Abstract
BackgroundMultiple factors, including interactions between genetic and environmental risks, are important in susceptibility to rheumatoid arthritis (RA). However, the underlying mechanism is not fully understood. This study was undertaken to evaluate whether DNA methylation can mediate the interaction between genotype and smoking in the development of anti-citrullinated peptide antibody (ACPA)-positive RA.MethodsWe investigated the gene-smoking interactions in DNA methylation using 393 individuals from the Epidemiological Investigation of Rheumatoid Arthritis (EIRA). The interaction between rs6933349 and smoking in the risk of developing ACPA-positive RA was further evaluated in a larger portion of the EIRA (1119 controls and 944 ACPA-positive patients with RA), and in the Malaysian Epidemiological Investigation of Rheumatoid Arthritis (MyEIRA) (1556 controls and 792 ACPA-positive patients with RA). Finally, mediation analysis was performed to investigate whether DNA methylation of cg21325723 mediates this gene-environment interaction on the risk of developing of ACPA-positive RA.ResultsWe identified and replicated one significant gene-environment interaction between rs6933349 and smoking in DNA methylation of cg21325723. This gene-smoking interaction is a novel interaction in the risk of developing ACPA-positive in both Caucasian (multiplicative P value = 0.056; additive P value = 0.016) and Asian populations (multiplicative P value = 0.035; additive P value = 0.00027), and it is mediated through DNA methylation of cg21325723.ConclusionsWe showed that DNA methylation of cg21325723 can mediate the gene-environment interaction between rs6933349 and smoking, impacting the risk of developing ACPA-positive RA, thus being a potential regulator that integrates both internal genetic and external environmental risk factors.
Highlights
Multiple factors, including interactions between genetic and environmental risks, are important in susceptibility to rheumatoid arthritis (RA)
Genotype and smoking interaction in DNA methylation analyzed using a linear regression model We decided to focus on the single nucleotide polymorphisms (SNPs) within the major histocompatibility complex (MHC region) (chr6: 29,500,000–33,500,000) and the 10 differentially methylated positions (DMPs), which we identified previously to be associated with the development of anti-citrullinated peptide antibody (ACPA)-positive RA [12]
Genotype and smoking interaction in ACPA-positive RA Two statistical models were used to evaluate the interaction between rs6933349 and smoking status in the development of ACPA-positive RA: (1) we performed interaction analysis by means of logistic regression with adjustment for age and sex, and interaction was evaluated on the multiplicative scale by calculating the interaction term in the logistic regression model, and (2) we evaluated the interaction between genotype and smoking in ACPA-positive RA by departure from the additivity of effects, and biological interaction was estimated by calculating the attributable proportion due to interaction (AP)
Summary
Multiple factors, including interactions between genetic and environmental risks, are important in susceptibility to rheumatoid arthritis (RA). Rheumatoid arthritis (RA) is a chronic autoimmune disease that leads to inflammation of the joints and surrounding tissues. It can cause severe functional disabilities, pain, and other disorders, such as cardiovascular disease. It has been shown that the two major subgroups of RA, anti-citrullinated peptide antibody (ACPA)-positive and ACPA-negative RA, have in part different etiology. One example of this is the shared epitope (SE) alleles of the human leukocyte antigen DR beta chain 1 (HLADRB1), which is a major risk factor for ACPA-positive RA, but not to the same extent for ACPA-negative RA. Environmental/lifestyle factors, such as smoking [1,2,3] and other noxious airway exposures [4, 5], have been shown to be risk factors for RA, mainly for the ACPApositive subset of RA
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