Genome-Wide DNA Epigenetic Profiling of Monozygotic Twins[L1] Discordant for ACPA or ACPA-Positive Rheumatoid Arthritis Reveals Novel Associated Genes

David Gomez¹, Malin Almgren², Louise Sjoholm², Aase Haj Hensvold³, Andrew Feinberg⁴, L. Klareskog⁵, Tomas Ekstrom^2,6 and Anca I Catrina⁵, ¹Unit of Computational Medicine Karolinska Institutet Center for Molecular Medicine Karolinska University Hospital, stockholm, Sweden, ²Laboratory for Medical Epigenetics, Dept. of Clinical Neuroscience, Karolinska Institutet, Karolinska Hospital, Stockholm, Sweden, ³Rheumatology Unit, Department of Medicine, Solna, Karolinska Institute, Stockholm, Sweden, Stockholm, Sweden, ⁴Department of Genetics, Johns Hopkins University School of Medicine, Baltimore, MD, ⁵Rheumatology Unit, Department of Medicine, Karolinska Institutet, Stockholm, Sweden, ⁶Departmen of Clinical Neuroscience, karolinska Institute, Stockholm, Sweden

Meeting: 2015 ACR/ARHP Annual Meeting

Date of first publication: September 29, 2015

Keywords: anti-CCP antibodies, epigenetics and rheumatoid arthritis (RA)

Session Information

Date: Sunday, November 8, 2015

Session Title: Genetics, Genomics and Proteomics Poster I

Session Type: ACR Poster Session A

Session Time: 9:00AM-11:00AM

Background/Purpose:

Occurrence and progression of complex autoimmune diseases are orchestrated by interactions between genes and environment, in part mediated by epigenetic mechanisms. It is yet unclear how these interactions operate over time for different disease sub-phenotypes. We aimed to investigate how epigenetic modifications might contribute to different development phases of an autoimmune disease, using ACPA (antibodies to citrullinated protein antigens)-positive rheumatoid arthritis (RA) as a disease model and an epigenome-wide DNA methylation analysis of two sets of monozygotic (MZ) twins.

Methods:

Five healthy twin pairs discordant for presence of ACPA but not having RA and seven twin pairs discordant for ACPA-positive RA were included in this study. The selected twin pairs belong to a population based twin cohort (Twingene) which is part of the Swedish twin register ACPA status is defined by testing sera with CCP2 ELISA assay (Immunoscan CCPlus). None of the healthy twins have reported chronic rheumatic joint disease (rheumatoid arthritis) at time point of blood donation. During a median follow up of 3 years (IQR 2-4) they all continued to lack an RA diagnosis (or other rheumatic joint disease diagnosis e.g. polyarthritis) in the Swedish National Patient Register. The ACPA positive RA twins have also tested positive for ACPA while their co-twin have tested negative for ACPA. The RA twins reported RA at the time of blood donation and this was verified by review of the medical records. Co-twins of these ACPA positive RA twins did not report RA and this was again verified by linkage to the Swedish National Patient Register. Genome wide gene specific methylation was analysed by CHARM methodology.

Results:

CHARM analysis of the healthy twin pairs, discordant for ACPA, revealed 17 genome wide significant (family wise error rate (FWER) <0.2) differentially methylated gene regions (DMRs), after cell-type distribution correction. Profiling of the seven twin pairs discordant for ACPA-positive RA identified 36 significant DMRs (where one associated with an exosome component) after cell-type distribution correction. Interestingly, one ACPA-discordant associated DMR associated to a protocadherine (PCDH) gene showed a high probability to be also found in ACPA-positive RA. None of the identified DMRs were found in the proximity of previously known genetically associated genes, including MHC, suggesting a successful neutralization of genetic influence in our design with MZ twins.

Conclusion:

We describe here novel associations between DNA methylation and different phases of ACPA-positive RA, prompting further studies to address the potential pathogenic relevance of these epigenetic modifications for RA.

Disclosure: D. Gomez, None; M. Almgren, None; L. Sjoholm, None; A. H. Hensvold, None; A. Feinberg, None; L. Klareskog, None; T. Ekstrom, None; A. I. Catrina, None.

To cite this abstract in AMA style:

Gomez D, Almgren M, Sjoholm L, Hensvold AH, Feinberg A, Klareskog L, Ekstrom T, Catrina AI. Genome-Wide DNA Epigenetic Profiling of Monozygotic Twins[L1] Discordant for ACPA or ACPA-Positive Rheumatoid Arthritis Reveals Novel Associated Genes [abstract]. Arthritis Rheumatol. 2015; 67 (suppl 10). https://acrabstracts.org/abstract/genome-wide-dna-epigenetic-profiling-of-monozygotic-twinsl1-discordant-for-acpa-or-acpa-positive-rheumatoid-arthritis-reveals-novel-associated-genes/. Accessed March 1, 2021.

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