Smoking increases rheumatoid arthritis susceptibility in individuals carrying the HLA–DRB1 shared epitope, regardless of rheumatoid factor or anti–cyclic citrullinated peptide antibody status

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Smoking is associated with rheumatoid arthritis (RA) in individuals with the HLA-DRB1 shared epitope (SE). SE alleles have been shown to be predominantly associated with anti-cyclic citrullinated peptide (anti-CCP)-positive RA. These risk factors have not been identified for anti-CCP-negative RA. The aim of this study was to investigate whether SE-containing HLA-DRB1 alleles, smoking, or the combination of these factors contributes to the development of RA, depending on the presence or absence of serologic markers, in a Korean population. All of the patients with RA (n =1,482) and all of the control subjects (n = 1,119) were Korean. Four-digit HLA-DRB1 typing was performed by a conventional polymerase chain reaction-sequence-based typing method. Information about smoking history was obtained through a questionnaire. The patients with RA were tested for anti-CCP antibodies and rheumatoid factor (RF). The SE alleles had significant effects on anti-CCP antibody and RF formation. The DRB1*0901 allele was associated with the presence of anti-CCP antibodies (odds ratio [OR] 2.49) and RF (OR 2.09). SE alleles and smoking were associated with both anti-CCP-positive and anti-CCP-negative RA. The combination of smoking and double copies of the SE allele increased the risk of anti-CCP-positive RA 36.11-fold and increased the risk of anti-CCP-negative RA 12.29-fold, compared with the risk among nonsmokers not carrying SE alleles. Interactions between SE alleles and smoking were observed for both anti-CCP-positive and RF-positive RA, although the associations of RF-positive RA could be consequences of the underlying anti-CCP antibody status. We demonstrated that the combination of SE alleles and smoking is associated with RA susceptibility regardless of anti-CCP antibody or RF status, but that the combination shows stronger effects in anti-CCP-positive/RF-positive patients with RA than in anti-CCP-negative/RF-negative patients with RA. The SE-smoking interactions were present in anti-CCP-positive and RF-positive RA.