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Mechanisms of Disease: genetic susceptibility and environmental triggers in the development of rheumatoid arthritis

Abstract

Rheumatoid arthritis (RA) is a complex disease in which environmental agents are thought to interact with genetic factors that influence susceptibility. This interaction triggers immunologic events that eventually result in the clinical signs of arthritis. Knowledge of the chain of etiological events that lead to the development of RA is incomplete. In this review, we describe the experimental approaches that are used to address the issue of gene–environment interactions in the etiology of RA, and discuss relevant examples of such interactions. We focus on how smoking, the best-known environmental risk factor for RA, interacts with HLA-DR shared epitope genes, the main genetic risk factors for RA, and result in a high risk of RA in individuals exposed to both of these risk factors. From these and other related findings, we can begin to define the distinct environmental risk factors (such as smoking) that in certain genetic contexts (for example, the presence of HLA-DR shared epitope alleles) can trigger immune reactions (such as autoantibodies to citrullinated peptides) many years before onset of RA, and consider how these immune reactions might contribute to clinical symptoms in a subset of affected patients. Increased knowledge about these and other events involved in the development of RA should enable the design of new tools for suppressing RA pathogenesis before the onset of disease.

Key Points

  • Rheumatoid arthritis (RA) is a heterogeneous disease, and the genetic and environmental risk factors for the major disease subtypes (rheumatoid-factor-positive, rheumatoid-factor- negative, positive for antibodies tthat bind cyclic citrullinated proteins [anti-CCP], or anti-CCP-negative) might be different

  • There is a major gene–environment interaction between HLA-DR shared epitope genes as a central genetic risk factor, and smoking as a major environmental risk factor, in the etiology of anti-CCP-positive (but not anti-CCP-negative) RA

  • A possible mechanism behind the interaction between smoking, HLA-DR shared epitope genes and anticitrulline autoimmunity is discussed

  • Several other environmental agents, such as silica dust and mineral oil, have been identified as risk factors for RA

  • The dramatically increased risk of RA that has been identified in individuals carrying certain genes should lead to counseling against smoking in patients who have relatives with RA

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Figure 1: Gene–environment interactions seem to have a threshold effect that determines arthritis susceptibility, as interpreted from experimental data for multiple combinations of adjuvants in inbred rat strains.
Figure 2: Gene–environment interactions between HLA-DR shared epitope genes and smoking, in (A) rheumatoid-factor-positive and (B) rheumatoid-factor-negative individuals.
Figure 3: Gene–environment interactions between HLA-DR shared epitope genotype and smoking in (A) anti-CCP-positive and (B) anti-CCP-negative individuals.
Figure 4: Longitudinal course of anti-CCP-positive and anti-CCP-negative rheumatoid arthritis.
Figure 5: Possible options for intervention in different stages of rheumatoid arthritis pathogenesis.

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Acknowledgements

We thank members of our research team for valuable discussions, and members of the Epidemiological Investigation of Risk Factors in Rheumatoid Arthritis (EIRA) study group for contributing data on patients in the EIRA study. Funding for the EIRA study was provided by the Swedish Research Council, the Swedish Council for Working Life and Social Research, the Swedish Rheumatism Association, King Gustaf V's 80-year Foundation, the Torsten och Ragnar Söderberg Foundation and the insurance company American Fidelity Assurance.

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Correspondence to Lars Klareskog.

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Klareskog, L., Padyukov, L., Lorentzen, J. et al. Mechanisms of Disease: genetic susceptibility and environmental triggers in the development of rheumatoid arthritis. Nat Rev Rheumatol 2, 425–433 (2006). https://doi.org/10.1038/ncprheum0249

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