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Abstract
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.
Highlights
Osteoarthritis (OA) is an age-related, complex disease characterized by the irreversible breakdown of articular cartilage, most commonly in the hip or knee [1]
Stratification by genotype at OA-associated single nucleotide polymorphisms (SNPs) highlighted the arcOGEN OA SNP rs10948172 as showing strong correlation with the methylation at the differentially methylated region (DMR). This was an important observation as it suggests a mechanism by which this OA risk-conferring signal mediates its effect, namely modulating methylation at the DMR, which alters gene expression at the allelic level (Fig. S5)
To determine whether this was plausible, we first assessed whether SUPT3H and RUNX2 were subject to an rs10948172 eQTL in OA tissues
Summary
Osteoarthritis (OA) is an age-related, complex disease characterized by the irreversible breakdown of articular cartilage, most commonly in the hip or knee [1]. Under non-pathological conditions, articular cartilage facilitates joint function by minimizing friction and bearing the impact of mechanical loading [2]. Loss of this cartilage is painful and, debilitating. Genetic risk factors confer 50% of disease susceptibility and, to date, genome-wide association studies (GWAS) have reported up to 30 risk loci for OA (https://www.nature.com/articles/s41588-018-0079-y). Functional correlations have been established between genetic risk and epigenetic variation, principally via DNA methylation changes at CpG sites [4]
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