Abstract
Previously-proposed rheumatoid arthritis (RA) HLA-DRB1 susceptibility and protective models were compared, based on amino acids at positions 67-74 and autoantibody combinations. 3 657 RA patients and 1 357 controls were studied using logistic regression, with secondary stratification by anti-citrullinated peptide antibodies(ACPA) and rheumatoid factor(RF). Susceptibility models were based on previously defined HLA-DRB1 shared epitope(SE) subgroups. (70)DERAA(74), D-70 and I-67 protective models were compared, adjusting for HLA-DRB1 SE. A hierarchy of risk was observed within the HLA-DRB1 SE, particularly for ACPA-positive and RF-positive RA: HLA-DRB1*0401 similar to*0404>*0101 similar to*1001 (*0404>* 0101: P = 0.0003). HLA-DRB1*0401/*0404 compound heterozygosity conferred a risk similar to *0401 homozygosity (P = 0.70). Protective effects of D-70 and I-67 were similar. Predictions of the D-70 model fitted the data better than those of the I-67 model. The protective effect of D-70 showed a gene-dose effect (OR 0.82, 95% CI 0.73-0.92, P = 5.8 x 10(-4)), but was only seen in RA patients positive for RF or ACPA. HLA-DRB1 SE alleles were also associated with ACPA-negative, RF-positive RA (OR 1.42 (1.15-1.76), P = 0.0012). In conclusion, HLA-DRB1 SE alleles show heterogeneity in RA susceptibility; their major effect appears to be mediated by ACPA positivity, but a significant association of HLA-DRB1 SE with RF-positive, ACPA-negative RA was also observed. D-70 specifically protected against antibody-positive RA.
Original language | English |
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Pages (from-to) | 120-128 |
Number of pages | 9 |
Journal | GENES AND IMMUNITY |
Volume | 13 |
Issue number | 2 |
DOIs | |
Publication status | Published - Feb 2012 |
Keywords
- rheumatoid arthritis
- HLA-DRB1
- shared epitope
- genetic susceptibility
- logistic regression
- CYCLIC CITRULLINATED PEPTIDE
- SHARED EPITOPE HYPOTHESIS
- MAJOR HISTOCOMPATIBILITY COMPLEX
- HUMAN-LEUKOCYTE ANTIGEN
- PROTEIN ANTIBODY
- INFLAMMATORY POLYARTHRITIS
- RISK-FACTOR
- ALLELES
- ASSOCIATION
- DISEASE