title: DNA methylation mediates genotype and smoking interaction in the development of anti-citrullinated peptide antibody-positive rheumatoid arthritis.
abstract: Multiple 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.
  
  
  
  We 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.
  
  
  
  We 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.
  
  
  
  We 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.
authors.affiliation: Department of Biochemistry and Molecular Biology, The Ministry of Education Key Laboratory of Metabolism and Molecular Medicine, School of Basic Medical Sciences, Fudan University, West Building 13, 130 Dong An Road, Shanghai, China.|State Key Laboratory of Medical Neurobiology, Fudan University, Shanghai, China.
authors.forename: Weida
authors.initials: W
authors.lastname: Meng
authors.affiliation: Division of Rheumatology, Huashan Hospital, Fudan University, Shanghai, China.
authors.forename: Zaihua
authors.initials: Z
authors.lastname: Zhu
authors.affiliation: Institute of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Xia
authors.initials: X
authors.lastname: Jiang
authors.affiliation: Institute for Medical Research, Jalan Pahang, 50588, Kuala Lumpur, Malaysia.|Rheumatology Unit, Department of Medicine, Center for Molecular Medicine, Karolinska Institutet and Karolinska University Hospital, Stockholm, Sweden.
authors.forename: Chun Lai
authors.initials: CL
authors.lastname: Too
authors.affiliation: Institute of Human Genetics, Friedrich-Alexander-Universität Erlangen-Nürnberg (FAU), Erlangen, Germany.
authors.forename: Steffen
authors.initials: S
authors.lastname: Uebe
authors.affiliation: Department of Clinical Neuroscience, Center for Molecular Medicine, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Maja
authors.initials: M
authors.lastname: Jagodic
authors.affiliation: Department of Clinical Neuroscience, Center for Molecular Medicine, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Ingrid
authors.initials: I
authors.lastname: Kockum
authors.affiliation: Institute for Medical Research, Jalan Pahang, 50588, Kuala Lumpur, Malaysia.
authors.forename: Shahnaz
authors.initials: S
authors.lastname: Murad
authors.affiliation: Instramural Research Program, National Institute on Aging, National Institutes of Health, Baltimore, MD, USA.
authors.forename: Luigi
authors.initials: L
authors.lastname: Ferrucci
authors.affiliation: Institute of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden.|Center for Occupational and Environmental Medicine, Stockholm County Council, Stockholm, Sweden.
authors.forename: Lars
authors.initials: L
authors.lastname: Alfredsson
authors.affiliation: Division of Rheumatology, Huashan Hospital, Fudan University, Shanghai, China.
authors.forename: Hejian
authors.initials: H
authors.lastname: Zou
authors.affiliation: Rheumatology Unit, Department of Medicine, Center for Molecular Medicine, Karolinska Institutet and Karolinska University Hospital, Stockholm, Sweden.
authors.forename: Lars
authors.initials: L
authors.lastname: Klareskog
authors.affiliation: Center for Epigenetics and Departments of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
authors.forename: Andrew P
authors.initials: AP
authors.lastname: Feinberg
authors.affiliation: Department of Clinical Neuroscience, Center for Molecular Medicine, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Tomas J
authors.initials: TJ
authors.lastname: Ekström
authors.affiliation: Rheumatology Unit, Department of Medicine, Center for Molecular Medicine, Karolinska Institutet and Karolinska University Hospital, Stockholm, Sweden. leonid.padyukov@ki.se.
authors.forename: Leonid
authors.initials: L
authors.lastname: Padyukov
authors.affiliation: Department of Biochemistry and Molecular Biology, The Ministry of Education Key Laboratory of Metabolism and Molecular Medicine, School of Basic Medical Sciences, Fudan University, West Building 13, 130 Dong An Road, Shanghai, China. yliu39@fudan.edu.cn.|State Key Laboratory of Medical Neurobiology, Fudan University, Shanghai, China. yliu39@fudan.edu.cn.
authors.forename: Yun
authors.initials: Y
authors.lastname: Liu
mesh_terms: D000328:Adult; D000368:Aged; D001172:Arthritis, Rheumatoid / Q000235:genetics* / Q000276:immunology; D001323:Autoantibodies / Q000276:immunology*; D001324:Autoantigens / Q000276:immunology; D019175:DNA Methylation / Q000235:genetics*; D005260:Female; D059647:Gene-Environment Interaction; D005838:Genotype; D006801:Humans; D008285:Major Histocompatibility Complex / Q000235:genetics; D008297:Male; D008875:Middle Aged; D020411:Oligonucleotide Array Sequence Analysis; D010456:Peptides, Cyclic / Q000276:immunology; D020641:Polymorphism, Single Nucleotide; D012907:Smoking / Q000009:adverse effects*
chemical_list: D001323:Autoantibodies; D001324:Autoantigens; D010456:Peptides, Cyclic; C487763:cyclic citrullinated peptide
keywords: Epidemiology; Rheumatoid arthritis; Smoking