Abstract
SummaryObjectiveIn 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.MethodCartilage, 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 (MSC) line using CRISPR/Cas9 and cells phenotyped by RNA-sequencing.ResultsmQTLs 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.ConclusionsSynovium 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.
Highlights
Osteoarthritis (OA) is an extremely common musculoskeletal disorder that is characterised by focal loss of articular cartilage leading to chronic pain, disability, co-morbidities including cardiovascular disease, and premature death1e3
Using allelic expression imbalance (AEI) analysis we demonstrated that the OA risk-conferring A allele of rs11780978 correlated with reduced PLEC expression, and that expression of the gene correlated with methylation at CpGs in the cg19405177 and cg14598846 clusters[16]
We modelled the transcriptional effect that the OA risk-conferring allele of rs11780978 has on PLEC by knocking-down plectin in a mesenchymal stem cell (MSC) line using CRISPR/Cas[9] and assessing the impact on global gene expression
Summary
Osteoarthritis (OA) is an extremely common musculoskeletal disorder that is characterised by focal loss of articular cartilage leading to chronic pain, disability, co-morbidities including cardiovascular disease, and premature death1e3. PLEC is expressed widely and in this report, we set out to test whether the mQTL, eQTL and meQTL effects that we had discovered were cartilage specific or whether they were active in other joint or non-joint tissues.
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