scholarly journals Gene-environment interaction between the DRB1 shared epitope and smoking in the risk of anti-citrullinated protein antibody-positive rheumatoid arthritis: All alleles are important

2009 ◽  
Vol 60 (6) ◽  
pp. 1597-1603 ◽  
Author(s):  
Emeli Lundström ◽  
Henrik Källberg ◽  
Lars Alfredsson ◽  
Lars Klareskog ◽  
Leonid Padyukov
Keyword(s):  
Rheumatoid Arthritis ◽  
Shared Epitope ◽  
Environment Interaction ◽  
Gene Environment Interaction ◽  
Gene Environment ◽  
Citrullinated Protein

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.

scholarly journals POS1429 ORAL DYSBIOSIS REFLECTS THE IMMUNOLOGICAL ALTERATION OF RA REGARDING TO HLA DRB1*SE, ACPA AND CIGARETTE SMOKING: NAGASAKI ISLAND STUDY

2021 ◽  
Vol 80 (Suppl 1) ◽  
pp. 998-998
Author(s):  
Y. Tsuji ◽  
M. Tamai ◽  
S. Morimoto ◽  
D. Sasaki ◽  
S. Y. Kawashiri ◽  
...  
Keyword(s):  
Cigarette Smoking ◽  
Shared Epitope ◽  
Current Smoker ◽  
Environment Interaction ◽  
Positive Group ◽  
Gene Environment Interaction ◽  
Β Diversity ◽  
Gene Environment ◽  
Α Diversity ◽  
The Difference

Background:Anti-citrullinated protein antibody (ACPA) production is observed in several organs even prior to the onset of rheumatoid arthritis (RA), and oral mucosa is considered to be one of the important tissues. Saliva is considered to reflect the oral microbiota(oralMB) including periodontal disease. A gene-environment interaction between cigarette smoking and shared epitope genes in HLA-DRB1*shared epitope (SE) provides a high risk of ACPA-positive RA. However, the interaction of HLA-DRB1*SE, ACPA, cigarette smoking and oralMB of RA patients remains to be elucidated.Objectives:We investigated that the difference of oralMB among RA patients and healthy subjects(HS) regarding to ACPA, HLA-DRB1*SE and cigarette smoking.Methods:The Nagasaki Island Study, which had started in 2014 collaborating with Goto City, Nagasaki Prefecture, Japan, is intended for research of the preclinical stage of RA, including ACPA, HLA genotype screening, oralMB and lifestyle habit. Both of blood and salivary samples were obtained from 1422 subjects out of 4276 participants in this study from 2016 to 2018. ACPA positivity was 1.7 % in total 4276 subjects. At this point, we selected 291 subjects, who were ACPA positive non-RA HS(n=22) and patients with RA (n=33, 11 subjects were ACPA positive and 22 ACPA negative, respectively) as the case, age and gender matched ACPA negative non-RA HS (n=236) as the control. In RA subjects, current smoker was n=1(3.0%) and ever smoker was n=8(24.2%). In HS, current smoker was n=29(11.2%) and ever smoker was n=55(21.3%). ACPA was measured by ELISA, and HLA genotyping was quantified by next-generation sequencing (Ref.1). The operational taxonomic unit (OTU) analysis using 16S rRNA gene sequencing were performed. The richness of microbial diversity within subject (α-diversity) was scaled via Shannon entropy. The dissimilarity between microbial community composition was calculated using Bray-Curtis distance as a scale, and differences between groups (β-diversity) were tested by permutational multivariate analysis of variance (PERMANOVA). In addition, UniFrac distance calculated in consideration of the distance on the phylogenetic tree were performed.Results:Median age 71 y.o., % Female 58.4 %. Among RA and non-RA subjects, not α-diversity but β-diversity was statistically smaller significantly in RA (p=0.022). In the HS, there was no decrease in α-diversity between the ACPA-positive and HLA-DRB1*SE-positive groups, but in the ACPA-positive group, there was a decrease in α-diversity in the HLA-DRB1*SE-positive group. When we compared α-diversity stratified by the presence or absence of three factors (RA, ACPA, and HLA-DRB1*SE), the RA group with ACPA and HLA-DRB1*SE positive tended to have the lowest diversity (Figure 1 lower right). RA subjects, presence of HLA-DRB1*SE did not show the difference but the tendency of lower α-diversity (p=0.29).Conclusion:HS with ACPA-positive HLA-DRB1*SE tended to show lower α-diversity than ACPA-positive HS and HLA-DRB1*SE positive HS. Furthermore, RA subjects with ACPA-positive HLA-DRB1*SE showed lower α-diversity than HS with ACPA-positive HLA-DRB1*SE.Our study suggested that the oral dysbiosis may reflect the immunological status of patients with RA. Because of the small number of ACPA-positive patients, stratification by smoking history was difficult. Further examination is needed to clarify the gene-environment interaction and microbiome.References:[1]Kawaguchi S, et al. Methods Mol Biol 2018;1802: 22.Disclosure of Interests:None declared

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