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Mediation of the Same Epigenetic and Transcriptional Effect by Independent Osteoarthritis Risk–Conferring Alleles on a Shared Target Gene, COLGALT2

Lookup NU author(s): Yulia Kehayova, Dr Sarah RiceORCiD, Professor John LoughlinORCiD

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


Abstract

Objective. Over 100 DNA variants have been associated with osteoarthritis (OA), including rs1046934, located within a linkage disequilibrium block encompassing part of COLGALT2 and TSEN15. Here, we used human foetal cartilage, cartilage from arthroplasty patients, and a chondrocyte cell model to determine the target gene(s) at the locus and the mechanism of action. Methods. Genotyping and methylation array data of cartilage DNA (n=87) were used to determine if rs1046934 genotype associated with differential DNA methylation at proximal CpGs. Results were replicated in arthroplasty (n=132) and foetal (n=77) cartilage DNA using pyrosequencing. Allelic expression imbalance (AEI) measured effect of genotype upon COLGALT2 and TSEN15 expression. Reporter gene assays and epigenetic editing determined the functional role of regions harbouring differentially methylated CpGs. In silico analyses complemented these experiments. Results. Three differentially methylated CpGs residing within regulatory regions were detected, two of which replicated. AEI was detected for COLGALT2 and TSEN15, with associations between expression and methylation for COLGALT2. Reporter assays confirmed that the CpGs are in chondrocyte enhancers with epigenetic editing directly linking methylation with COLGALT2 expression. Conclusion. COLGALT2 is a target of this OA locus. We previously characterised another OA locus, marked by rs11583641, that independently targets COLGALT2. rs1046934, like rs11583641, mediates its effect by modulating expression of COLGALT2 via methylation changes to CpGs located in enhancers. The SNPs, CpGs and enhancers are distinct between the loci but the effect on COLGALT2 is the same. COLGALT2 is the target of independent OA risk loci sharing a common mechanism of action.


Publication metadata

Author(s): Kehayova YS, Wilkinson JM, Rice SJ, Loughlin J

Publication type: Article

Publication status: Published

Journal: Arthritis & Rheumatology

Year: 2023

Volume: 75

Issue: 6

Pages: 910-922

Print publication date: 01/06/2023

Online publication date: 20/12/2022

Acceptance date: 15/12/2022

Date deposited: 22/12/2022

ISSN (print): 2326-5191

ISSN (electronic): 2326-5205

Publisher: John Wiley & Sons, Inc.

URL: https://doi.org/10.1002/art.42427

DOI: 10.1002/art.42427

PubMed id: 36538011


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Funding

Funder referenceFunder name
20771VERSUS Arthritis (formerly Arthritis Research UK)
22615
MR/R502182/1
MR/P020941/1
Ruth & Lionel Jacobson Charitable Trust

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