A spectrum of susceptibility to rheumatoid arthritis within HLA-DRB1: stratification by autoantibody status in a large UK population

S. L. Mackie, J. C. Taylor, S. G. Martin, U. K. R. A. G. ChokkalinConsortium, P. Wordsworth, Sophia Steer, A. G. Wilson, J. Worthington, P. Emery, J. H. Barrett, A. W. Morgan*, YEAR Consortium

*Corresponding author for this work

    Research output: Contribution to journalArticlepeer-review

    49 Citations (Scopus)

    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 languageEnglish
    Pages (from-to)120-128
    Number of pages9
    JournalGENES AND IMMUNITY
    Volume13
    Issue number2
    DOIs
    Publication statusPublished - 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

    Fingerprint

    Dive into the research topics of 'A spectrum of susceptibility to rheumatoid arthritis within HLA-DRB1: stratification by autoantibody status in a large UK population'. Together they form a unique fingerprint.

    Cite this