期刊
HUMAN MOLECULAR GENETICS
卷 27, 期 19, 页码 3464-3474出版社
OXFORD UNIV PRESS
DOI: 10.1093/hmg/ddy257
关键词
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资金
- Arthritis Research UK [20771]
- Medical Research Council
- Arthritis Research UK as part of the MRC-Arthritis Research UK Centre for Integrated Research into Musculoskeletal Ageing (CIMA) [JXR 10641]
- Newcastle upon Tyne Hospitals NHS Charity
- European Union Seventh Framework Program for research, technological development and demonstration [305815]
- National Institute for Health Research Integrated Academic Training programme
- NIHR Newcastle Biomedical Research Centre (BRC)
- MRC [MR/P020941/1] Funding Source: UKRI
Osteoarthritis (OA) is a common, multifactorial and polygenic skeletal disease that, in its severest form, requires joint replacement surgery to restore mobility and to relieve chronic pain. Using tissues from the articulating joints of 260 patients with OA and a range of in vitro experiments, including CRISPR-Cas9, we have characterized an intergenic regulatory element. Here, genotype at an OA risk locus correlates with differential DNA methylation, with altered gene expression of both a transcriptional regulator (RUNX2), and a chromatin remodelling protein (SUPT3H). RUNX2 is a strong candidate for OA susceptibility, with its encoded protein being essential for skeletogenesis and healthy joint function. The OA risk locus includes single nucleotide polymorphisms (SNPs) located within and flanking the differentially methylated region (DMR). The OA association SNP, rs10948172, demonstrates particularly strong correlation with methylation, and two intergenic SNPs falling within the DMR (rs62435998 and rs62435999) demonstrate genetic and epigenetic effects on the regulatory activity of this region. We therefore posit that the OA signal mediates its effect by modulating the methylation of the regulatory element, which then impacts on gene expression, with RUNX2 being the principal target. Our study highlights the interplay between DNA methylation, OA genetic risk and the downstream regulation of genes critical to normal joint function.
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