Smoking interacts with HLA-DRB1 shared epitope in the development of anti-citrullinated protein antibody-positive rheumatoid arthritis: results from the Malaysian Epidemiological Investigation of Rheumatoid Arthritis (MyEIRA)

Abstract

IntroductionRheumatoid arthritis (RA) is a multifactorial autoimmune disease in which genetic and environmental factors interact in the etiology. In this study, we investigated whether smoking and HLA-DRB1 shared-epitope (SE) alleles interact differently in the development of the two major subgroups of rheumatoid arthritis (RA), anti-citrullinated proteins antibody (ACPA)-positive and ACPA-negative disease, in a multiethnic population of Asian descent.MethodsA case-control study comprising early diagnosed RA cases was carried out in Malaysia between 2005 and 2009. In total, 1,076 cases and 1,612 matched controls participated in the study. High-resolution HLA-DRB1 genotyping was performed for shared-epitope (SE) alleles. All participants answered a questionnaire on a broad range of issues, including smoking habits. The odds ratio (OR) of developing ACPA-positive and ACPA-negative disease was calculated for smoking and the presence of any SE alleles separately. Potential interaction between smoking history (defined as "ever" and "never" smoking) and HLA-DRB1 SE alleles also was calculated.ResultsIn our multiethnic study, both the SE alleles and smoking were associated with an increased risk of developing ACPA-positive RA (OR SE alleles, 4.7; 95% confidence interval (CI), 3.6 to 6.2; OR smoking, 4.1; 95% CI, 1.9 to 9.2). SE-positive smokers had an odds ratio of ACPA-positive RA of 25.6 (95% CI, 10.4 to 63.4), compared with SE-negative never-smokers. The interaction between smoking and SE alleles was significant (attributable proportion due to interaction (AP) was 0.7 (95% CI, 0.5 to 1.0)). The HLA-DRB1*04:05 SE allele, which is common in Asian populations, but not among Caucasians, was associated with an increased risk of ACPA-positive RA, and this allele also showed signs of interaction with smoking (AP, 0.4; 95% CI, -0.1 to 0.9). Neither smoking nor SE alleles nor their combination was associated with an increased risk of ACPA-negative RA.ConclusionsThe risk of developing ACPA-positive RA is associated with a strong gene-environment interaction between smoking and HLA-DRB1 SE alleles in a Malaysian multiethnic population of Asian descent. This interaction seems to apply also between smoking and the specific HLA-DRB1*04:05 SE allele, which is common in Asian populations but not in Caucasians.

Genetics, Environment, and Gene-Environment Interactions in the Development of Systemic Rheumatic Diseases

“…Studies initially performed by Klareskog and colleagues demonstrated a strongly significant multiplicative GEI between cigarette smoking and HLA-DRB1 in determining RA risk. 42, 72–76 This association was strongest for seropositive RA and has been replicated in several populations, including US women, and Swedish, and Malaysian populations. 72–74 The presence of heavy smoking and two HLA-DRB1 genes increased the odds for RA by 23-fold compared to those with neither risk factor.…”

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.…”

Smoking, the HLA-DRB1 shared epitope and ACPA fine-specificity in Koreans with rheumatoid arthritis: evidence for more than one pathogenic pathway linking smoking to disease

“…Xue et al 20 found that the SE was associated with RA but not with ACPA production in a small Chinese RA cohort, whereas such associations have been reported in Malaysian, Chinese and Japanese patients 21 22. In a mixed Malaysian population, smoking, the SE and the interaction between them, only conferred risk for ACPA-positive RA 23. However, in a Korean population, Bang et al 16 reported that the SE was associated with ACPA-negative and ACPA-positive RA.…”