Differential DNA methylation patterns in whole blood from ACPA-positive patients with DMARD naïve rheumatoid arthritis at clinical disease onset.

Anders Jørgen Svendsen^1,2*Jonas Mengel-From³Peter Junker⁴Christine Dalgård⁵George Davey Smith⁶Caroline L Relton⁶Hannah R Elliott⁶Kirsten Ohm Kyvik⁷Hanne Merete Lindegaard⁴Anne Friesgaard Christensen⁸Qihua Tan²

• ¹University of Southern Denmark, Odense, Denmark
• ²Research Unit for Epidemiology, Biostatistics and Biodemography, Department of Public Health, Faculty of Health Sciences, University of Southern Denmark, Odense, Denmark
• ³Research Unit of Human Genetics, Department of Clinical Research, Faculty of Health Sciences, University of Southern Denmark, Odense, Denmark
• ⁴Department of Rheumatology, Odense University Hospital, Odense, Denmark
• ⁵Research unit of Clinical Pharmacology, Department of Clinical Research, Faculty of Health Sciences, University of Southern Denmark, Odense, Denmark
• ⁶MRC Integrative Epidemiology Unit, Department of Population Health Sciences, Bristol Medical School, Faculty of Health Sciences, University of Bristol, Bristol, England, United Kingdom
• ⁷Department of Clinical Genetics, Odense University Hospital, Odense, Denmark
• ⁸a.friesgaard@gmail.coma.friesgaard@gmail.com, Vejle, Denmark

ObjectiveEpigenetic DNA imprints are increasingly being recognized as co-drivers of disease in complex conditions. In this exploratory and hypothesis generating epigenome-wide study (EWAS) we investigated differential methylation patterns in peripheral blood cells from patients with early untreated ACPA positive RA versus controls. MethodsWhole blood DNA was isolated from 101 DMARD naïve patients with recent clinical onset of ACPA positive RA and 200 controls. DNA methylation was studied using the Illumina MethylationEPIC BeadChips (Illumina). We assessed our findings against previously reported differentially methylated DNA positions associated with RA including an EWAS on peripheral blood mononuclear cells from a similar Nordic cohort.ResultsWe identified 16583 CpG sites and 14 differentially methylated regions (DMRs) associated with RA. The most robust DMRs were in the gene body of LAMP1 and the TNSF14 GENE known as light. We identified three novel KEGG pathways, the taste transduction pathway, the olfactory pathway and the viral carcinogenesis pathway, which have not previously been associated with RA. We replicated 2248 CpG sites reported earlier in an EWAS study on peripheral blood leukocytes from RA patients of Scandinavian ancestry with incipient untreated ACPA positive disease.ConclusionWe have detected a considerable number of epigenetic marks with potential relevance to the pathogenesis of RA. These findings may pave the way for development of narrowly targeted new drugs and possibly assist to retrieve persons at particular risk of acquiring RA.