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DNA methylation mediates genotype and smoking interaction in the development of anti-citrullinated peptide antibody-positive rheumatoid arthritis

Meng W 1 , Zhu Z 2 , Jiang X 3 , Too CL 4 , Uebe S 5 , Jagodic M 6 Show all authors , Kockum I 6 , Murad S 4 , Ferrucci L 7 , Alfredsson L 3 , Zou H 2 , Klareskog L 8 , Feinberg AP 9 , Ekström TJ 6 , Padyukov L 10 , Liu Y 11

Affiliations 

  • 1 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
  • 2 Division of Rheumatology, Huashan Hospital, Fudan University, Shanghai, China
  • 3 Institute of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden
  • 4 Institute for Medical Research, Jalan Pahang, 50588, Kuala Lumpur, Malaysia
  • 5 Institute of Human Genetics, Friedrich-Alexander-Universität Erlangen-Nürnberg (FAU), Erlangen, Germany
  • 6 Department of Clinical Neuroscience, Center for Molecular Medicine, Karolinska Institutet, Stockholm, Sweden
  • 7 Instramural Research Program, National Institute on Aging, National Institutes of Health, Baltimore, MD, USA
  • 8 Rheumatology Unit, Department of Medicine, Center for Molecular Medicine, Karolinska Institutet and Karolinska University Hospital, Stockholm, Sweden
  • 9 Center for Epigenetics and Departments of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, USA
  • 10 Rheumatology Unit, Department of Medicine, Center for Molecular Medicine, Karolinska Institutet and Karolinska University Hospital, Stockholm, Sweden. leonid.padyukov@ki.se
  • 11 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
Arthritis Res Ther, 2017 03 29;19(1):71.
PMID: 28356135 DOI: 10.1186/s13075-017-1276-2

Abstract

BACKGROUND: 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.

METHODS: 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.

RESULTS: 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.

CONCLUSIONS: 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.

* Title and MeSH Headings from MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

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