Regulation of anti-cyclic citrullinated peptide antibodies in rheumatoid arthritis: Contrasting effects of HLA-DR3 and the shared epitope alleles

Patricia Irigoyen, Annette T. Lee, Mark H. Wener, Wentian Li, Marlena Kern, Franak Batliwalla, Raymond F. Lum, Elena Massarotti, Michael Weisman, Claire Bombardier, Elaine F. Remmers, Daniel L. Kastner, Michael F Seldin, Lindsey A. Criswell, Peter K. Gregersen

Research output: Contribution to journalArticlepeer-review

167 Scopus citations


Objective. 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). Methods. 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). Results. 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. Conclusion. 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.

Original languageEnglish (US)
Pages (from-to)3813-3818
Number of pages6
JournalArthritis and Rheumatism
Issue number12
StatePublished - Dec 2005

ASJC Scopus subject areas

  • Immunology
  • Rheumatology


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