EU support for the study came from the AUTOCURE (Curing autoimmune disease; a translational approach to autoimmune diseases in the post-genomic era using inflammatory arthritis and myositis as prototypes and learning examples) project, which received EUR 11 million under the 'Life sciences, genomics and biotechnology for health' Thematic area of the Sixth Framework Programme (FP6).
RA is an autoimmune disease characterised by joint swelling, pain, stiffness and fatigue. It usually arises between the ages of 40 and 60 and can cause severe disability as it progresses. Although treatments exist to control the spread of the condition, there is as yet no definitive cure.
Previous research has shown that smoking interacts with genetic risk factors to raise an individual's risk of developing RA. However, the proportion of RA cases caused by smoking remained a mystery, and little was known about the details of how a person's genes interact with smoking to affect their risk of developing the condition.
In this study, scientists in Sweden sought to answer these questions by examining the smoking history and genetic background of just over 1,200 RA patients from central and southern Sweden as well as 871 healthy controls. The controls, who were matched by age, sex and area of residence to the patients, were randomly picked from the population register. Study participants were quizzed about their smoking habits, past and present. Blood samples revealed individuals' genetic susceptibility to RA (as measured by the presence of the risk gene HLA-DRB1 SE) and the severity of their disease (as measured by levels of the anticitrullinated protein/peptide antibody, or ACPA).
The results revealed that the more a person smokes, the greater their risk of developing ACPA-positive RA, which is the most common and severe form of the disease. The heaviest smokers (i.e. those who had smoked 20 cigarettes a day for at least 20 years) were more than 2.5 times likely to test positive for ACPA. For ex-smokers, the risk of developing RA dwindles the longer they stay away from tobacco and after 20 smoke-free years, their risk of developing the condition is the same as for people who have never smoked. However, people who smoked heavily in the past remain at greater risk of RA even 20 years after smoking cessation.
These figures led the researchers to conclude that 35% of ACPA-positive RA cases and 20% of all RA cases can be attributed to smoking. "[This] indicates that smoking plays an important role in the occurrence of RA overall because ACPA-positive RA is the most common form of RA," the researchers write. In addition, the risk appears to be higher for men than for women.
The study also demonstrated that smoking is particularly risky for people who are already genetically susceptible to RA; in this group, 55% of cases can be attributed to smoking.
"The fact that more than 50% of RA cases can be attributed to smoking in individuals carrying two copies of the HLA-DRB1 SE genes illustrates drastically how smoking may affect disease risk differently in different individuals," the researchers point out.
The team stresses that they are not suggesting that healthy individuals should undergo genetic testing for these genes. Nevertheless, they note, their data may "provide a rationale for specific counselling against smoking for individuals with a family history of RA." For individuals who already have RA, the impact of stopping smoking on symptoms is still not fully clear, although smoking is known to cause cardiovascular disease, which is the leading cause of premature death among RA patients.
The researchers conclude: "There are many reasons for the medical community to communicate the known facts on smoking and RA, with the aim of reducing the incidence of smoking and preventing RA and its consequences."
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