Interactions between amino acid-defined major histocompatibility complex class II variants and smoking in seropositive rheumatoid arthritis

Arthritis Rheumatol. 2015 Oct;67(10):2611-23. doi: 10.1002/art.39228.

Abstract

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 RA-associated amino acid positions (positions 11, 13, 71, and 74 in HLA-DRβ1, position 9 in HLA-B, and position 9 in HLA-DPβ1), as well as the interaction effects of heavy smoking and the GRS of HLA-DRβ1 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-DRβ1 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-DRβ1 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-DRβ1 4-amino acid haplotype, primarily by positions 11 and 13.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Alleles
  • Amino Acids / genetics*
  • Case-Control Studies
  • Female
  • Genes, MHC Class II / genetics*
  • Genetic Predisposition to Disease / genetics*
  • Genetic Variation / genetics*
  • HLA-B Antigens / genetics
  • HLA-DP beta-Chains / genetics
  • HLA-DRB1 Chains / genetics
  • Haplotypes / genetics
  • Humans
  • Male
  • Middle Aged
  • Models, Genetic
  • Rheumatic Fever / genetics*
  • Risk Factors
  • Smoking / genetics*

Substances

  • Amino Acids
  • HLA-B Antigens
  • HLA-DP beta-Chains
  • HLA-DPB1 antigen
  • HLA-DRB1 Chains