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

We analyzed the distribution of DRB1, DQA1, DQB1, and DPB1 allelic variants in 48 rheumatoid arthritis (RA) patients, compared with 109 Italian random controls, using PCR amplification and hybridization with specific oligonucleotides. We confirm the previously reported increase of DR4 specificity, in comparison with healthy Italian individuals. In particular, we find a statistically significant positive association of DRB1*0401 and DRB1*0404 alleles with RA. However, when we compare the DR4+ groups, none of the DRB1*04 alleles is increased in the RA group. By sequence analysis, performed on 10 patients, we demonstrate that the DRB1*04 genes of RA show no difference from the DRB1*04 sequences previously published. From the molecular analysis of the other DRB1 polymorphic variants, we find a trend of positive association of DRB1*0101 in DR4-negative patients versus DR4-negative healthy controls and, in the group of DR4-negative and/or DR1-negative patients, a similar increase of DRB1*06. Also, we observe in RA patients a statistically significant increase of DQA1*0301 and DQB1*0302 accompanied by a significant decrease of DQA1*0201, DQA1*0501 and DQB1*0201. Finally, from the analysis of DPB1 gene, it can be assessed that the distribution of DPB1 alleles does not differ significantly between RA patients and healthy controls.
 ...
PMID:Analysis of HLA DP, DQ, and DR alleles in adult Italian rheumatoid arthritis patients. 142 34

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.
 ...
PMID:[Contribution of genetic factors to RA]. 158 28

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.
 ...
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.
 ...
PMID:Strong primary selection for the Dw4 subtype of DR4 accounts for the HLA-DQw7 association with Felty's syndrome. 168 90

Although HLA genes have been shown to be associated with certain diseases, the basis for this association is unknown. Recent studies, however, have documented patterns of nucleotide sequence variation among some HLA genes associated with a particular disease. For rheumatoid arthritis, HLA genes in most patients have a shared nucleotide sequence encoding a key structural element of an HLA class II polypeptide; this sequence element is critical for the interaction of the HLA molecule with antigenic peptides and with responding T cells, suggestive of a direct role for this sequence element in disease susceptibility. We describe the serological and cellular immunologic characteristics encoded by this rheumatoid arthritis-associated sequence element. Site-directed mutagenesis of the DRB1 gene was used to define amino acids critical for antibody and T-cell recognition of this structural element, focusing on residues that distinguish the rheumatoid arthritis-associated alleles Dw4 and Dw14 from a closely related allele, Dw10, not associated with disease. Both the gain and loss of rheumatoid arthritis-associated epitopes were highly dependent on three residues within a discrete domain of the HLA-DR molecule. Recognition was most strongly influenced by the following amino acids (in order): 70 greater than 71 greater than 67. Some alloreactive T-cell clones were also influenced by amino acid variation in portions of the DR molecule lying outside the shared sequence element.
 ...
PMID:Structural requirements for recognition of the HLA-Dw14 class II epitope: a key HLA determinant associated with rheumatoid arthritis. 170 Apr 25

Starting with the historical background and ending with the most recent data obtained by DNA typing, using PCR and oligonucleotide probes, the role of HLA antigens in rheumatoid arthritis (RA) and in several forms of juvenile arthritis (JA) is reviewed. RA is thought to be associated with an epitope of the third hypervariable region of DRB1 which is shared by several alleles including DR4-Dw4, Dw14, Dw15, DR1, DRw14.2, and DRw10. Rheumatoid factor-positive JA is also associated with DR4, but in rheumatoid factor-negative JA DR4 is absent, or markedly decreased, suggesting that it has a protective effect. Typing for the HLA-DP alleles has confirmed the association of pauciarticular JA with DPBI*0201. Recent studies in the author's laboratory have shown that DPB1*0301 is the main susceptibility factor for rheumatoid factor-negative polyarticular onset JA. It is of interest that also adult rheumatoid factor-negative RA patients have an increase of DPB1*0301, suggesting that these two clinical subsets may represent related diseases.
 ...
PMID:Immunogenetics of rheumatoid arthritis and juvenile arthritis. 171 86

The relative distributions of 12 HLA-DR4-related DRB1 alleles in indigenous populations of Australia, Melanesia, Micronesia, Polynesia, and northern and southern China have been determined by analysis of oligonucleotide hybridization patterns of 406 examples of HLA-DR4. DRB1*0405 and DRB1*0410 were common DR4 alleles in Australian aborigines and in Melanesians, while DRB1*0403 was the predominant DR4 allele in coastal Melanesians, Micronesians, and Polynesians; DRB1*0406 was confined to Chinese. A novel DR4 allele, found in 30% of DR4-positive Australian aborigines but exclusive to one aboriginal population, was a combination of DRB1*04 and 0803 nucleotide sequences and was carried on a haplotype with DR4-like DQ linkage arrangements. DQA1 and DQB1 typing generated 12 DR4-related haplotypes; the population distributions of these reflected the ancestral affinities of aborigines and Melanesians, the overlaying of coastal Melanesia with pre-Polynesian DR4 alleles and the colonization of Micronesia by an independent, non-Polynesian group. DR4-related autoimmune disorders such as rheumatoid arthritis (RA) and insulin-dependent diabetes mellitus (IDDM) are virtually unknown in indigenous populations of Australia and Oceania and this study confirmed that high-risk RA determinants, Dw4 and Dw14, occurred rarely. However, the DQw8 allele, thought particularly to predispose to IDDM, was present in the majority of DR4-positive Polynesians and Micronesians.
 ...
PMID:Diversity in HLA-DR4-related DR,DQ haplotypes in Australia, Oceania, and China. 178 73

Rheumatoid arthritis (RA) is known to be associated with class II HLA antigens in most populations, but recent studies in Israeli Jewish patients showed no significant differences in either DR4 or DR1 between patients and controls. In a previous DR4 subset study we found DR4-Dw15 to be associated with susceptibility (RR = 9.2) but this allele occurred in only 12% of the patients. We analyzed all DRB1 genes, using the polymerase chain reaction (PCR) and hybridization with allele specific oligonucleotides, in 49 Jewish patients with RA and 40 normal Jewish controls. Six DRB1 alleles that are similar to the prototype DR4-Dw4 (DRB1*0401) appeared to contribute to the risk for developing RA. In addition to DR4-Dw15 (DRB1*0405) 2 other alleles having substitutions in codons 71 only (DR1-Dw1/DRB1*0101, DR4-Dw14.2/DRB1*0408) or in codons 70 and 71 (DRw10/DRB1*1001) gave highly significant relative risks. Together, this group, with valine in position 85, and glycine in codon 86, gave a relative risk of 11.0 (p = 0.0002). Two other alleles with the same sequence in the third hypervariable region (amino acids 67-74) but with valine in codon 86 (DR4-Dw14.1/DRB1*0404) or alanine in 85 and valine in 86 (DR1-Dw20, DRB1*0102) gave a combined risk of 3.6 (p = 0.049). Altogether these 7 alleles with similar sequences in the third hypervariable region accounted for 55.6% of the patients, with an overall relative risk of 8.6 (p = 0.00002). Our results in this population indicate that shared epitopes in the third hypervariable region of DRB1 alleles also play a role in susceptibility to RA.(ABSTRACT TRUNCATED AT 250 WORDS)
 ...
PMID:Rheumatoid arthritis in Israeli Jews: shared sequences in the third hypervariable region of DRB1 alleles are associated with susceptibility. 189 59

Genetic variants at DRB1 (Dw subtypes), DQB, and C4 loci were compared in rheumatoid disease subjects with or without the extra-articular feature of Felty's syndrome or major vasculitis. DR4 positive subjects with rheumatoid arthritis alone showed no preferential associations with DQB or Dw variants or with C4 null alleles. Felty's subjects showed associations with the DQB encoded DQw7 allele and with the C4B null allele but no preferential associations with any Dw subtype of DR4. By contrast DR4 +ve rheumatoid-vasculitic subjects showed associations with the Dw14 as well as with DQw7 and the C4A null allele. These different MHC associations in different clinical disease subsets show that rheumatoid disease is immunogenetically heterogeneous and suggest that MHC genes outside the DRB1 locus may also influence susceptibility or modify expression of the rheumatoid disease process.
 ...
PMID:Immunogenetic heterogeneity in rheumatoid disease as illustrated by different MHC associations (DQ, Dw and C4) in articular and extra-articular subsets. 199 Dec 18

HLA-DR4 is associated with risk for developing rheumatoid arthritis (RA) in most populations. In Israeli Jews, in whom the Dw10 subtype of DR4 predominates, no association of RA with DR4 has been found. The inability to detect an association could be due to the high frequency of DR4-Dw10. We used DNA typing with amplification by the polymerase chain reaction and dot-blotting with allele-specific oligonucleotides to determine DR4 variants in 131 Jewish RA patients living in Israel and 134 controls. In both Ashkenazi Jews and non-Ashkenazi Jews, the rare variant Dw15 (previously identified in Japanese populations and in Japanese patients with RA) was found to be the main allele associated with the risk of developing RA (relative risk = 9.2, corrected P less than 0.001). However, this low-frequency allele could be responsible for susceptibility in only 11.5% of the patients. Susceptibility for rheumatoid factor-positive RA was associated with Dw4 and Dw15; the risk for rheumatoid factor-negative RA was associated only with Dw14. The distribution of the HLA-DQ alleles associated with DR4 showed that more than half of the RA patients with Dw15 also had HLA-DQw2. The frequencies of DQw7 and DQw8 were not different in RA patients compared with controls. The results suggest that, as in other populations, susceptibility for the development of RA in Israeli Jews is associated with DRB1 locus alleles of the DR4 group.
 ...
PMID:A variant of HLA-DR4 determines susceptibility to rheumatoid arthritis in a subset of Israeli Jews. 202 8


1 2 3 4 5 6 7 8 9 10 Next >>