Journal
EUROPEAN JOURNAL OF HUMAN GENETICS
Volume 21, Issue 5, Pages 517-521Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/ejhg.2012.197
Keywords
osteoarthritis; GDF5; association; expression; YY1; EMSA
Funding
- Arthritis Research UK
- UK NIHR Biomedical Research Center for ageing and age-related disease award
- Dr William Harker Foundation studentship
- Oliver Bird Rheumatism Program studentship from the Nuffield Foundation
- MRC [MR/K006312/1] Funding Source: UKRI
- Medical Research Council [MR/K006312/1] Funding Source: researchfish
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Osteoarthritis (OA) is a polygenic disease characterized by cartilage loss, with the single-nucleotide polymorphism (SNP) rs143383 (C/T) influencing OA susceptibility across a range of ethnic groups. The SNP resides within the 5'-UTR of the growth and differentiation factor 5 gene (GDF5), with the OA-associated T-allele mediating reduced GDF5 expression. As GDF5 codes for a cartilage anabolic protein, this reduced expression may explain why the T-allele of rs143383 is an OA risk factor. Our deep sequencing of GDF5 identified a C/A transversion located -41 bp relative to the gene's transcription start site. This promoter variant is predicted to affect transcription factor binding and it may therefore highlight a regulatory site that could be exploited to manipulate GDF5 expression and alleviate the detrimental effect mediated by the T-allele of rs143383. Here, we describe our functional assessment of the -41 bp variant. Using reporter constructs we demonstrated that the transversion leads to increased gene expression to such a degree that the A-allele is able to compensate for the reduced expression mediated by the T-allele of rs143383. Using electrophoretic mobility shift assays we identified YY1 as a trans-acting factor that differentially binds to the alleles of the -41 bp variant, with more avid binding to allele A. Knockdown of YY1 led to a significant reduction in GDF5 expression, supporting YY1 as a GDF5 activator. In conclusion, we demonstrated that the -41 bp variant is functional and we have identified a regulatory region of GDF5 that can be exploited to overcome the OA genetic deficit mediated by the T-allele of rs143383. European Journal of Human Genetics (2013) 21, 517-521; doi:10.1038/ejhg.2012.197; published online 29 August 2012
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