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

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Query: UMLS:C0003873 (rheumatoid arthritis)
53,068 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Mouse class II-deficient HLA-DQB1*0302, DQA1*0301 (DQ8) transgenic mice are susceptible to severe collagen-induced arthritis (CIA), an animal model for rheumatoid arthritis. To examine whether polymorphism at the DRB1 locus can modulate DQ-restricted arthritis, we generated double-transgenic (DR/DQ) mice. HLA-DRB1*1502 (DR2) and DRB1*0301 (DR3) were introduced separately into CIA susceptible DQ8.Abeta transgenic mice to generate DQ8/DR2.Abeta and DQ8/ DR3.AbetaO mice. The HLA-DR molecules in these mice were found to be functional on the basis of their positive/negative selection of the Vbeta T cell repertoire. Introduction of the DR2 gene led to a significant decrease in disease incidence in DQ8.Abeta mice, while the DR3 transgene had no effect. In vitro T cell proliferative responses against bovine Cll collagen in primed mice were higher in DQ8/DR3 mice compared with DQ8/DR2 mice. Cytokine analysis showed a Th2 profile in DQ8/DR2 mice, while DQ8/DR3 mice showed a Th1 profile. These results suggest that DRB1 polymorphism can modulate the disease.
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PMID:Modulation of HLA-DQ-restricted collagen-induced arthritis by HLA-DRB1 polymorphism. 979 11

In the present study, we tested our hypothesis on the role of a DQ-DR haplotype in rheumatoid arthritis (RA) predisposition. Using two groups of patients and controls, one from The Netherlands and one from Switzerland, we found that DQA1*0301-homozygous and DQA1*0301//DQA1*0101/04-heterozygous individuals are highly predisposed to RA in both populations, while DQA1*0101/04-homozygous are not. The DQA1*0301-DRB1*0403/06/07 and DQA1*0301-DRB1*0901 haplotypes are not associated with RA by themselves but strongly increase the risk of developing disease in DQA1*0301- and DQA1*0101/04-heterozygous. DRB1 alleles carrying the motif DERAA in their third hypervariable region, i.e., *0103, *0402, *1102, *1103, *1301, and *1302, provide a long-lasting protection against RA in DQA1*0101/04- but not in DQA1*0301-positive individuals. These data show that considering both DQ and DR gives a better distinction between patients and controls than the shared epitope hypothesis.
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PMID:An extended HLA-DQ-DR haplotype rather than DRB1 alone contributes to RA predisposition. 979 35

To explore the role of HLA-DRB1 genes in the development of rheumatoid arthritis (RA) and the correlations between HLA-DR alleles and clinical manifestations of patients with RA we studied 86 patients and 106 race matched controls in whom HLA-DR typing was performed by the method of DNA amplification with sequence-specific primers (PCR-SSP). The subtypes of HLA-DR4 were determined by the method of hybridization of PCR products with sequence-specific oligonucletides (PCR-SSO). The absence or presence of HLA-DR4 and its subtypes was evaluated with the clinical and serological characteristics of the patients. Compared with controls, an increased gene frequency of HLA-DR4 (48.8% vs 17.9%, P < 0.001) and a decreased frequency of HLA-DR5 (16.3% vs 27.4%, P = 0.06) were found. The DRB1 * 0405 accounted for 61.9% of DR4+ RA patients and 21.1% of DR+4 controls (P < 0.01). There was no difference between the DR4+ and DR4- patients with respect to age, sex, duration of disease, extra-articular manifestations including secondary Sjogren's syndrome. But rheumatoid factor (RF) was associated with HLA-DR4 (P < 0.05). According to the X-ray stage, the patients of DR4+ were more severe than those of DR4- (P < 0.05). HLA-DR4 and DR4 subtype of DRB1 * 0405 were related to the development of RA in Chinese. HLA-DR4 can be a useful prognostic marker in the patients with RA.
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PMID:[HLA-DRB1 alleles genotyping in patients with rheumatoid arthritis in Chinese]. 981 72

Rheumatoid arthritis (RA) is a chronic articular inflammatory disease associated with HLA-DR genes that share a five amino acid sequence motif, QKRAA or QRRAA, from position 70 to 74 in the third hypervariable region of the DRB1 molecule. Since these associations between DRB1 genes and susceptibility to RA are incomplete, we examined the role of a CA repeat polymorphic microsatellite marker, D6S273, located between HSP70 and Bat2 genes in the class III region of MHC, in susceptibility to RA. Ninety-seven adult patients with seropositive RA and 100 normal healthy subjects were studied. Two D6S273 alleles (132 and 138) showed significant differences in their prevalence in RA patients as compared to normal controls; allele 132 was significantly higher in total patients and in DRB1 QKRAA/QRRAA epitope-positive patients, and allele 138 was significantly higher in QKRAA/QRRAA-negative patients. Analysis of data suggested that the association of D6S273 132 allele with RA was secondary to that of DRB1 genes. On the other hand, D6S273 138 allele showed primary association with RA susceptibility in QKRAA/QRRAA epitope-negative patients. The D6S273 138 allele thus provides an additional risk in RA susceptibility. The results in the present study therefore suggest that two regions in MHC, DRB1 and D6S273, contribute to susceptibility to RA.
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PMID:D6S273 microsatellite polymorphism and susceptibility to rheumatoid arthritis. 982 May 98

The dog is a valuable model for studying several human diseases as well as one of the most important models for organ transplantation. Important to understanding the pathophysiology or development of some of these diseases is an understanding of the canine major histocompatibility complex (MHC) or dog leukocyte antigen (DLA). Initial characterization of the DLA involved primarily cellular, serological, and biochemical analyses. Later a molecular analysis of the DLA region was begun. There are at least four complete class I genes: DLA-88, DLA-12, DLA-64, and DLA-79. DLA-88 is highly polymorphic, with more than 40 alleles obtained from an examination of 50 mixed breed dogs. The other class I loci are less polymorphic, with fewer than 12 alleles each. In the class II region there is one complete DRB gene called DLA-DRB1 with at least 24 alleles and one full-length DQB gene, DLA-DQB1, with 20 alleles characterized to date. DLA-DQA is less polymorphic with nine alleles and DLA-DRA appears monomorphic. Two highly polymorphic canine microsatellite markers, one located in the class I region and one located in the class II region, can be used to identify DLA-matched and -mismatched dogs within families for organ transplantation experiments. Future projects include mapping the DLA region by pulsed-field gel electrophoresis and using a recently constructed canine bacterial artificial chromosome (BAC) library to search for new genes within the DLA. The dog has been a useful model for understanding several human diseases such as gluten-sensitive enteropathy (Hall and Batt 1990), rheumatoid arthritis (Halliwell et al. 1972), narcolepsy (Tafti et al. 1996), and systemic lupus erythematosus (Lewis and Schwartz 1971, Teichner et al. 1990), as well as an important model for solid organ and hematopoietic stem cell transplantation (Storb and Deeg 1985). Much of the impetus behind efforts to characterize the canine MHC comes from its importance in transplantation. In spite of the dog's importance in studying human disease and in immunology, molecular analysis of the DLA has lagged behind that of the mouse and human as well as several agricultural animals.
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PMID:Organization of the canine major histocompatibility complex: current perspectives. 998

We have recently proposed a new hypothesis to explain the association of Human Leukocyte Antigen (HLA) with rheumatoid arthritis (RA) predisposition. In this model, which challenges the Shared Epitope (SE) hypothesis, HLA-DQ predisposes while HLA-DR protects. In the present study, we have compared these two models in an Early Arthritis Clinic started in 1993 in the Department of Rheumatology at the Leiden University Medical Centre. Out of 524 patients who enrolled this programme in the period 1993-1998 and completed the one year follow-up, 155 have been classified as RA. These patients along with 306 consecutive cadaveric renal organ donors have been typed for HLA-DR and -DQ. The distributions of predisposing DR alleles according to SE, and predisposing DQ and protective DR according to our model were analysed. We found that two doses of predisposing DQ alleles strongly predisposed to RA, even in individuals with a single dose of SE while DRB1 alleles carrying the motif DERAA confered a dominant protection in DQ5-positive individuals. We conclude that the present findings are consistent with our previously described model of HLA and RA association. Using this new model, we have been able to characterise two novel groups of individuals on the basis of their HLA typing: one strongly predisposed to RA and one protected. Knowing the mechanism of HLA-related dominant natural protection may help in designing novel treatment modalities for RA.
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PMID:HLA-DQ-associated predisposition to and dominant HLA-DR-associated protection against rheumatoid arthritis. 1002 83

We analysed the associations of DR and DQ alleles with rheumatoid arthritis (RA) in Han nationality of China. PCR-RFLP technique was used to determine DRB1, DQA1 and DQB1 alleles in 35 unrelated patients with RA and 100 healthy controls from the Hans. The frequency of DR4 was 51.4% in RA patients and 24.0% in the healthy controls (P < 0.01, RR = 3.30). Subtyping of DR4 revealed no differences in the relative distributions of the DR4 alleles between the RA group and the controls, which both were predominated by DRB1 * 0405 allele, but there was a significant increase in the absolute frequency of DRB1 * 0405 in RA patients compared with the healthy controls (31.4% vs 12.0%, P < 0.01). DQ4 (DQB1 * 04) was also increased both in the RA patients compared with the healthy controls (37.1% vs 10.0%, P < 0.001) and in DR4+ RA patients compared with DR4+ healthy ones (72.2% vs 41.6%, P = 0.0376). Further analysis showed that the haplotype DR4-DQ4 was associated with RA (RR = 5.17, P < 0.001), and that the DR4(+)-DQ4+ patients had more severe disease than the DR4- patients. These results suggest that DR4, mainly the DRB1 * 0405, is associated with RA in Han nationality, and DQ4 may play a role in DR4 conferring susceptibility to RA. The DR4-DQ4 haplotype could be taken as a predictive marker for disease severity.
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PMID:[DNA typing for HLA-DR and HLA-DQ alleles in Chinese patients with rheumatoid arthritis]. 1037 84

We analyzed HLA-DR antigens and microsatellite Bat2 alleles in 97 adult caucasian patients with classical seropositive rheumatoid arthritis (RA) and 95 normal healthy controls. The results demonstrate that the prevalence of microsatellite Bat2 138 allele was significantly higher in RA-susceptibility DRB1 QKRAA/QRRAA epitope-negative patients as compared with normal controls. Analysis of the data suggested that Bat2 138 allele has primary association with RA-susceptibility in QKRAA/QRRAA epitope-negative patients. The Bat2 138 allele thus provides an additional risk in RA-susceptibility. In addition, microsatellite Bat2 138 allele showed a highly significant positive association with microsatellite D6S273 138 allele, which has similar (identical) association with RA development in DRB1 QKRAA/QRRAA epitope-negative patients. The present data demonstrate that DRB1 QKRAA/QRRAA epitope and microsatellite Bat2 138/D6S273 138 alleles more completely define the risk for development of RA. The results in the present study therefore suggest that two regions in MHC, class II (DRB1) and class III (Bat2 and D6S273 in HSP70-Bat2 region), contribute to susceptibility to RA.
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PMID:Genetics of rheumatoid arthritis (RA): two separate regions in the major histocompatibility complex contribute to susceptibility to RA. 1052 92

Tumor necrosis factor alpha plays a substantial role in a number of conditions such as inflammation, autoimmunity, insulin resistance and sleep. Three new single nucleotide polymorphisms, -1,031 T/C, -863 C/A and -857 T/C, were recently identified in the upstream 5'-flanking region of TNFA in the Japanese population. In the present study, we developed polymerase chain reaction (PCR)-preferential homoduplex formation assay for the single-step allele typing of TNFA, and determined the genotypes of 271 healthy unrelated Japanese individuals. Four haplotypes, -1,031/-863/-857 TCC, TCT, CAC and CCC, were found to constitute the majority, if not all, of the TNFA alleles of healthy Japanese population. These alleles were designated as TNFA-U01, -U02 -U03 and -U04, respectively, in the order of frequency. Based on HLA-A, -B and -DRB1 genotypes together with TNFA genotypes, multi-locus haplotypes were analyzed. Significant positive associations were observed between TNFA-U01 and A*3303, B*5201, B*4403, B*4601, B*0702, DRB1*1502, DRB1*0101, DRB1*1302, between TNFA-U02 and B*5401, B*3501, DRB1*0405, DRB1*0407, between TNFA-U03 and B*4006, B*4002, DRB1*0803, DRB1*0802, DRB1*0403, DRB1*0901, and between TNFA-U04 and B*4801. Four-locus haplotype estimation revealed that A*3303-B*4403-TNFA-U01-DRB1*1302, A*2402-B*5201-TNFA-U01-DRB1*1502 and A*2402-B*5401-TNFA-U02-DRB1*0405 constitute major extended haplotypes in Japanese. Interestingly, TNFA alleles previously shown to have a higher promoter activity (U02, U03) were found to form haplotypes with certain DRB1 alleles associated with T helper 1 (Th1)-dominant diseases such as rheumatoid arthritis, insulin dependent diabetes mellitus and Crohn's disease in Japanese. In contrast, TNFA allele with a low promoter activity (U01) is in linkage disequilibrium with the DRB1 alleles associated with T helper 2 (Th2)-dominant diseases such as atopic dermatitis and ulcerative colitis. These observations raise the possibility that TNFA upstream promoter region polymorphisms contribute to some of the HLA-disease associations.
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PMID:Allele typing of human TNFA 5'-flanking region using polymerase chain reaction-preferential homoduplex formation assay (PCR-PHFA): linkage disequilibrium with HLA class I and class II genes in Japanese. 1059 87

Rheumatoid arthritis (RA) is a common disabling disorder of unknown etiology. In the past 2 decades, a number of studies have examined the genetic basis for RA. One major focus of these studies has been to identify genes within the MHC class II (HLA-DR) chromosomal region, which confer susceptibility/resistance to RA. A strong association between HLA-DR4 and adult seropositive RA has been observed in majority of populations. In addition, there is evidence of a positive association between HLA-DR1 and RA. On the basis of prevalence of DR1 (B1*0101) and of subtypes of DR4 (B1*0401, B1*0404 and B1*0405), it has been suggested that a five amino acid sequence motif (QKRAA/QRRAA) from position 70 to 74 in the third hypervariable region of DRbeta1 molecules is associated with susceptibility to RA. These associations between RA and HLA-DR genes are however incomplete in that about 1/4 of patients do not carry RA-susceptibility DRB1 epitope. Since MHC class III region contains genes that are involved in immune response, we have recently examined the role of a number of microsatellites (D6S273, Bat2, TNFa) and HSP70 promoter region alleles in susceptibility to RA. The results demonstrate that two regions in MHC, class II (DRbeta1) and class III (D6S273, HSP70, Bat2, TNFa) more completely define the risk for development of RA.
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PMID:Genetic basis for rheumatoid arthritis. 1060 36


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