A gene-environment interaction between smoking and shared epitope genes in HLA-DR provides a high risk of seropositive rheumatoid arthritis

2004 ◽  
Vol 50 (10) ◽  
pp. 3085-3092 ◽  
Author(s):  
Leonid Padyukov ◽  
Camilla Silva ◽  
Patrik Stolt ◽  
Lars Alfredsson ◽  
Lars Klareskog ◽  
...  
Keyword(s):  
Rheumatoid Arthritis ◽  
High Risk ◽  
Shared Epitope ◽  
Environment Interaction ◽  
Gene Environment Interaction ◽  
Seropositive Rheumatoid Arthritis ◽  
Hla Dr ◽  
Gene Environment

scholarly journals Gene–environment interaction between HLA-DRB1 shared epitope and heavy cigarette smoking in predicting incident rheumatoid arthritis

2009 ◽  
Vol 69 (01) ◽  
pp. 54-60 ◽  
Author(s):  
E W Karlson ◽  
S-C Chang ◽  
J Cui ◽  
L B Chibnik ◽  
P A Fraser ◽  
...  
Keyword(s):  
Rheumatoid Arthritis ◽  
Cigarette Smoking ◽  
Shared Epitope ◽  
Cumulative Exposure ◽  
Health Study ◽  
Environment Interaction ◽  
Additive Interaction ◽  
Heavy Smoking ◽  
Gene Environment Interaction ◽  
Gene Environment

Background:Previous studies have reported an interaction between ever cigarette smoking and the presence of the human leukocyte antigen (HLA)-DRB1 shared epitope (SE) genotype and rheumatoid arthritis (RA) risk. To address the effect of dosage, a case-control study nested within two prospective cohorts to determine the interaction between heavy smoking and the HLA-SE was conducted.Methods:Blood was obtained from 32 826 women in the Nurses’ Health Study and 29 611 women in the Nurses’ Health Study II. Incident RA diagnoses were validated by chart review. Controls were matched for age, menopausal status and postmenopausal hormone use. High-resolution HLA-DRB1 genotyping was performed for SE alleles. HLA-SE, smoking, HLA-SE* smoking interactions and RA risk, were assessed using conditional logistic regression models, adjusted for age and reproductive factors. Additive and multiplicative interactions were tested.Results:In all, 439 Caucasian matched pairs were included. Mean age at RA diagnosis was 55.2 years; 62% of cases were seropositive. A modest additive interaction was observed between ever smoking and HLA-SE in seropositive RA risk. A strong additive interaction (attributable proportion due to interaction (AP) = 0.50; p<0.001) and significant multiplicative interaction (p = 0.05) were found between heavy smoking (>10 pack-years) and any HLA-SE in seropositive RA risk. The highest risk was in heavy smokers with double copy HLA-SE (odds ratio (OR) 7.47, 95% CI 2.77 to 20.11).Conclusions:A strong gene–environment interaction was observed between HLA-SE and smoking when stratifying by pack-years of smoking rather than by ever smoking. Future studies should assess cumulative exposure to cigarette smoke when testing for gene–smoking interactions.

Gene-environment interaction influences the reactivity of autoantibodies to citrullinated antigens in rheumatoid arthritis

2010 ◽  
Vol 42 (10) ◽  
pp. 814-816 ◽  
Author(s):  
Diane van der Woude ◽  
Wendimagegn Ghidey Alemayehu ◽  
Willem Verduijn ◽  
René R P de Vries ◽  
Jeanine J Houwing-Duistermaat ◽  
...  
Keyword(s):  
Rheumatoid Arthritis ◽  
Environment Interaction ◽  
Gene Environment Interaction ◽  
Gene Environment

scholarly journals Reply to “Gene-environment interaction influences the reactivity of autoantibodies to citrullinated antigens in rheumatoid arthritis”

2010 ◽  
Vol 42 (10) ◽  
pp. 816-816
Author(s):  
Karin Lundberg ◽  
Lars Alfredsson ◽  
Henrik Källberg ◽  
Hiba Mahdi ◽  
Benjamin A Fisher ◽  
...  
Keyword(s):  
Rheumatoid Arthritis ◽  
Environment Interaction ◽  
Gene Environment Interaction ◽  
Gene Environment

scholarly journals Shared epitope–aryl hydrocarbon receptor crosstalk underlies the mechanism of gene–environment interaction in autoimmune arthritis

2018 ◽  
Vol 115 (18) ◽  
pp. 4755-4760 ◽  
Author(s):  
Jiaqi Fu ◽  
Sarah V. Nogueira ◽  
Vincent van Drongelen ◽  
Patrick Coit ◽  
Song Ling ◽  
...  
Keyword(s):  
Aryl Hydrocarbon Receptor ◽  
Genetic Risk ◽  
Shared Epitope ◽  
Environmental Pollutants ◽  
Autoimmune Arthritis ◽  
Environment Interaction ◽  
Gene Environment Interaction ◽  
Aryl Hydrocarbon ◽  
Gene Environment

The susceptibility to autoimmune diseases is affected by genetic and environmental factors. In rheumatoid arthritis (RA), the shared epitope (SE), a five-amino acid sequence motif encoded by RA-associated HLA-DRB1 alleles, is the single most significant genetic risk factor. The risk conferred by the SE is increased in a multiplicative way by exposure to various environmental pollutants, such as cigarette smoke. The mechanism of this synergistic interaction is unknown. It is worth noting that the SE has recently been found to act as a signal transduction ligand that facilitates differentiation of Th17 cells and osteoclasts in vitro and in vivo. Intriguingly, the aryl hydrocarbon receptor (AhR), a transcription factor that mediates the xenobiotic effects of many pollutants, including tobacco combustion products, has been found to activate similar biologic effects. Prompted by these similarities, we sought to determine whether the SE and AhR signaling pathways interact in autoimmune arthritis. Here we uncovered a nuclear factor kappa B-mediated synergistic interaction between the SE and AhR pathways that leads to markedly enhanced osteoclast differentiation and Th17 polarization in vitro. Administration of AhR pathway agonists to transgenic mice carrying human SE-coding alleles resulted in a robust increase in arthritis severity, bone destruction, overabundance of osteoclasts, and IL17-expressing cells in the inflamed joints and draining lymph nodes of arthritic mice. Thus, this study identifies a previously unrecognized mechanism of gene–environment interaction that could provide insights into the well-described but poorly understood amplification of the genetic risk for RA upon exposure to environmental pollutants.

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