Regulation of anti-cyclic citrullinated peptide antibodies in rheumatoid arthritis: contrasting effects of HLA-DR3 and the shared epitope alleles.
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.
Irigoyen
Patricia
P
North Shore-Long Island Jewish Institute for Medical Research, Manhasset, New York 11030, USA.
Lee
Annette T
AT
Wener
Mark H
MH
Li
Wentian
W
Kern
Marlena
M
Batliwalla
Franak
F
Lum
Raymond F
RF
Massarotti
Elena
E
Weisman
Michael
M
Bombardier
Claire
C
Remmers
Elaine F
EF
Kastner
Daniel L
DL
Seldin
Michael F
MF
Criswell
Lindsey A
LA
Gregersen
Peter K
PK
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*
D001323:Autoantibodies; D000939:Epitopes; D006684:HLA-DR Antigens; D015803:HLA-DR3 Antigen; D059811:HLA-DRB1 Chains; D010456:Peptides, Cyclic; C487763:cyclic citrullinated peptide