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Lookup NU author(s): Dr Tony Sorial, Ines Hofer, Maria Tselepi, Kat Cheung, Dr Eleanor Parker, Professor David Deehan, Dr Sarah RiceORCiD, Professor John LoughlinORCiD
This work is licensed under a Creative Commons Attribution 4.0 International License (CC BY 4.0).
Objective: In cartilage, the osteoarthritis (OA) associated single nucleotide polymorphism (SNP) rs11780978 correlates with differential expression of PLEC, and with differential methylation of PLEC CpG dinucleotides, forming eQTLs and mQTLs respectively. This implies that methylation links chondrocyte genotype and phenotype, thus driving the functional effect of this genetic risk signal. PLEC encodes plectin, a cytoskeletal protein that enables tissues to respond to mechanical forces. We sought to assess whether these PLEC functional effects were cartilage specific. Method: Cartilage, fat pad, synovium and peripheral blood were collected from patients undergoing arthroplasty. PLEC CpGs were analysed for mQTLs and allelic expression imbalance (AEI) was performed to test for eQTLs. Plectin was knocked down in a mesenchymal stem cell line using CRISPR/Cas9 and cells phenotyped by RNA-sequencing. Results: mQTLs were discovered in fat pad, synovium and blood. Their effects were however stronger in the joint tissues and of comparable effect between these tissues. We observed AEI in synovium in the same direction as for cartilage and correlations between methylation and PLEC expression. Knocking-down plectin impacted on pathways reported to have a role in OA, including Wnt signalling, glycosaminoglycan biosynthesis and immune regulation. Conclusions: Synovium is also a target of the rs11780978 OA association functionally operating on PLEC. In fat pad, mQTLs were identified but these did not correlate with PLEC expression, suggesting the functional effect is not joint-wide. Our study highlights interplay between genetic risk, DNA methylation and gene expression in OA, and reveals clear differences between tissues from the same diseased joint.
Author(s): Sorial AK, Hofer IM, Tselepi M, Cheung K, Parker E, Deehan DJ, Rice SJ, Loughlin J
Publication type: Article
Publication status: Published
Journal: Osteoarthritis and Cartilage
Year: 2020
Volume: 28
Issue: 11
Pages: 1448-1458
Print publication date: 01/11/2020
Online publication date: 21/06/2020
Acceptance date: 09/06/2020
Date deposited: 29/06/2020
ISSN (print): 1063-4584
ISSN (electronic): 1522-9653
Publisher: Elsevier
URL: https://doi.org/10.1016/j.joca.2020.06.001
DOI: 10.1016/j.joca.2020.06.001
PubMed id: 32580029
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