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

Abstract

Objective. An interaction effect for developing rheumatoid arthritis (RA) was previously observed between HLA-DRB1 shared epitope (SE) alleles and smoking. We aimed to further investigate this interaction between distinct SE alleles and smoking regarding the risk of developing RA with and without anticitrullinated protein antibodies (ACPAs).Methods. We used data regarding smoking habits and HLA-DRB1 genotypes from 1,319 patients and 943 controls from the Epidemiological Investigation of Rheumatoid Arthritis, in which 972 patients and 488 controls were SE positive. Subsequently, 759 patients and 328 controls were subtyped for specific alleles within the DRB1*04 group. Odds ratios with 95% confidence intervals (95% CIs) were calculated by means of logistic regression. Interaction was evaluated by calculating attributable proportion due to interaction, with 95% CIs. Conclusion.There is a statistically significant interaction between distinct DRB1 SE alleles and smoking in the development of ACPA-positive RA. Interaction occurs with the *04 group as well as the *01/*10 group, demonstrating that regardless of fine specificity, all SE alleles strongly interact with smoking in conferring an increased risk of ACPA-positive RA.

Smoke exposure as a determinant of autoantibody titre in 1-antitrypsin deficiency and COPD

“…Alternatively the effect on synovium could depend upon a further genetic or environmental influence, given that ACPA positive individuals here did not always exhibit rheumatoid arthritis (or indeed other autoimmune diseases). Shared epitope alleles, contained within class II of the human leukocyte antigen system (HLA-DRB1*04, *01 and *10), are important in determining risk of rheumatoid arthritis [26] and ACPA status [27]. Recent data suggest that smoking is a key feature of determining ACPA-positive disease risk in the presence of these alleles [27,28], consistent with this hypothesis.…”

“…Shared epitope alleles, contained within class II of the human leukocyte antigen system (HLA-DRB1*04, *01 and *10), are important in determining risk of rheumatoid arthritis [26] and ACPA status [27]. Recent data suggest that smoking is a key feature of determining ACPA-positive disease risk in the presence of these alleles [27,28], consistent with this hypothesis. ACPA may occur up to 10 yrs before clinical features of rheumatoid arthritis appear [29], the titre relating inversely to the time until diagnosis [30], such that highly positive individuals are likely to be diagnosed soon.…”

How the microbiota shapes rheumatic diseases

“…In other instances (such as reactive arthritis), the genetic component can be much less prominent, with the microbial component being the dominating trigger. In RA, established risk factors, including smoking status and sex, influence the gut microbiota, with the effect of smoking on ACPA production being particularly obvious in patients carrying HLA-DRB1 shared-epitope alleles 137,[151][152][153][154][155] . The principal difference between the multidirectional and the linear models is the reversibility of the multidirectional model.…”

Interaction of HLA-DRB1*09:01 and *04:05 with Smoking Suggests Distinctive Mechanisms of Rheumatoid Arthritis Susceptibility Beyond the Shared Epitope

“…Van der Helm-van Mil, et al 25 found a significant interaction between smoking and the HLA-DRB1*01 or *10 group, but there was no interaction between smoking and the HLA-DRB1*04 group in their case-only analysis. In contrast, interactions between smoking and the *04 group as well as the *01 or *10 group were observed in a case-control study of the Swedish Epidemiological Investigation of Rheumatoid Arthritis (EIRA) 26 .…”