Abstract
BackgroundOsteoarthritis (OA) is a painful, debilitating disease characterised by loss of articular cartilage with concurrent changes in other tissues of the synovial joint. Genetic association studies have shown that a number of common variants increase the risk of developing OA. Investigating their activity can uncover novel causal pathways and potentially highlight new treatment targets. One of the reported OA association signals is marked by the single nucleotide polymorphism (SNP) rs11842874 at chromosome 13q34. rs11842874 is positioned within a small linkage disequilibrium (LD) block within intron 4 of MCF2L, a gene encoding guanine-nucleotide exchange factor DBS. There are no non-synonymous SNPs that correlate with this association signal and we therefore set out to assess whether its effect on OA susceptibility is mediated by alteration of MCF2L expression.MethodsNucleic acid was extracted from cartilage, synovial membrane or infrapatellar fat pad tissues from OA patients. Expression of MCF2L was measured by quantitative PCR and RNA-sequencing whilst the presence of DBS was studied using immunohistochemistry. The functional effect of SNPs within the 13q34 locus was assessed using public databases and in vitro using luciferase reporter analysis.ResultsMCF2L gene and protein expression are detectable in joint tissues, with quantitative differences in the expression of the gene and in the transcript isoforms expressed between the tissues tested. There is an expression quantitative trait locus (eQTL) operating within synovial membrane tissue, with possession of the risk-conferring A allele of rs11842874 correlating with increased MCF2L expression. SNPs within the rs11842874 LD block reside within transcriptional regulatory elements and their direct analysis reveals that several show quantitative differences in regulatory activity at the allelic level.ConclusionsMCF2L is subject to a cis-acting eQTL in synovial membrane that correlates with the OA association signal. This signal contains several functional SNPs that could account for the susceptibility and which therefore merit further investigation. As far as we are aware, this is the first example of an OA susceptibility locus operating as an eQTL in synovial membrane tissue but not in cartilage.Electronic supplementary materialThe online version of this article (doi:10.1186/s12881-015-0254-2) contains supplementary material, which is available to authorized users.
Highlights
Osteoarthritis (OA) is a painful, debilitating disease characterised by loss of articular cartilage with concurrent changes in other tissues of the synovial joint
For the RNA sequencing (RNA-seq) analysis, involving an independent panel of OA hip and NOF patients, MCF2L expression was again found to be higher in the NOF patients, this time by 1.5-fold (Fig. 1c, p = 0.042)
We initially demonstrated the expression of MCF2L and the presence of its protein product, DBS, in three major tissues of the synovial joint; cartilage, synovial membrane and infrapatellar fat pad
Summary
Osteoarthritis (OA) is a painful, debilitating disease characterised by loss of articular cartilage with concurrent changes in other tissues of the synovial joint. With the global population increasing in size and in age, and with the incidence of obesity rising, OA is a growing burden on public health budgets It would be beneficial, to identify novel therapeutic targets within OA pathways to improve patient outcomes. Candidate gene and genome-wide association studies (GWAS) have so far identified 16 novel OA risk loci across various joint sites and populations (reviewed in [1] and [2]).
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