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




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.