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

BMC Medical Genetics

Research Article

Colin Shepherd¹  John Loughlin¹  Louise N. Reynard¹  Michael D. Rushton¹  Andrew J. Skelton² 

[1] Musculoskeletal Research Group, Institute of Cellular Medicine, Newcastle University, 4th Floor Catherine Cookson Building, Framlington Place, NE2 4HH, Newcastle-upon-Tyne, UK;Musculoskeletal Research Group, Institute of Cellular Medicine, Newcastle University, 4th Floor Catherine Cookson Building, Framlington Place, NE2 4HH, Newcastle-upon-Tyne, UK;Bioinformatics Support Unit, Faculty of Medical Sciences, Newcastle University, 2nd floor, William Leech Building, Framlington Place, NE2 4HH, Newcastle-upon-Tyne, UK;

关键词: Osteoarthritis;    Association;    Single nucleotide polymorphism;    Gene expression;    MCF2L;    Luciferase reporter assays;    Allelic expression;   

DOI  :  10.1186/s12881-015-0254-2

 received in 2015-08-27, accepted in 2015-11-11,  发布年份 2015

来源: Springer

【 摘 要 】

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.

【 授权许可】

CC BY   
© Shepherd et al. 2015