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Correlation of the Osteoarthritis Susceptibility Variants That Map to Chromosome 20q13 With an Expression Quantitative Trait Locus Operating on NCOA3 and With Functional Variation at the Polymorphism rs116855380

Lookup NU author(s): Dr Fiona Gee, Dr Michael Rushton, Professor John LoughlinORCiD, Dr Louise Reynard



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


Objective To functionally characterize the osteoarthritis (OA) susceptibility that maps to the single nucleotide polymorphism (SNP) rs6094710 on chromosome 20q13, in a region of high linkage disequilibrium (LD) encompassing NCOA3 and SULF2. Methods Nucleic acid was extracted from the cartilage of OA patients. Overall and allelic expression of NCOA3 and SULF2 were measured by quantitative PCR and pyrosequencing, respectively. The functional effect of SNPs within the 20q13 locus was assessed in vitro using luciferase reporter constructs and electrophoretic mobility shift assays (EMSAs). The in vivo effect of NCOA3 depletion on patient chondrocytes was assessed using RNA interference. Results Expression of NCOA3 correlated with genotype at rs6094710 (p = 0.006), and the gene demonstrated allelic expression imbalance in individuals heterozygous for the SNP (mean AEI = 1.21, p < 0.0001). In both instances, expression of the OA-associated allele was reduced. rs116855380, a SNP in perfect LD with rs6094710, showed reduced enhancer activity from the OA-associated allele in luciferase assays (p < 0.001). EMSAs demonstrated a protein complex binding with reduced affinity to this allele. NCOA3 depletion led to changes (p < 0.05) in the expression of genes involved in cartilage homeostasis. Conclusion NCOA3 is subject to a cis-acting expression quantitative trait locus (eQTL) in cartilage, which correlates with the OA association signal and with the OA-associated allele of the functional SNP rs116855380. This SNP is located only 10.3 kb upstream of NCOA3. This study has elucidated the effect of the 20q13 association on cartilage and identified a compelling causal candidate SNP. This article is protected by copyright. All rights reserved.

Publication metadata

Author(s): Gee F, Rushton MD, Loughlin J, Reynard LN

Publication type: Article

Publication status: Published

Journal: Arthritis & Rheumatology

Year: 2015

Volume: 67

Issue: 11

Pages: 2923-2932

Print publication date: 01/11/2015

Online publication date: 20/07/2015

Acceptance date: 07/07/2015

Date deposited: 05/11/2015

ISSN (print): 2326-5191

ISSN (electronic): 2326-5205

Publisher: John Wiley & Sons, Inc.


DOI: 10.1002/art.39278

PubMed id: 26211391


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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
305815European Union