex (MHC) HLA-DR beta 1 molecule. On the basis of recent findings in the experimental mouse model of collagen-induced arthritis, Eric Zanelli, Miguel Gonzalez-Gay and Chella David propose that the HLA-DRB1 locus is associated with protection to RA and that the actual arthritogenic peptide-presenting molecule is HLA-DQ. Thus, the development of RA would depend upon the expression of the susceptible DQ allele and the nonprotective DRB1 alleles, along with environmental factors that trigger the autoimmune process.
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PMID:Could HLA-DRB1 be the protective locus in rheumatoid arthritis? 754 77

The aetiology of rheumatoid arthritis (RA) has both genetic and environmental origins. However, the relationship of these with each other and with RA disease is complicated as both genes and environment may be protective or render individuals susceptible. Diagnostic certainty and disease heterogeneity have posed serious hurdles for investigating RA. Patients with similar disease phenotypes may have different aetiologies and it may now be more appropriate to investigate genetic susceptibility with respect to disease process or characteristic immunopathology. Disease concordance studies have been a classical approach to estimating the upper threshold of the genetic contribution to RA and recent studies have approximately halved the much quoted figure of 32% reported by Lawrence for RA concordance in monozygotic twins. However, the interpretation of twin data has to be treated with caution as MZ twins can differ in terms of somatic rearrangement/mutation of immunoglobulin and T cell receptor genes, X chromosome inactivation in females, genomic imprinting and in utero immune relationship. Calculations based on heritability put the genetic component in RA much higher. HLA is an important genetic factor in RA and risk is thought to be associated with a consensus sequence of amino acids within the third hypervariable region of certain DRB1 alleles. It is now clear that HLA is not particularly associated with onset of synovitis but is more associated with progression and severity of the disease process. The HLA-DRB1*0401/0404 genotype is particularly associated with severe, erosive and seropositive RA. Clear differences in RA susceptibility exist between males and females and this may be attributed to hormonal status. Males have a higher threshold requirement for developing RA and this may explain why RA in males is more associated with HLA risk alleles. We have now reached a critical time for the investigation of RA aetio-pathology. Recent advances in molecular biology and automated microsatellite gene scanning technology are making it possible to map disease susceptibility genes over the whole genome in common disorders such as RA. This will require large numbers of well characterised multiplex affected families. It is anticipated that some of the genes identified will fit in with our current concepts of which inflammatory and immune processes are pathologically important in RA. However others may be a major surprise.
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PMID:Genetic epidemiology of rheumatoid disease. 755 63

We used polymerase chain reaction amplification and hybridization with specific oligonucleotides to analyze the distribution of DPB1, DQA1, DQB1, and DRB1 allelic variants in 48 patients with rheumatoid arthritis (RA) and compared our results with those from 109 randomly chosen, healthy control subjects. Our work confirms a previously reported increase in DR4 specificity in RA: in particular, we found a statistically significant positive association of the DRB1*0401 and DRB1*0404 alleles with RA. When we compared the DR4 groups, however, none of the DRB1*04 alleles were increased in the RA group. Molecular analysis of the other DRB1 polymorphic variants disclosed the trend of a positive association of DRB1*0101 (DR1) in DR4 negative patients vs DR4 negative healthy control subjects, and an increase in DRw6 (DRB1*13,*14) in the DR4 and/or DR1 negative patient group. Moreover, analysis of the association between RA and a heptapeptide motif (positions 67-74) in the third hypervariable region confirmed that this epitope confers enhanced risk for the development of RA with respect to the allele DRB1*0404 (etiologic fraction = 0.53 vs 0.12). We also observed a statistically significant increase in DQA1*0301 and DQB1*0302 accompanied by a significant decrease in DQA1*0202, DQA1*0501 and DQB1*0201 in RA patients. Analysis of DPB1 alleles disclosed no significant differences between RA patients and healthy control subjects.
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PMID:[Allelic variations of DPB1, DQA1, DQB1 and DRB1 and rheumatoid arthritis: further genetic and statistical considerations]. 757 14

Clinical and biological profiles at the onset of the disease, obtained retrospectively, and human leucocyte antigen typing were studied in 47 rheumatoid arthritis (RA) patients with severe articular damage (group 1) and in 47 patients with limited radiological abnormalities (group 2). The two groups were matched according to disease duration (mean: 8.1 yr). Systemic manifestations were more frequent in group 1. Erythrocyte sedimentation rate (ESR), platelet counts, C-reactive protein (CRP), rheumatoid factor and IgG titres were higher and haemoglobin level lower in group 1. HLA class II genotyping demonstrated that 95.7% of patients in group 1 were Dw4, Dw14 or DR1 as compared to 55.3% in group 2 and 37.1% in normal controls. Two RA-linked DRB1 genes were detected in 34.1% of patients in group 1, vs 8.5% in group 2 and 7.9% in controls. Multiple logistic regression analysis demonstrated that ESR, CRP and genetic markers were the most relevant independent variables and when combined could indicate the outcome in early RA. These data confirmed that different RA subtypes with different prognoses could be associated with particular clinical, biological and genetic profiles. Moreover, some of these factors could serve as predictive markers for outcome at the onset of RA.
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PMID:Prognostic factors in rheumatoid arthritis. Comparative study of two subsets of patients according to severity of articular damage. 763 94

Rheumatoid arthritis is a frequently and potentially severe disease which causes a functional handicap in nearly half the patients 10 years after the identification of the first clinical manifestations. Some patients develop very severe forms with joint destruction and multiple organ involvement while in others the disease remains benign, even after a long clinical course of several years. Theoretically, the future intensity of rheumatoid arthritis in a given patient cannot be predicted at the time of early diagnosis. No prognosis factor has been identified and universally accepted and validated. A marker of prognosis would be highly appreciated by clinicians who could then more closely adapt their management decisions to the disease potential. Clinical and biological data collected to date have provided a limited amount of prognostic information but recent progress in molecular biology suggests that genetic markers could be correlated with disease severity. Several HLA-DRB1 alleles including DR1*0401, DRB1*0404, DRB1*0101 and sometimes DRB1/1001 and DRB1/1402 are potential markers. In France 85% of the patients with rheumatoid arthritis have one of these genes compared with 25% in the general population. In patients with a "high risk" alleles, the second haplotype could also have prognostic value. It would appear possible to distinguish immunogenetically homogeneous subpopulations corresponding to the more severe forms of the disease. It is still too early to propose therapeutic strategies based on current prognosis markers, but a combination of the most pertinent markers should be already used to select homogeneous subsets of patients in fundamental research and clinical trials.
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PMID:[Can the prognosis of early rheumatoid arthritis be predicted?]. 763 13

Over the last two decades, much progress has been made in our understanding of the genetics of rheumatoid arthritis since the discovery of a link between the HLA DR4 antigen and rheumatoid arthritis in 1974. In molecular biology, the precise alleles of the HLA DRB1 gene which encode for different specific molecules have been identified. They have been used to link rheumatoid arthritis to certain HLA DRB1 subtypes recognized as "high risk" alleles. It has been hypothesized that the shared epitope would be one way for a molecular approach to susceptibility of allelic variants in rheumatoid arthritis. More recently, the notion that high risk DRB1 alleles might contribute to disease severity has also been put forward. HLA DRB1 alleles carrying a risk of rheumatoid arthritis would have two properties: they could serve as a marker of the risk of developing the disease and of disease severity both essential elements for the clinician.
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PMID:[Rheumatoid arthritis: its relationship with HLA DR molecules]. 763 18


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