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Lymphocyte DNA methylation mediates genetic risk at shared immune-mediated disease loci

Lookup NU author(s): Alex Clark, Dr Amy AndersonORCiD, Dr Nishanthi Thalayasingam, Najib NaamaneORCiD, Julie Diboll, Professor John IsaacsORCiD, Dr Arthur PrattORCiD, Dr Louise ReynardORCiD

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This work is licensed under a Creative Commons Attribution 4.0 International License (CC BY 4.0).

Abstract

BACKGROUND: Defining regulatory mechanisms through which noncoding risk variants influence the cell-mediated pathogenesis of immune-mediated disease (IMD) has emerged as a priority in the post-genome-wide association study era.OBJECTIVES: With a focus on rheumatoid arthritis, we sought new insight into genetic mechanisms of adaptive immune dysregulation to help prioritize molecular pathways for targeting in this and related immune pathologies.METHODS: Whole-genome methylation and transcriptional data from isolated CD4⁺ T cells and B cells of more than 100 genotyped and phenotyped patients with inflammatory arthritis, all of whom were naive to immunomodulatory treatments, were obtained. Analysis integrated these comprehensive data with genome-wide association study findings across IMDs and other publicly available resources.RESULTS: We provide strong evidence that disease-associated DNA variants regulate cis-CpG methylation in CD4⁺ T and/or B cells at 37% RA loci. Using paired, cell-specific transcriptomic data and causal inference testing, we identify examples where site-specific DNA methylation in turn mediates gene expression, including FCRL3 in both cell types and ORMDL3/GSDMB, IL6ST/ANKRD55, and JAZF1 in CD4⁺ T cells. A number of genes regulated in this way highlight mechanisms common to RA and other IMDs including multiple sclerosis and asthma, in turn distinguishing them from osteoarthritis, a primarily degenerative disease. Finally, we corroborate the observed effects experimentally.CONCLUSIONS: Our observations highlight important mechanisms of genetic risk in RA and the wider context of immune dysregulation. They confirm the utility of DNA methylation profiling as a tool for causal gene prioritization and, potentially, therapeutic targeting in complex IMD.

Publication metadata

Author(s): Clark AD, Nair N, Anderson AE, Thalayasingam N, Naamane N, Skelton AJ, Diboll J, Barton A, Eyre S, Isaacs JD, Pratt AG, Reynard LN

Publication type: Article

Publication status: Published

Journal: Journal of Allergy and Clinical Immunology

Year: 2020

Volume: 145

Issue: 5

Pages: 1438-1451

Print publication date: 01/05/2020

Online publication date: 13/01/2020

Acceptance date: 10/12/2019

Date deposited: 06/03/2020

ISSN (print): 0091-6749

ISSN (electronic): 1097-6825

Publisher: Elsevier Inc.

URL: https://doi.org/10.1016/j.jaci.2019.12.910

DOI: 10.1016/j.jaci.2019.12.910

PubMed id: 31945409

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