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Expression analysis of the osteoarthritis genetic susceptibility locus mapping to an intron of the MCF2L gene and marked by the polymorphism rs11842874

Lookup NU author(s): Dr Colin Shepherd, Andrew Skelton, Dr Michael Rushton, Dr Louise Reynard, Professor John LoughlinORCiD



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


Background: Osteoarthritis (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.Methods: Nucleic 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.Results: MCF2L 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.Conclusions: MCF2L 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.

Publication metadata

Author(s): Shepherd C, Skelton AJ, Rushton MD, Reynard LN, Loughlin J

Publication type: Article

Publication status: Published

Journal: BMC Medical Genetics

Year: 2015

Volume: 16

Issue: 1

Pages: 108

Online publication date: 19/11/2015

Acceptance date: 11/11/2015

Date deposited: 25/11/2015

ISSN (electronic): 1471-2350

Publisher: BioMed Central Ltd.


DOI: 10.1186/s12881-015-0254-2

PubMed id: 26584642


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Funder referenceFunder name
Arthritis Research UK
NIHR Newcastle Biomedical Research Centre
Arthritis Research UK, MRC-Arthritis Research UK Centre for Integrated Research into Musculoskeletal Ageing (CIMA)
Medical Research Council
Newcastle University
305815European Union Seventh Framework Program