Dataset Information

Expression analysis of the osteoarthritis genetic susceptibility mapping to the matrix Gla protein gene MGP.

ABSTRACT: BACKGROUND:Osteoarthritis (OA) is a common disease of older individuals that impacts detrimentally on the quality and the length of life. It is characterised by the painful loss of articular cartilage and is polygenic and multifactorial. Genome-wide association scans have highlighted over 90 osteoarthritis genetic signals, some of which reside within or close to highly plausible candidate genes. An example is an association to polymorphisms within and adjacent to the matrix Gla protein gene MGP. We set out to undertake a functional study of this gene. METHODS:Nucleic acid was extracted from cartilage, infrapatellar fat pad, synovium, trabecular bone, trapezium and peripheral whole blood from OA patients and also from mesenchymal stem cells (MSCs) subjected to chondrogenesis. Expression of MGP was measured by quantitative PCR (qPCR), RNA-sequencing and allelic expression imbalance (AEI) analysis. Matrix Gla protein was depleted in chondrocytes by knocking down MGP expression using RNA interference (RNAi) and the effect on a range of genes assessed by qPCR. RESULTS:MGP is expressed in joint tissues, blood and chondrocytes cultured from MSCs. There is a higher expression in diseased versus non-diseased cartilage. Polymorphisms that are associated with OA also correlate with the expression of MGP, with the OA risk-conferring allele showing significantly reduced expression in cartilage, fat pad and synovium but increased expression in blood. Depletion of Matrix Gla protein had a significant effect on the majority of genes tested, with an increased expression of catabolic genes that encode enzymes that degrade cartilage. CONCLUSIONS:MGP expression is subject to cis-acting regulators that correlate with the OA association signal. These are active in a range of joint tissues but have effects which are particularly strong in cartilage. An opposite effect is observed in blood, highlighting the context-specific nature of the regulation of this gene's expression. Recapitulation of the genetic deficit in cartilage chondrocytes is pro-catabolic.

SUBMITTER: Shepherd C

PROVIDER: S-EPMC6582465 | biostudies-literature | 2019 Jun

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Expression analysis of the osteoarthritis genetic susceptibility mapping to the matrix Gla protein gene MGP.

Shepherd Colin C Reese Abigail E AE Reynard Louise N LN Loughlin John J

Arthritis research & therapy 20190618 1

<h4>Background</h4>Osteoarthritis (OA) is a common disease of older individuals that impacts detrimentally on the quality and the length of life. It is characterised by the painful loss of articular cartilage and is polygenic and multifactorial. Genome-wide association scans have highlighted over 90 osteoarthritis genetic signals, some of which reside within or close to highly plausible candidate genes. An example is an association to polymorphisms within and adjacent to the matrix Gla protein g ...[more]

PMID: 31215457

Similar Datasets

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

Expression analysis of the osteoarthritis genetic susceptibility mapping to the matrix Gla protein gene MGP.

Publications

Expression analysis of the osteoarthritis genetic susceptibility mapping to the matrix Gla protein gene MGP.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets