Interpreting studies of interactions between RA risk factors

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Interactions between HLA and PTPN22 genotypes and smoking have been implicated in overall susceptibility to rheumatoid arthritis as well as the incidence of particular disease phenotypes in case–control and case-only studies. As recent epidemiological evidence shows, deciphering these interactions demands consideration of the analytical approach used.

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Figure 1: Study designs used to analyze risk factor interactions in RA.


  1. 1

    Costenbader, K. H., Feskanich, D., Mandl, L. A. & Karlson, E. W. Smoking intensity, duration, and cessation, and the risk of rheumatoid arthritis in women. Am. J. Med. 119, 503–511 (2006).

  2. 2

    Morgan, A. W. et al. Reevaluation of the interaction between HLA-DRB1 shared epitope alleles, PTPN22, and smoking in determining susceptibility to autoantibody-positive and autoantibody-negative rheumatoid arthritis in a large UK Caucasian population. Arthritis Rheum. 60, 2565–2576 (2009).

  3. 3

    Rothman, K. J. Epidemiology: an Introduction (Oxford University Press, New York, 2002).

  4. 4

    Padyukov, L., Silva, C., Stolt, P., Alfredsson, L. & Klareskog, L. A gene–environment interaction between smoking and shared epitope genes in HLA-DR provides a high risk of seropositive rheumatoid arthritis. Arthritis Rheum. 50, 3085–3092 (2004).

  5. 5

    Klareskog, L. et al. A new model for an etiology of rheumatoid arthritis: smoking may trigger HLA-DR (shared epitope)-restricted immune reactions to autoantigens modified by citrullination. Arthritis Rheum. 54, 38–46 (2006).

  6. 6

    Hill, J. A. et al. Cutting edge: the conversion of arginine to citrulline allows for a high-affinity peptide interaction with the rheumatoid arthritis-associated HLA-DRB1*0401 MHC class II molecule. J. Immunol. 171, 538–541 (2003).

  7. 7

    Karlson, E. W. et al. Gene–environment interaction between HLA-DRB1 shared epitope and heavy cigarette smoking in predicting incident rheumatoid arthritis. Ann. Rheum. Dis. 69, 54–60 (2010).

  8. 8

    Linn-Rasker, S. P. et al. Smoking is a risk factor for anti-CCP antibodies only in rheumatoid arthritis patients who carry HLA-DRB1 shared epitope alleles. Ann. Rheum. Dis. 65, 366–371 (2006).

  9. 9

    Lee, H. S. et al. Interaction between smoking, the shared epitope, and anti-cyclic citrullinated peptide: a mixed picture in three large North American rheumatoid arthritis cohorts. Arthritis Rheum. 56, 1745–1753 (2007).

  10. 10

    Kallberg, H. et al. Gene–gene and gene–environment interactions involving HLA-DRB1, PTPN22, and smoking in two subsets of rheumatoid arthritis. Am. J. Hum. Genet. 80, 867–875 (2007).

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Correspondence to Elizabeth W. Karlson.

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