A history of smoking increases the risk of developing rheumatoid arthritis (RA), but only for people who test positive for anticitrulline antibodies, researchers reported in the January issue of Arthritis & Rheumatism.
Smoking is the major known environmental risk factor for RA, although 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.
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 people and relatively rare in people with other inflammatory conditions, citrulline-modified proteins are common in about two-thirds of patients with RA and may be an underlying factor in the development of the disease. To investigate whether smoking and SE genes trigger immune reactions to citrullinat-ed proteins, the team conducted a case-control study.
Nine hundred thirty patients with early RA, ranging in age from 18 to 70 years, were drawn from the Epidemiological Investigation of Rheumatoid Arthritis Study Group. Three hundred eighty-three healthy control subjects, drawn from the blood bank of northern Sweden, were matched for age, sex 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 patients with RA, including both current heavy smokers and lifelong nonsmokers, and was tested with immunostaining for the presence of citrullinated protein in cells.
The researchers found that a history of smoking increases the risk of developing RA, but only for people 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 of developing RA, but only for people who test positive for anti-citrulline antibodies, including those who have never smoked. However, for people who test positive for anticitrulline antibodies, the interaction of smoking and carrying two copies of the SE gene increases the risk of 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," said team spokesperson Lars Klareskog, MD, PhD, Karolinska Institutet, Stockholm, Sweden. "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."
This study was funded by The Swedish National Research Council, Swedish Council for Working Life and Social Research, Swedish Rheumatism Association, insurance company AFA, Flight Attendants Medical Research Institute, King Gustaf V’s 80-Year Foundation, Söderberg Foundation and the Swedish Heart-Lung Foundation.
