Kehayova, Y.S., Wilkinson, J.M. orcid.org/0000-0001-5577-3674, Rice, S.J. et al. (1 more author) (2023) Osteoarthritis genetic risk acting on the galactosyltransferase gene COLGALT2 has opposing functional effects in articulating joint tissues. Arthritis Research & Therapy, 25 (1). 83. ISSN 1478-6362
Abstract
Background Investigation of cartilage and chondrocytes has revealed that the osteoarthritis risk marked by the independent DNA variants rs11583641 and rs1046934 mediate their effects by decreasing the methylation status of CpG dinucleotides in enhancers and increasing the expression of shared target gene COLGALT2. We set out to investigate if these functional effects operate in a non-cartilaginous joint tissue.
Methods Nucleic acids were extracted from the synovium of osteoarthritis patients. Samples were genotyped, and DNA methylation was quantified by pyrosequencing at CpGs within the COLGALT2 enhancers. CpGs were tested for enhancer effects using a synovial cell line and a reporter gene assay. DNA methylation was altered using epigenetic editing, with the impact on gene expression determined using quantitative polymerase chain reaction. In silico analysis complemented laboratory experiments.
Results The rs1046934 genotype did not associate with DNA methylation or COLGALT2 expression in the synovium, whereas the rs11583641 genotype did. Surprisingly, the effects for rs11583641 were opposite to those previously observed in cartilage. Epigenetic editing in synovial cells revealed that enhancer methylation is causally linked to COLGALT2 expression.
Conclusions This is the first direct demonstration for osteoarthritis genetic risk of a functional link between DNA methylation and gene expression operating in opposite directions between articular joint tissues. It highlights pleiotropy in the action of osteoarthritis risk and provides a cautionary note in the application of future genetically based osteoarthritis therapies: an intervention that decreases the detrimental effect of a risk allele in one joint tissue may inadvertently increase its detrimental effect in another joint tissue.
Metadata
Item Type: | Article |
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Authors/Creators: |
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Copyright, Publisher and Additional Information: | © The Author(s) 2023. Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. |
Keywords: | Genetics; Epigenetics; DNA methylation; COLGALT2; Synovium |
Dates: |
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Institution: | The University of Sheffield |
Academic Units: | The University of Sheffield > Faculty of Medicine, Dentistry and Health (Sheffield) > The Medical School (Sheffield) > Division of Genomic Medicine (Sheffield) > Department of Oncology and Metabolism (Sheffield) |
Depositing User: | Symplectic Sheffield |
Date Deposited: | 23 May 2023 10:44 |
Last Modified: | 23 May 2023 10:44 |
Status: | Published |
Publisher: | Springer Science and Business Media LLC |
Refereed: | Yes |
Identification Number: | 10.1186/s13075-023-03066-y |
Open Archives Initiative ID (OAI ID): | oai:eprints.whiterose.ac.uk:199427 |