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 Access through your

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[thesis]. Stockholm: Karolinska Institutet ISBN 91-7140-227-6 [http://diss.kib.ki.se/2005/91-7140-227-6/thesis.pdf] (accessed 22 June 2006) Download references 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. AUTHOR INFORMATION AUTHORS AND

AFFILIATIONS * Professor of Rheumatology at the Rheumatology Unit, Lars Klareskog, Leonid Padyukov, Johnny Lorentzen & Lars Alfredsson * Department of Medicine of the Karolinska

Institutet, Senior Scientists in the Rheumatology Research Laboratory (linked to the Rheumatology Unit), Karolinska University Hospital, Lars Klareskog, Leonid Padyukov, Johnny Lorentzen 

& Lars Alfredsson * Professor of Epidemiology at the Institute of Environmental Medicine, Karolinska Institutet, and Stockholm Center for Public Health, Stockholm County Council,

Stockholm, Sweden Lars Klareskog, Leonid Padyukov, Johnny Lorentzen & Lars Alfredsson Authors * Lars Klareskog View author publications You can also search for this author inPubMed 

Google Scholar * Leonid Padyukov View author publications You can also search for this author inPubMed Google Scholar * Johnny Lorentzen View author publications You can also search for this

author inPubMed Google Scholar * Lars Alfredsson View author publications You can also search for this author inPubMed Google Scholar CORRESPONDING AUTHOR Correspondence to Lars Klareskog.

ETHICS DECLARATIONS COMPETING INTERESTS The authors declare no competing financial interests. RIGHTS AND PERMISSIONS Reprints and permissions ABOUT THIS ARTICLE CITE THIS ARTICLE 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 Download citation * Received: 18 July 2005 * Accepted: 08 June 2006 * Issue Date: August 2006 * DOI: https://doi.org/10.1038/ncprheum0249 SHARE

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