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A variant in MCF2L is associated with osteoarthritis.

ABSTRACT: Osteoarthritis (OA) is a prevalent, heritable degenerative joint disease with a substantial public health impact. We used a 1000-Genomes-Project-based imputation in a genome-wide association scan for osteoarthritis (3177 OA cases and 4894 controls) to detect a previously unidentified risk locus. We discovered a small disease-associated set of variants on chromosome 13. Through large-scale replication, we establish a robust association with SNPs in MCF2L (rs11842874, combined odds ratio [95% confidence interval] 1.17 [1.11-1.23], p = 2.1 × 10(-8)) across a total of 19,041 OA cases and 24,504 controls of European descent. This risk locus represents the third established signal for OA overall. MCF2L regulates a nerve growth factor (NGF), and treatment with a humanized monoclonal antibody against NGF is associated with reduction in pain and improvement in function for knee OA patients.

SUBMITTER: Day-Williams AG

PROVIDER: S-EPMC3169824 | biostudies-literature | 2011 Sep

REPOSITORIES: biostudies-literature

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A variant in MCF2L is associated with osteoarthritis.

Day-Williams Aaron G AG Southam Lorraine L Panoutsopoulou Kalliope K Rayner Nigel W NW Esko Tonu T Estrada Karol K Helgadottir Hafdis T HT Hofman Albert A Ingvarsson Throvaldur T Jonsson Helgi H Keis Aime A Kerkhof Hanneke J M HJ Thorleifsson Gudmar G Arden Nigel K NK Carr Andrew A Chapman Kay K Deloukas Panos P Loughlin John J McCaskie Andrew A Ollier William E R WE Ralston Stuart H SH Spector Timothy D TD Wallis Gillian A GA Wilkinson J Mark JM Aslam Nadim N Birell Fraser F Carluke Ian I Joseph John J Rai Ashok A Reed Mike M Walker Kirsten K Doherty Sally A SA Jonsdottir Ingileif I Maciewicz Rose A RA Muir Kenneth R KR Metspalu Andres A Rivadeneira Fernando F Stefansson Kari K Styrkarsdottir Unnur U Uitterlinden Andre G AG van Meurs Joyce B J JB Zhang Weiya W Valdes Ana M AM Doherty Michael M Zeggini Eleftheria E

American journal of human genetics 20110825 3

Osteoarthritis (OA) is a prevalent, heritable degenerative joint disease with a substantial public health impact. We used a 1000-Genomes-Project-based imputation in a genome-wide association scan for osteoarthritis (3177 OA cases and 4894 controls) to detect a previously unidentified risk locus. We discovered a small disease-associated set of variants on chromosome 13. Through large-scale replication, we establish a robust association with SNPs in MCF2L (rs11842874, combined odds ratio [95% conf ...[more]

PMID: 21871595

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Project description: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.

Dataset Information

A variant in MCF2L is associated with osteoarthritis.

Publications

A variant in MCF2L is associated with osteoarthritis.

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