[PubMed] [Google Scholar] 43. which it will become possible to disentangle the complex interactions between different environmental and genetic risk factors and to understand what different pathologically associated immune reactions may be triggered in the context of various combinations of genes and environmental factors. We must carefully separate different subsets of RA in studies and descriptions of how environmental factors interact with genes in providing the basis for onset of and disease course for different forms of RA. Having provided this general comment on the complexity as well as promise for studies on environmental factors and RA, the rest of this review will be devoted to the description of recent discoveries concerning the role of environment in this disease. Notably, almost all such studies have been conducted for RA without subdivision into subsets, and most studies on environment have not taken genetics into account. Smoking Smoking is the strongest known environmental risk factor for RA. This association was first described XCL1 over a decade ago but has been further characterized recently with the use of ACPA tests [8,9]. A recent study found that tobacco smoking was specifically associated with Gramine an increased risk of ACPA-positive and not ACPA-negative RA [4]. As the majority of RA patients who are ACPA positive are also rheumatoid factor positive, these findings concur with previous studies which show an overall risk of RA for smokers, specifically for rheumatoid factor-positive RA [5,10]. The risk of RA increases with amount and duration of cigarette use [5]. Findings from a large prospective cohort study, the Nurses Health Study (NHS), showed a linear relationship between smoking and risk of RA whereby increasing doses of cigarettes (pack-years of smoking) was associated with an increased risk of RA [11]. The heaviest smokers with more than 40 pack-years had approximately two-fold increase of risk for RA than those who had never smoked. Furthermore, an individual remains at increased risk even after cessation for 20 years or more. The risk of RA from smoking is further modified by the number of shared epitope copies suggesting geneCenvironment interaction. The shared epitope, a specific sequence of amino acids on the allele, is the strongest known genetic risk factor for RA [12]. A report from the Swedish population-based caseCcontrol study Epidemiologic Investigation of Rheumatoid Arthritis (EIRA), in which RA cases are recruited within 1 year of onset, found that smokers who do not carry the shared epitope have a 1.5-fold elevated risk Gramine of developing ACPA-positive RA over nonsmokers who also do not carry the shared epitope. The risk of developing ACPA and RA for an individual who smokes and carries two copies of the shared epitope Gramine is 21-fold higher than nonsmokers who do not carry the shared epitope; this greatly elevated risk is attributed to the geneCenvironment interaction between smoking and the shared epitope [6]. The authors also demonstrated that smoking increases the proportion of citrulline-positive cells in the lungs (conducted through bronchoalveolar lavage). Citrullinated cells were not present in nonsmokers. Through these findings, the authors hypothesized that smoking induces citrullination and that carriers of the shared epitope may be genetically predisposed to developing antibodies against citrulline. The geneCenvironment interaction between smoking and the shared epitope and risk of ACPA-positive RA was also observed in several other European cohorts [9,13,14]. A study of the presence or absence of ACPA or rheumatoid factor among RA cases only found no interaction between the shared epitope and smoking in predicting antibody positivity among three large North American cohorts [9,15]. With regards to rheumatoid factor-positive RA, a similar geneCenvironment interaction between smoking and the Gramine shared epitope has been observed for rheumatoid factor-positive RA in most studies with the exception of a female cohort of older onset RA [13,16,17]. The risk of developing RA from geneCenvironment interactions increases with the intensity of smoking. In the NHS,.
