title: Regulation of anti-cyclic citrullinated peptide antibodies in rheumatoid arthritis: contrasting effects of HLA-DR3 and the shared epitope alleles.
abstract: 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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: North Shore-Long Island Jewish Institute for Medical Research, Manhasset, New York 11030, USA.
authors.forename: Patricia
authors.initials: P
authors.lastname: Irigoyen
authors.forename: Annette T
authors.initials: AT
authors.lastname: Lee
authors.forename: Mark H
authors.initials: MH
authors.lastname: Wener
authors.forename: Wentian
authors.initials: W
authors.lastname: Li
authors.forename: Marlena
authors.initials: M
authors.lastname: Kern
authors.forename: Franak
authors.initials: F
authors.lastname: Batliwalla
authors.forename: Raymond F
authors.initials: RF
authors.lastname: Lum
authors.forename: Elena
authors.initials: E
authors.lastname: Massarotti
authors.forename: Michael
authors.initials: M
authors.lastname: Weisman
authors.forename: Claire
authors.initials: C
authors.lastname: Bombardier
authors.forename: Elaine F
authors.initials: EF
authors.lastname: Remmers
authors.forename: Daniel L
authors.initials: DL
authors.lastname: Kastner
authors.forename: Michael F
authors.initials: MF
authors.lastname: Seldin
authors.forename: Lindsey A
authors.initials: LA
authors.lastname: Criswell
authors.forename: Peter K
authors.initials: PK
authors.lastname: Gregersen
mesh_terms: D000328:Adult; D000483:Alleles; D001172:Arthritis, Rheumatoid / Q000235:genetics* / Q000276:immunology*; D001323:Autoantibodies / Q000097:blood*; D000939:Epitopes / Q000235:genetics / Q000276:immunology; D005260:Female; D020022:Genetic Predisposition to Disease; D006684:HLA-DR Antigens / Q000235:genetics*; D015803:HLA-DR3 Antigen / Q000235:genetics*; D059811:HLA-DRB1 Chains; D006239:Haplotypes; D006801:Humans; D008297:Male; D008875:Middle Aged; D010456:Peptides, Cyclic / Q000276:immunology*
chemical_list: D001323:Autoantibodies; D000939:Epitopes; D006684:HLA-DR Antigens; D015803:HLA-DR3 Antigen; D059811:HLA-DRB1 Chains; D010456:Peptides, Cyclic; C487763:cyclic citrullinated peptide