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Content archived on 2024-05-14

The predictive value of HLA and other candidate genes for disease severity in Spanish, Greek and UK rheumatoid arthritis patients

Objective

- To investigate the relationship between genetic factors and the severity of rheumatoid arthritis in different European populations.
- To determine the usefulness of HLA-DR genotypes in predicting the extent of joint erosions in UK, Spanish and Greek RA patients.
- To examine the association of microsatellite markers for TNF-alpha, glutathione S-transferase superoxide dismutase and natural resistance associated macrophage protein with RA.

Greeks Spanish and UK populations differ with respect to the HLA associations that exist with RA. In UK patients, associations are observed with DRB1*0401, 0404 and 0101 whereas in Greek patients DRB1*1001 and 0405 are found. HLA-DRB1*0101 and 0405 are associated with RA in Spanish. All these alleles carry the shared DRB1 epitope sequence associated with RA, however it is apparent from preliminary studies that they are not equal in conveying risk for developing severe disease. In UK RA patients the risk for progressing to severe disease in individuals with the DRB1 0401/0404 genotype is 50 times greater than for shared epitope negative patients. The ability to identify such high risk genotypes may be of great clinical importance in predicting a severe erosive outcome and which patients would receive early and aggressive treatment. Similarly the use of toxic therapies could be avoided in those with a good prognosis.

As HLA associations with RA differ in these three populations it is important to establish whether similar relationships exist between DR genotypes and severity of erosions. In addition to the potential for predicting clinical prognosis it will be helpful in understanding how particular genotypes contribute to disease aetiology and pathology.

Several other genes may also be helpful in predicting RA outcome. Polymorphisms of tumour necrosis factor-a, glutathione S-transferases, superoxide dismutase and natural resistance associated macrophage protein will be analyzed using microsatellite markers inside or in close proximity to these genes. The three participating centres will be HLA-DRB1 typing large series of RA patients and determining their shared epitope status. Genotyping for TNF-a, GST, SOD and NRAMP microsatellites will be performed in Manchester. Patients will be radiologically assessed for erosive changes and these will be analyzed centrally in relation to genotype status. Multivariate analysis allowing for gender and disease duration will also be performed.

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University of Manchester
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Oxford Road
M13 9PT Manchester
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