Interactions Between Amino Acid–Defined Major Histocompatibility Complex Class II Variants and Smoking in Seropositive Rheumatoid Arthritis

Objective. To define the interaction between cigarette smoking and HLA polymorphisms in seropositive rheumatoid arthritis (RA), in the context of a recently identified amino acid–based HLA model for RA susceptibility. Methods. We imputed Immunochip data on HLA amino acids and classical alleles from 3 case–control studies (the Swedish Epidemiological Investigation of Rheumatoid Arthritis [EIRA] study [1,654 cases and 1,934 controls], the Nurses’ Health Study [NHS] [229 cases and 360 controls], and the Korean RA Cohort Study [1,390 cases and 735 controls]). We examined the interaction effects of heavy smoking (>10 pack-years) and the genetic risk score (GRS) of multiple RAassociated amino acid positions (positions 11, 13, 71, and 74 in HLA–DRb1, position 9 in HLA–B, and position 9 in HLA–DPb1), as well as the interaction effects of heavy smoking and the GRS of HLA–DRb1 4–amino acid haplotypes (assessed via attributable proportion due to interaction [AP] using the additive interaction model). Results. Heavy smoking and all investigated HLA amino acid positions and haplotypes were associated with RA susceptibility in the 3 populations. In the interaction analysis, we found a significant deviation from the expected additive joint effect between heavy smoking and the HLA–DRb1 4–amino acid haplotype (AP 0.416, 0.467, and 0.796, in the EIRA, NHS, and Korean studies, respectively). We further identified the key interacting variants as being located at HLA–DRb1 amino acid positions 11 and 13 but not at any of the other RA risk–associated amino acid positions. For residues in positions 11 and 13, there were similar patterns between RA risk effects and interaction effects. Conclusion. Our findings of significant gene– environment interaction effects indicate that a physical interaction between citrullinated autoantigens produced by smoking and HLA–DR molecules is characterized by the HLA–DRb1 4–amino acid haplotype, primarily by positions 11 and 13.