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

Abstract

Objective This study aimed to refine the interaction between cigarette smoking and human leukocyte antigen (HLA) polymorphisms in seropositive rheumatoid arthritis (RA), in the context of a recent amino-acid based HLA model for RA susceptibility. Methods We imputed HLA amino acids and classical alleles from case-control Immunochip array data of 3,588 Swedish Epidemiological Investigation of Rheumatoid Arthritis (EIRA; case/control=1654/1934), 589 Nurses’ Health Study (NHS; 229/360) and 2,125 Korean (1390/735) subjects. We examined interaction effects between heavy smoking (>10 pack-years) and genetic risk score (GRS) from RA-associated amino-acid positions (11, 13, 71 and 74 in HLA-DRβ1; 9 in HLA-B; and 9 in HLA-DPβ1) and from HLA-DRβ1 four-amino-acid haplotypes with an 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 all three populations. In the interaction analysis, we found a significant deviation from the expected additive joint effect between heavy smoking and the HLA-DRβ1 amino-acid haplotype in all three studies (0.416≤AP≤0.796). We further identified the key interacting variants as being located at amino-acid positions 11 and 13 of HLA-DRβ1 but not the other RA-risk amino-acid positions in all populations. At the positions 11 and 13, there were similar patterns between RA-risk effects and interaction effects of residues. Conclusion Our findings of significant gene-environment interaction effects implicate that a physical interaction between citrullinated auto-antigens produced by smoking and HLA-DR molecules is characterized by the HLA-DRβ1 four-amino-acid haplotype, primarily by the positions 11 and 13.

The Roles of Cigarette Smoking and the Lung in the Transitions Between Phases of Preclinical Rheumatoid Arthritis

“…These sites also have statistical interactions with cigarette smoking for risk of seropositive, especially ACPA-positive, RA [51–57]. In a trans-ethnic study using data from the Nurses’ Health Studies in the US, the Swedish Epidemiological Investigations of RA, and the Korean RA Cohort Study, heavy smoking (defined as >10 pack-years) interacted with HLA-DRβ1 positions 11 and 13 for increased risk for seropositive RA [65]. Specific amino acid haplotypes conferred increased risk of seropositive RA (RF or CCP in the Nurses’ Health Study; CCP in both the Swedish and Korean studies) [65].…”

“…In a trans-ethnic study using data from the Nurses’ Health Studies in the US, the Swedish Epidemiological Investigations of RA, and the Korean RA Cohort Study, heavy smoking (defined as >10 pack-years) interacted with HLA-DRβ1 positions 11 and 13 for increased risk for seropositive RA [65]. Specific amino acid haplotypes conferred increased risk of seropositive RA (RF or CCP in the Nurses’ Health Study; CCP in both the Swedish and Korean studies) [65]. For example, presence of valine at HLA-DRβ1 position 11 or histidine at position 13 significantly increased seropositive RA risk while presence of serine at HLA-DRβ1 positions 11 or 13 significantly decreased RA risk [65].…”

Smoking and Air Pollution as Pro-Inflammatory Triggers for the Development of Rheumatoid Arthritis

“…Moreover, the combination of a smoking history and double copies of HLA-DRB1 SE genes increases the risk for RA by 21-fold relative to that of non-smokers with no SE genes [35]. The smoking/SE allele interaction is, however, complex [40]. This is clearly illustrated by the findings of a recent study which reported that ever-smoking per se is associated with production of ACPA of the IgA isotype, possibly consistent with a pulmonary origin, while SE in the absence of smoking is associated with ACPA of the IgG isotype, and the combination of smoking and SE with seropositivity for both isotypes [41].…”

Physical workload is associated with increased risk of rheumatoid arthritis: results from a Swedish population-based case–control study

“…It has recently been shown that the interaction between smoking and human leucocyte antigen (HLA) polymorphisms relies on specific amino acid sequences in the peptide-binding groove of the HLA-DR molecule 18. Furthermore, such gene–environment interactions seem to vary across subtypes of RA defined by the presence or absence of ACPA targeting different citrullinated peptides 19–22.…”