Smoking and the risk of rheumatoid arthritis

Rheumatoid arthritis (RA), like many chronic diseases of the immune system, likely results from a combination of genetic susceptibility and environmental triggers. Recently, a team of researchers in Sweden set out to investigate the interaction of two specific risk factors: the presence of a gene encoding protein sequence called the shared epitope (SE), the major genetic risk factor so far defined for RA, and cigarette smoking. The results, published in the October 2004 issue of Arthritis & Rheumatism indicate that smoking significantly increases the risk of RA among men and women with a genetic predisposition for the disease.

Conducted by a research team in Sweden, this population-based study focused on a large sample of patients with a confirmed diagnosis of the disease–858 individuals, 612 women and 246 men, with an average age of 49 years. The researchers also recruited 1,048 healthy individuals to serve as controls. Participants donated blood samples for DNA genotyping. Every participant also completed lifestyle questionnaires, including smoking habits. Since former smokers tend to have a wide variation in their cumulative smoking history, the researchers chose to restrict their analysis to current smokers and men and women who had never smoked.

The DNA samples of the RA patients were studied for evidence of genes for the SE. The SE is a protein sequence found in cell surface molecules that regulate specific immune responses. The blood samples were also tested for rheumatoid factor, a hallmark of this disease. Then, analyzing women and men together, the researchers compared current smokers with never smokers for the risk of rheumatoid factor positive RA. For people with the SE gene who never smoked, the increased risk for RA was assessed at 2.8 times. For current cigarette smokers without the SE gene, the risk factor was comparable–2.4 times. These findings affirm the SE gene and smoking as independently related to the development of rheumatoid factor positive RA. Among current smokers with the SE gene, however, the disease risk increased to 7.5 times. “The interaction was even more pronounced in smoking subjects with double SE genes, whose relative risk of rheumatoid factor positive RA was 15.7 times higher,” observes one of the authors Leonid Padyukov, M.D., Ph.D. However, no risk was found for rheumatoid factor negative RA in this study.

Beyond strengthening the case against cigarette smoking as a health hazard, this study has important implications for ongoing research into the factors contributing to RA and other autoimmune diseases. “Our study also emphasizes the need to include data on environmental exposures in genetic analyses of a complex disease,” the authors note.