Genomic Risk Score for Advanced Osteoarthritis in Older Adults

Lacaze, Paul; Wang, Y.; Polekhina, Galina; Bakshi, Andrew; Riaz, Moeen; Owen, Alice; Franks, Amy M.; Abidi, J.; Tiller, Jane; McNeil, John J; Cicuttini, F.

doi:10.1016/j.joca.2022.02.484

Cited by 5 publications

(4 citation statements)

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“…This is the rst study to identify the presence of mQTLs in human fetal cartilage and limb tissues, and our report demonstrates that the functional genetic risk of OA can be laid down during human skeletogenesis. Strides are being made within the eld, with the rst recent reports of polygenic risk scores (PRS) for the disease (51,52), yet the clinical utility of such systems is still lacking (53). We would encourage the integration of epigenetic data at the loci, along with clinical and biochemical parameters to further advance these tools for patient bene t.…”

Section: Discussionmentioning

confidence: 99%

Genetic risk of osteoarthritis operates during human skeletogenesis

Rice

Brumwell

Falk

et al. 2022

Human Molecular Genetics

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Osteoarthritis (OA) is a polygenic disease of older people resulting in the breakdown of cartilage within articular joints. Although a leading cause of disability, there are no disease-modifying therapies. Evidence is emerging to support the origins of OA in skeletogenesis. Whilst methylation QTLs (mQTLs) co-localizing with OA GWAS signals have been identified in aged human cartilage and used to identify effector genes and variants, such analyses have never been conducted during human development. Here, for the first time, we have investigated the developmental origins of OA genetic risk at seven well-characterized OA risk loci, comprising 39 OA-mQTL CpGs, in human foetal limb (FL) and cartilage (FC) tissues using a range of molecular genetic techniques. We compared our results to aged cartilage samples (AC) and identified significant OA-mQTLs at 14 CpGs and 29 CpGs in FL and FC tissues, respectively. Differential methylation was observed at 26 sites between foetal and aged cartilage, with the majority becoming actively hypermethylated in old age. Notably, 6/9 OA effector genes showed allelic expression imbalances during foetal development. Finally, we conducted ATAC-sequencing in cartilage from the developing and aged hip and knee to identify accessible chromatin regions, and found enrichment for transcription factor binding motifs including SOX9 and FOS/JUN. For the first time, we have demonstrated the activity of OA-mQTLs and expression imbalance of OA effector genes during skeletogenesis. We show striking differences in the spatiotemporal function of these loci, contributing to our understanding of OA aetiology, with implications for the timing and strategy of pharmacological interventions.

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Section: Discussionmentioning

confidence: 99%

Genetic risk of osteoarthritis operates during human skeletogenesis

Rice

Brumwell

Falk

et al. 2022

Human Molecular Genetics

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“…OA is a multimodal disease, with multiple factors leading to its development and progression that can be targeted to delay or even prevent its progression. The ideal scenario for future patients is a multimodal approach from personalized lifestyle modifications informed by polygenic risk scores that characterize an individual genetic risk profile as reported by the group of F. Cicuttini* (Lacaze et al, 2022) to the study of the degenerative and inflammatory state of the joint down to a cellular level to counteract destructive processes and even stimulate regeneration. Combining these different levels of therapeutic impact, one could potentially modulate the disease progression by targeting therapies to different patient phenotype in OA.…”

Section: Discussionmentioning

confidence: 99%

Women’s contribution to stem cell research for osteoarthritis: an opinion paper

Velot,

Balmayor,

Bertoni

et al. 2023

Front. Cell Dev. Biol.

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“…However, some of these data sets might be used much earlier as prognostic tools, to determine patient risk and to direct prevention. For example, two recent studies used the loci identified in GWAS studies to determine the 'Polygenic Risk Score' (PRS) for OA patients, with encouraging results ( [30,31], discussed in [32]). Steinbeck et al [33] provide another example of using multiomics approaches to stratify patients and potentially direct more personalized treatments in the future.…”

Section: Outlook and Conclusionmentioning

confidence: 99%

The impact of omics research on our understanding of osteoarthritis and future treatments

Beier¹

2022

Current Opinion in Rheumatology

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Purpose of reviewTo review recent studies using Omics approaches (genomics, proteomics, metabolomics, single cell analyses) in patient populations and animal models of osteoarthritis (OA), with the goal of identifying disease-modifying mechanisms that could serve as therapeutic and diagnostic targets. Recent findingsThe number of genes, pathways and molecules with potential roles in OA pathogenesis has grown substantially over the last 18 months. Studies have expanded from their traditional focus on cartilage and gene expression to other joint tissues, proteins and metabolites. Single cell approaches provide unprecedented resolution and exciting insights into the heterogeneity of cellular activities in OA. Functional validation and investigation of underlying mechanisms in animal models of OA, in particular genetically engineered mice, link Omics findings to pathophysiology and potential therapeutic applications.

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Genomic Risk Score for Advanced Osteoarthritis in Older Adults

Cited by 5 publications

References 0 publications

Genetic risk of osteoarthritis operates during human skeletogenesis

Genetic risk of osteoarthritis operates during human skeletogenesis

Women’s contribution to stem cell research for osteoarthritis: an opinion paper

The impact of omics research on our understanding of osteoarthritis and future treatments

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