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THU0454 Changes in DNA Methylation Related to Smoking Are Associated with Ra. an Epigenome Wide Association Study in Monozygotic RA Discordant Twin Pairs
  1. A.J. Svendsen1,
  2. K. Gervin2,
  3. R. Lyle3,
  4. C. Nielsen4,
  5. G. Houen5,
  6. P. Junker4,
  7. K. Kyvik4,
  8. Q. Tan4
  1. 1The Danish Twin Registry, University of Southern Denmark, Odense, Denmark
  2. 2Medical Genetics, Oslo University Hospital
  3. 3Medical Genetics, Oslo University Hospital, Oslo, Norway
  4. 4University of Southern Denmark, Odense
  5. 5Statens Serum Institute, Copenhagen, Denmark

Abstract

Background There is increasing evidence for a pathogenetic role of DNA methylation changes in RA. Monozygotic (MZ) twins provide a unique opportunity to study the epigenetic effects in complex diseases like RA. Recent estimates on DNA methylation in twins showed a mean genome-wide heritability of 18%. Recent studies indicate that DNA methylation may be an intermediary factor of genetic risk in RA.1 In addition, tobacco smoking, which has emerged as the single most important environmental risk factor for RA, leads to extensive Genome-Wide changes in DNA methylation.2

Objectives To identify differentially methylated positions (DMPs) associated with RA and smoking.

Methods Blood-derived DNA from 28 monozygotic RA discordant twin pairs was analyzed for epigenome wide methylation (EWAS) using Illumina HumanMethylation450 array. The twins were characterized with regard to smoking, DMARD-treatment, anti-CCP, and the pair specific genetic variables shared epitope and PTPN22 as well as age and sex. We used a mixed model designed for EWAS on discordant twins taking these covariates as well as batch effects into consideration.

Results A total of 407 CpG sites were differentially methylated in RA patients related to smoking with p<0.01, adjusted for false discovery rates. Biological pathway analysis revealed that a large number of functional gene clusters were affected, e.g. macrophage activation, sphingomyelin metabolic process, apoptotic cell clearance, and histone demethylase activity.

Conclusions These observations indicate that tobacco smoking elicits profound epigenetic modifications in RA when adjusting other RA associated covariates.

References

  1. Liu Y, Aryee MJ, Padyukov L, Fallin MD, Hesselberg E, Runarsson A, et al. Epigenome-wide association data implicate DNA methylation as an intermediary of genetic risk in rheumatoid arthritis. Nat Biotech 2013; 31(2): 142-7.

  2. Zeilinger S, Kuhnel B, Klopp N, Baurecht H, Kleinschmidt A, Gieger C, et al. Tobacco smoking leads to extensive genome-wide changes in DNA methylation. PLoS One 2013; 8(5): e63812.

Disclosure of Interest : None declared

DOI 10.1136/annrheumdis-2014-eular.2461

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