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Functional characterisation of the osteoarthritis susceptibility locus at chromosome 6q14.1 marked by the polymorphism rs9350591

Lookup NU author(s): Dr Katherine JohnsonORCiD, Dr Louise Reynard, Professor John LoughlinORCiD



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


BACKGROUND: The arcOGEN genome-wide association study reported the rs9350591 C/T single nucleotide polymorphism (SNP) as marking a region on chromosome 6q14.1 that is associated with hip osteoarthritis (OA) in Europeans, with an odds ratio (OR) of 1.18 and a p-value of 2.42 × 10(-9). rs9350591 is an intergenic SNP surrounded by seven genes within 1 Mb. Six of the genes are expressed in cartilage. We sought to characterise this signal to assess whether the association of rs9350591 with OA is mediated by modulating gene expression.METHODS: Total RNA was extracted from hip or knee cartilage of 161 OA patients and from hip cartilage of 29 non-OA patients who had undergone hip replacements as a result of neck-of-femur (NOF) fractures. We used quantitative PCR (qPCR) to measure overall gene expression, and pyrosequencing to assess allelic expression of the genes. A mesenchymal stem cell (MSC) differentiation model was used to assess gene expression during chondrogenesis.RESULTS: We identified a significant decrease in the expression of SENP6 (p = 0.005) and MYO6 (p = 0.026) in OA hip cartilage relative to the non-OA hip control cartilage. However, we found no evidence for a correlation between gene expression and rs9350591 genotype for any of the six genes. In addition, we identified expression quantitative trait loci (eQTLs) operating on COL12A1, TMEM30A, SENP6 and MYO6, although these were not relevant to the OA associated signal. Finally, all genes were dynamically expressed during chondrogenesis.CONCLUSIONS: The regulation of gene expression at this locus is complex, highlighted by the down-regulation of SENP6 and MYO6 in OA hip cartilage and by eQTLs operating on four of the genes at the locus. However, modulation of gene expression in the end-stage OA cartilage that we have investigated is not the mechanism by which this association signal is operating. As implied by the dynamic patterns of gene expression throughout chondrogenesis, the association signal marked by rs9350591 could instead be exerting its effects during joint development.

Publication metadata

Author(s): Johnson K, Reynard LN, Loughlin J

Publication type: Article

Publication status: Published

Journal: BMC Medical Genetics

Year: 2015

Volume: 16

Issue: 1

Online publication date: 07/09/2015

Acceptance date: 12/08/2015

Date deposited: 02/10/2015

ISSN (electronic): 1471-2350

Publisher: BioMed Central Ltd


DOI: 10.1186/s12881-015-0215-9

PubMed id: 26346884


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