Rheumatoid Arthritis Basic Science Studies
Protection against anti–citrullinated protein antibody–positive rheumatoid arthritis is predominantly associated with HLA–DRB1*1301: A meta-analysis of HLA–DRB1 associations with anti–citrullinated protein antibody–positive and anti–citrullinated protein antibody–negative rheumatoid arthritis in four European populations
Article first published online: 29 JAN 2010
Copyright © 2010 by the American College of Rheumatology
Arthritis & Rheumatism
Volume 62, Issue 5, pages 1236–1245, May 2010
How to Cite
van der Woude, D., Lie, B. A., Lundström, E., Balsa, A., Feitsma, A. L., Houwing-Duistermaat, J. J., Verduijn, W., Nordang, G. B. N., Alfredsson, L., Klareskog, L., Pascual-Salcedo, D., Gonzalez-Gay, M. A., Lopez-Nevot, M. A., Valero, F., Roep, B. O., Huizinga, T. W. J., Kvien, T. K., Martín, J., Padyukov, L., de Vries, R. R. P. and Toes, R. E. M. (2010), Protection against anti–citrullinated protein antibody–positive rheumatoid arthritis is predominantly associated with HLA–DRB1*1301: A meta-analysis of HLA–DRB1 associations with anti–citrullinated protein antibody–positive and anti–citrullinated protein antibody–negative rheumatoid arthritis in four European populations. Arthritis & Rheumatism, 62: 1236–1245. doi: 10.1002/art.27366
- Issue published online: 29 APR 2010
- Article first published online: 29 JAN 2010
- Accepted manuscript online: 29 JAN 2010 12:00AM EST
- Manuscript Accepted: 20 JAN 2010
- Manuscript Received: 24 JUL 2009
- Centre for Medical Systems Biology within the framework of the Netherlands Genomics Initiative
- European Union (Sixth Framework Programme integrated project Autocure and Seventh Framework Programme integrated project Masterswitch)
- Plan Nacional de I+D, Spain. Grant Number: SAF2006-00398
- Junta de Andalucía. Grant Number: CTS11800
- Fundacion Mutua Madrileña
- NWO AGIKO grant from the Netherlands Organization for Scientific Research
- Dutch Arthritis Association. Grant Number: (LLP-16)
- NWO-ZonMW VIDI and VICI grant from the Netherlands Organization for Scientific Research
The protective effect of HLA–DRB1 alleles on the development of rheumatoid arthritis (RA) is poorly understood. The aim of this study was to perform a meta-analysis of 4 European populations to investigate which HLA–DRB1 alleles are associated with protection in anti–citrullinated protein antibody (ACPA)–positive RA and ACPA-negative RA.
Data for >2,800 patients and >3,000 control subjects for whom information on HLA–DRB1 typing and ACPA status was available were collected from 4 European countries: Norway, Sweden, The Netherlands, and Spain. The odds ratios (ORs) and 95% confidence intervals (95% CIs) associated with the different HLA–DRB1 alleles were analyzed in a combined meta-analysis focused on protective alleles and classifications. The analysis of ACPA-positive RA was stratified for the shared epitope (SE) alleles, to correct for skewing due to this association.
In ACPA-positive RA, the only alleles that conveyed protection after stratification for SE were HLA–DRB1*13 alleles (OR 0.54 [95% CI 0.38–0.77]). The protective effect of the allele classifications based on the DERAA and D70 sequences was no longer present after exclusion of DRB1*13 (for D70, OR 0.97 [95% CI 0.75–1.25]), indicating that DRB1*13, rather than the DERAA or D70 sequence as such, is associated with protection. Among the DRB1*13 alleles, only DRB1*1301 was associated with protection (OR 0.24 [95% CI 0.09–0.59]). Protection appeared to follow a north-to-south gradient, with the strongest association in northern European countries. In ACPA-negative RA, there were no robust associations with HLA–DRB1 alleles.
Our data do not support any of the classifications of protective alleles and indicate that protection against ACPA-positive RA is predominantly associated with HLA–DRB1*1301.