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

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.

• Authors: Kwangwoo Kim, Xia Jiang, Jing Cui, Bing Lu, Karen H Costenbader, Jeffrey A Sparks, So-Young Bang, Hye-Soon Lee, Yukinori Okada, Soumya Raychaudhuri, Lars Alfredsson, Sang-Cheol Bae, Lars Klareskog, Elizabeth W Karlson
• Journal: Arthritis & rheumatology (Hoboken, N.J.) (Arthritis Rheumatol) Vol. 67 Issue 10 Pg. 2611-23 (Oct 2015) ISSN: 2326-5205 [Electronic] United States
• PMID: 26098791 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: © 2015, American College of Rheumatology.

Chemical References

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

Topics

• 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)