Dr. Irigoyen is recipient of a Fellowship from Amgen. Dr. Criswell's work was supported by the Rosalind Russell Medical Research Center for Arthritis, University of California, San Francisco.
Regulation of anti–cyclic citrullinated peptide antibodies in rheumatoid arthritis: Contrasting effects of HLA–DR3 and the shared epitope alleles
Article first published online: 30 NOV 2005
Copyright © 2005 by the American College of Rheumatology
Arthritis & Rheumatism
Volume 52, Issue 12, pages 3813–3818, December 2005
How to Cite
Irigoyen, P., Lee, A. T., Wener, M. H., Li, W., Kern, M., Batliwalla, F., Lum, R. F., Massarotti, E., Weisman, M., Bombardier, C., Remmers, E. F., Kastner, D. L., Seldin, M. F., Criswell, L. A. and Gregersen, P. K. (2005), Regulation of anti–cyclic citrullinated peptide antibodies in rheumatoid arthritis: Contrasting effects of HLA–DR3 and the shared epitope alleles. Arthritis & Rheumatism, 52: 3813–3818. doi: 10.1002/art.21419
- Issue published online: 30 NOV 2005
- Article first published online: 30 NOV 2005
- Manuscript Accepted: 18 AUG 2005
- Manuscript Received: 13 MAY 2005
- Arthritis Foundation
- NIH. Grant Numbers: N01-AR-72232, R01-AR-44222
- National Institute of Arthritis and Musculoskeletal and Skin Diseases
- National Institute of Allergy and Infectious Diseases
- National Center for Research Resources, USPHS. Grant Number: 5-M01-RR-00079
- Fellowship from Amgen
- Rosalind Russell Medical Research Center for Arthritis, University of California, San Francisco
To examine the association between HLA–DRB1 alleles and the production of anti–cyclic citrullinated peptide (anti-CCP) and rheumatoid factor (RF) autoantibodies in patients with rheumatoid arthritis (RA).
We studied 1,723 Caucasian RA patients enrolled in the North American Rheumatoid Arthritis Consortium (NARAC) family cohort and the Study of New Onset Rheumatoid Arthritis (SONORA) cohort. All patients were tested for anti-CCP antibodies (by enzyme-linked immunosorbent assay), RF (by nephelometry), and HLA–DR genotype (by polymerase chain reaction and sequence-specific oligonucleotide hybridization).
When controlled for the presence of RF, anti-CCP positivity was strongly associated with the HLA–DRB1 shared epitope (SE). In RF+ patients, the presence of the SE was very significantly associated with anti-CCP positivity, with an odds ratio (OR) of 5.8 and a 95% confidence interval (95% CI) of 4.1–8.3. This relationship was also seen in RF– patients (OR 3.1 [95% CI 1.8–5.3]). In contrast, RF positivity was not significantly associated with presence of the SE independently of anti-CCP antibodies. Strikingly, HLA–DRB1*03 was strongly associated with reduced anti-CCP titers, even after controlling for the presence of the SE and restricting the analysis to anti-CCP+ patients. HLA–DR3 was also associated with anti-CCP– RA in our population.
The HLA–DRB1 SE is strongly associated with the production of anti-CCP antibodies, but not RF. In contrast, HLA–DR3 alleles are associated with anti-CCP– disease and with lower levels of anti-CCP antibodies, even when controlling for the SE. These data emphasize the complexity of the genetic effects of the major histocompatibility complex on the RA phenotype.