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 primarily associated with HLA-DR4 in a wide range of ethnic groups. DNA analysis of HLA-DRB1 sequences shows that a limited set of alleles are positively associated with the disease. Third hypervariable region sequences QRRAA, QKRAA and RRRAA are found in up to 85% of RA patients and may constitute the basic unit of association. Risk estimates for alleles and hypervariable regions differ between ethnic groups and subsets of patients. Severe RA and Felty's syndrome are significantly associated with DR4 Dw4 and, to a lesser extent, with DR4 Dw14. In patients the latter allele is almost exclusively found in combination with Dw4, suggesting that complementation is occurring. Critical substitutions in the peptide binding groove correlate with the presence of RA, suggesting that the disease may be driven by the presentation of specifically bound peptide and/or may be influenced by differential selection of the T cell repertoire.
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PMID:The HLA association with rheumatoid arthritis. 158 78

Multiplex families of rheumatoid arthritis (RA) and concordance of the development of RA in monozygotic twins strongly suggest the relationship of genetic factor to the onset of RA. Among many genetic markers, HLA shows the strongest association with RA and association between RA and HLA-DR4 has been reported in many ethnic groups. DNA typing of HLA class II genes revealed that DRB1 * 0405 (Dw 15) is the most susceptible DRB1 allele for RA in the Japanese. The particular epitope sequence at the third hypervariable region (position 70-74, and 86) and DR beta chain, expressed with the structure of the DR4 molecule seems to be important for the susceptibility to RA.
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PMID:[Contribution of genetic factors to RA]. 158 28

A follow-up study (mean duration five years) was undertaken on 370 previously unaffected first degree relatives from multicase rheumatoid arthritis (RA) families. The objectives were to determine the incidence of RA in this group and the possible predictors of disease development. In all, 14 individuals developed RA, equivalent to an incidence of 8/1000 person-years of observation. There was no control group included in this study as the intensive-follow-up required substantial compliance from highly motivated families. Population-based estimates, however, from a number of sources would suggest an annual incidence below 0.5/1000 per year, substantially less than the rate obtained in this study. The small number of incident cases precluded definitive conclusions about risk factors within these families but there were no important effects of age or sex. Possession of HLA-DR1 or DR4 explained only some of the increased risk. The increased incidence observed in the previously unaffected relatives of such families would suggest that this familial clustering did not for the most part arise by chance and that other shared genetic or environmental influences are relevant.
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PMID:Incidence of rheumatoid arthritis in a genetically predisposed population. 159 97

This study of 168 north Indian patients with rheumatoid arthritis (RA) confirms the significant association of susceptibility to RA with DR4 specificity (P less than 0.0001). This association was observed equally in familial as well as sporadic patients. The HLA-DR2 and DR5 alleles were identified to be conferring protection in RA, DR5 being reduced significantly in the non-familial patients only. None of the other DR antigens revealed any association with RA in this population, including the DR4 negative group of patients. An analysis of the DR phenotypes in patients and controls revealed that DR4 in combination with DR1 provided the highest relative risk (71.9) followed by DR4, DR4 (RR = 4.1). These results demonstrate that susceptibility to RA is not due to a single HLA specificity but the effect of a group of related epitopes occurring in common among subtypes of DR4 as well as in some DR1 alleles.
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PMID:Protective & risk DR phenotypes in Asian Indian patients with rheumatoid arthritis. 159 26

The precise nature of the HLA element associated with rheumatoid arthritis has been identified as a short sequence of amino acids on the alpha helix of a range of DR beta alleles. Recently the range of alleles known to bear this sequence and to be associated with rheumatoid arthritis has increased considerably. Although these findings lend further weight to the validity of the original hypothesis, they have also made it very difficult to propose a mechanism for the association. It has also become clear that the simple model of dominant susceptibility is unsatisfactory. Patients with early disease show little or no association with any HLA alleles, whereas patients with severe forms of rheumatoid arthritis are frequently homozygous for DR4, showing a disproportionate tendency toward compound heterozygocity--expressing two different molecules sharing the conserved sequence.
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PMID:The immunogenetic component of susceptibility to rheumatoid arthritis. 159 14

We performed retrospective analysis of 141 Northern Italian patients with rheumatoid arthritis (RA). This series represents all the patients seen as in and/or outpatients at the rheumatologic unit of Reggio Emilia Hospital during a 2 year period (1987-88). We observed a low frequency of nodules (16%) and vasculitis (2.1%). Thus, RA seems to be milder in our population compared to Caucasian patients with RA originating from North America or England. We observed a weak association with DR4 (RR = 2.4) in the total group of patients with RA. A low frequency of DR4 was observed in patients and controls (29 vs 14.5%, p = 0.001). When compared with controls the frequency of DR4 was significantly higher in seropositive (p = 0.001), but not in seronegative patients. We found that DR4 was significantly associated with nodules (RR = 6.4), with extraarticular features (EAF) (RR = 4) and with erosions (RR = 3) compared with controls. The subgroups with nodules and EAF had a DR4 frequency (respectively, of 52 and 40%) which was significantly higher than that observed in remaining patients (respectively, 25 and 24%). No significant difference was observed in the DR4 frequency between the patients with erosions and those without (34 vs 18%). Thus, DR4 in our population seems to be predominantly associated with a subgroup of patients characterized by seropositivity and EAF.
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PMID:Extraarticular manifestations of rheumatoid arthritis and HLA antigens in northern Italy. 162 22

The association of certain autoimmune diseases with HLA molecules is being refined through the use of sequence-specific oligonucleotide probes and amino acid sequencing, together with continuing elucidation of the functional features of HLA molecules derived from the milestone description by Bjorkman of the HLA molecular structure. The association of insulin-dependent diabetes mellitus and HLA began with weak associations of Class I antigens (B8 and B15) and progressed to Class II antigens (DR3 and DR4), then to subtypes of DR4 (Dw4, 10, and 14), and now to DQ molecules including the absence of aspartic acid at position 57 of the DQ beta chain and the presence of arginine at position 52 of the DQ alpha chain. In rheumatoid arthritis (RA) the HLA antigen association remains with certain Class II molecules of the DR series (DR4 and DR1) that share amino acid sequences with a restricted number of other DR antigens seen in RA, as well as a segment of the gp 110 protein of the Epstein-Barr virus. Although ankylosing spondylitis has a strong association with the Class I antigen B27, that association is not explained by any of the B27 subtypes defined by monoclonal antibodies, by the eight variable amino acids in B27 subtypes, or by the two unique amino acids on B27. The remarkable antibody cross-reactivity among lymphocytes bearing B27, a synthetic peptide sequence (63-84) of B27, and the 188-193 sequence of K. pneumoniae nitrogenase has provided strong support for molecular mimicry being an important mechanism in the association of HLA molecules with disease.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:HLA molecules in autoimmune diseases. 163 34

Two variants of the HLA-DR4-linked DQw3 allele, namely DQw7 and DQw8, were analysed in patients of mixed ancestry (Cape Coloureds) with rheumatoid arthritis and in healthy individuals from the same population group using a DQ beta-specific cDNA probe. The DQw7 allele, identified by 3,4 kb Hind III or 3,7 kb and 6,9 kb Bam HI DQ beta-specific restriction fragments, was expressed in 93% of DR4-positive patients (N = 15), compared with 12.5% DR4-positive normal individuals (N = 8). This DQ variant showed a highly significant association (relative risk = 98; P less than 0.0001) with rheumatoid arthritis in this population group and may play a role in their susceptibility to this disease.
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PMID:HLA DQ beta restriction fragment length polymorphism and rheumatoid arthritis. Association between DQw7 and rheumatoid arthritis in DR4-positive subjects. 167 66

HLA-DR, HLA-DQ, and T cell receptor beta (TCR beta) chain gene polymorphisms were investigated in 43 patients with rheumatoid arthritis (RA), in 10 patients with Felty's syndrome (FS), and in 5 RA multicase families. RA was found to be strongly associated with a DRB1 gene sequence motif present in DR1, DR4-Dw4, and DR4-Dw14 alleles. Ninety-three percent of RA patients were positive for at least 1 of these alleles, providing strong support for the "shared epitope hypothesis." The frequency distribution of this sequence motif suggests a dominant mode of inheritance. All 10 FS patients were DR4-Dw4 positive. Different DR-DQ associations among DR4 positive RA and FS patients indicate heterogeneity in the genetic susceptibility to these 2 disease entities. Furthermore, analyses of TCR V beta 8, V beta 11, and C beta gene polymorphisms did not support the notion of an influence of TCR beta germline allotypes on RA susceptibility.
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PMID:Association of rheumatoid arthritis with a dominant DR1/Dw4/Dw14 sequence motif, but not with T cell receptor beta chain gene alleles or haplotypes. 162 29

Felty's syndrome (FS) is a rare complication of rheumatoid arthritis (RA) previously shown to be strongly associated with HLA-DR4 and less significantly with HLA-DQw7. To map more precisely the HLA locus responsible for susceptibility to FS, we have examined HLA-DR4 and DQ beta-chain polymorphisms in FS patients and controls using restriction fragment length polymorphism analysis and polymerase chain reaction amplification in conjunction with oligonucleotide probing. The increased frequency of DR4 in FS (93% vs. 32% controls) was due almost entirely to enrichment for the Dw4 subtype (88% vs. 20% controls) with a secondary increase of the Dw14 subtype. Dw10 and Dw13 subtypes of DR4 were absent from the patient group. Increase in DQw7 frequency among DR4 FS patients could be accounted for by linkage disequilibrium between Dw4 and DQw7 alleles. Whereas susceptibility to RA is strongly associated with a conserved HLA-DR beta epitope associated with several DRB1 alleles, it is primarily the Dw4 allele which is associated with progression to Felty's syndrome. The finding that amino acid sequence variation at the DR4B1 locus rather than DQB1 is associated with development of FS will have important implications for the development of novel immunotherapies which are major histocompatibility complex allele-dependent.
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PMID:Strong primary selection for the Dw4 subtype of DR4 accounts for the HLA-DQw7 association with Felty's syndrome. 168 90


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