Rheumatoid arthritis (RA) is one of the most common systemic autoimmune diseases, and one of the least understood. Smoking is the major known environmental risk factor for RA, though little is known about the mechanisms involved. HLA-DR shared epitope (SE) genes are a widely recognized genetic risk factor for RA, though little is known about how these genes affect autoimmune reactions that lead to chronic inflammation and progressive joint and organ damage.
To better understand the interactions between smoking and HLA-DR SE genes in RA, a team of researchers in Sweden focused on the disease's distinctive autoimmune hallmark: citrulline, an amino acid not normally present in protein. While extremely rare in healthy individuals and relatively rare in other inflammatory conditions, citrulline-modified proteins are common in about two-thirds of RA patients and may be an underlying factor in the development of the disease. To investigate whether smoking and SE genes trigger immune reactions to citrullinated proteins, the team conducted a case-control study involving patients with recent-onset RA. The results, featured in the January 2006 issue of Arthritis & Rheumatism, suggest that smokers with SE genes are more susceptible to anticitrulline antibody-positive RA.
The study's 930 early RA patients, drawn from the Epidemiological Investigation of Rheumatoid Arthritis Study Group, ranged in age from 18 to 70 years. 383 healthy controls, drawn from the blood bank of northern Sweden, were matched for age, gender, and residential area. All participants completed questionnaires about their past and present smoking habits, as well as genotyping profiles. In addition, bronchial fluid was obtained from a representative sample of RA patients, including both current heavy smokers and lifelong non-smokers, and tested with immunostaining for the presence of citrullinated protein in cells.
Based on their series of experiments and comparisons, the researchers found that a history of smoking increases the risk for RA, but only for individuals who test positive for anticitrulline antibodies, regardless of the presence of SE genes. Similarly, inheriting HLA-DR SE genes in a single copy, as well as in double copies, increases the risk for RA, but only for individuals who test positive for anticitrulline antibodies, including individuals who have never smoked. Yet, for individuals who test positive for anticitrulline antibodies, the interaction of smoking and carrying 2 copies of the SE gene dramatically increases the risk for developing RA--by 21 times.
"The remarkable gene-environment interaction observed in the case-control study, together with the immunostaining for citrullinated proteins, might now provide a clue to the molecular mechanisms of importance for disease development in a subset of RA patients," notes team spokesperson Dr. Lars Klareskog of Karolinska Institutet, Stockholm. "We may thereby be given some new opportunities to both predict and understand the onset of RA and to interfere with RA-inducing events before clinical symptoms are apparent."