Rheumatology Advance Access originally published online on January 17, 2006
Rheumatology 2006 45(4):488-490; doi:10.1093/rheumatology/kel011
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LETTER TO THE EDITOR |
The RAGE G82S polymorphism is not associated with rheumatoid arthritis independently of HLA-DRB1*0401
1 Departments of Rheumatology and 2 Immunohematology and Blood Transfusion, Leiden University Medical Centre, Leiden and 3 Business Unit Biomedical Research, TNO Quality of Life, Leiden, The Netherlands
Corresponding author: R. E. M. Toes Leiden University Medical Centre, Department of Rheumatology, C4-R P.O. Box 9600, 2300 RC Leiden, The Netherlands. E-mail: R.E.M.Toes{at}lumc.nl
SIR, The receptor for advanced glycation end-products (RAGE) has been shown to play a role in several pathologies, including rheumatoid arthritis (RA) [1]. RAGE binding of ligands up-regulated in RA synovial tissue, fluid and serum can lead to increased cell activation, including migration, hyperplasia and increased cytokine production. Several animal studies have described a possible role for RAGE in the onset and severity of arthritis. In these animal studies, blockade of the receptor showed suppression of arthritis, while administration of RAGE ligands induced arthritis in healthy mice [2, 3]. In addition, increased levels of RAGE ligands have been found in RA patients and correlate with disease severity [4–6].
Previous studies have indicated that a gain-of-function mutation of RAGE correlates with RA. Linkage of RAGE with the HLA-DRB1-DQ region, a region known to associate with RA susceptibility and severity, could account for this correlation. To dissect the possible confounding effects of the HLA-DRB1 region in the possible association of RAGE with RA, we investigated the correlation of a gain-of-function mutation in RAGE to HLA-DRB1 alleles and RA.
Three hundred and seventy-seven consecutive RA patients of the Leiden Early Arthritis Cohort, an inception cohort for patients with recent-onset arthritis [7] (mean±S.D. age 48±17 yr, 55% female) and 535 non-RA controls of the same cohort (57±16 yr, 67% female) were included in the analysis (Table 1). All RA patients fulfilled the 1987 criteria of the American College of Rheumatology. The study was approved by the local ethics committee and written informed consent was obtained from all patients and controls according to the Declaration of Helsinki. HLA genotyping was available for all patients and controls. In addition, to type the participants for the RAGE G82S polymorphism we used PCR followed by overnight digestion with AluI. The 82S polymorphism results in the formation of an extra AluI restriction site.
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Hofmann et al. [2] reported that the RAGE 82S polymorphism correlated with susceptibility to RA. However, RAGE is in strong linkage disequilibrium with HLA-DR4 [8], in particular HLA alleles encoding a common shared epitope within the HLA-DRB1 allele. In the population studied by Hofmann et al., linkage was found with DR1*0401, and after correction for this allele the correlation between the RAGE 82S polymorphism and susceptibility to RA was lost. These data were not conclusive, since the numbers of patients and controls positive for the RAGE 82S polymorphism were very low (5 out of 95 and 2 out of 134, respectively). Here, we identified 46 out of 377 RA patients and 36 out of 535 controls harbouring the RAGE 82S polymorphism. We found an association between the RAGE 82S polymorphism and RA without correction for HLA alleles. However, in patients, RAGE 82S was in linkage (defined as P<0.01) with DRB1*0401 [odds ratio (OR) 6.5, P<0.0001]. In controls RAGE 82S was in linkage with DRB1*0401 (OR 4.43, P<0.00001) and 0901 (OR 5.05, P = 0.002). Correction for the presence or absence of these HLA alleles was done by the Svejgaard method [9]. When the association of RAGE 82S with RA was corrected for the absence or presence of DRB1*0901, the association between RAGE and RA remained present. Conversely, after correction for the presence/absence of HLA DRB1*0401, the association between RAGE 82S and RA was lost (Table 2), indicating that RAGE is not associated with RA independently of HLA DRB1*0401 in this cohort. Also in logistic regression analysis with DRB1*0401 and RAGE as possible explanatory variables and the presence of RA as dependent variable, only DRB1*0401 was independently associated with RA (OR 2.5, P<0.001).
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In conclusion, considering the size of our study, it is unlikely that the RAGE 82S polymorphism is associated with RA independently of HLA DRB1*0401. However, although this alternation in the receptor itself does not seem to play an important role in RA pathology, the correlation between RA severity and levels of RAGE ligands could still indicate that RAGE ligands do play an important role in RA pathology.
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The authors have declared no conflicts of interest.
References
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