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

Arthritis Rheumatol
Authors
Keywords
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.

Year of Publication
2015
Journal
Arthritis Rheumatol
Volume
67
Issue
10
Pages
2611-23
Date Published
2015 Oct
ISSN
2326-5205
URL
DOI
10.1002/art.39228
PubMed ID
26098791
PubMed Central ID
PMC4581918
Links
Grant list
R01-AR-065183-01 / AR / NIAMS NIH HHS / United States
CA-186107 / CA / NCI NIH HHS / United States
CA-49449 / CA / NCI NIH HHS / United States
P01 CA087969 / CA / NCI NIH HHS / United States
R01 CA067262 / CA / NCI NIH HHS / United States
U01-GM-092691-04 / GM / NIGMS NIH HHS / United States
UM1 CA176726 / CA / NCI NIH HHS / United States
R01 AR059073 / AR / NIAMS NIH HHS / United States
U01 CA067262 / CA / NCI NIH HHS / United States
U01 GM092691 / GM / NIGMS NIH HHS / United States
K24 AR052403 / AR / NIAMS NIH HHS / United States
CA-176726 / CA / NCI NIH HHS / United States
AR-052403 / AR / NIAMS NIH HHS / United States
AR-059073 / AR / NIAMS NIH HHS / United States
L30 AR066953 / AR / NIAMS NIH HHS / United States
UM1 CA186107 / CA / NCI NIH HHS / United States
R01 AR049880 / AR / NIAMS NIH HHS / United States
AR-049880 / AR / NIAMS NIH HHS / United States
R01 AR063759 / AR / NIAMS NIH HHS / United States
CA-67262 / CA / NCI NIH HHS / United States
R01 AR065183 / AR / NIAMS NIH HHS / United States
R01 CA049449 / CA / NCI NIH HHS / United States
U01 CA049449 / CA / NCI NIH HHS / United States
R01-AR-063759-01A1 / AR / NIAMS NIH HHS / United States