Molecular genetic and epigenetic analysis of the osteoarthritis risk residing downstream of the gene TGFB1

Rice, S.J.; Tselepi, M.; Roberts, J.B.; Loughlin, John

doi:10.1016/j.joca.2020.02.527

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“…The advent of CRISPR-Cas9 and subsequent development of the Cas9 toolbox has revolutionised targeted editing of the genome and epigenome 59 . For functional analyses of OA risk loci, CRISPR has been used to delete both putative regulatory elements and functional SNPs in Tc28a2 chondrocytes, confirming the RUNX family transcription factor gene RUNX2, the transforming growth factor gene TGFB1, and the collagen galactosyltransferase gene COLGALT2 as targets of OA genetic risk 52 , 60 , 61 . The development of a catalytically dead Cas9 (dCas9) fused to enzymes which either methylate (DNMT3a) or demethylate (TET1) CpGs has allowed precision editing of DNAm at targeted CpGs for the first time.…”

Section: Introductionmentioning

confidence: 99%

“…2 provides a schematic of how one can progress from an association SNP (sections A to H) towards a functional variant (sections I to M) and target gene (sections N to P). The OA targets so far discovered via such approaches include COLGALT2 , RUNX2 , PLEC (encoding plectin), MGP , ALDH1A2 (encoding aldehyde dehydrogenase), TGFB1 , GDF5 (encoding growth differentiation factor 5), and RWDD2B ( Table I ) 2 , 12 , 18 , 52 , 53 , 54 , 55 , 56 , 57 , 60 , 61 . These genes encode proteins with diverse roles, including extracellular signaling molecule ( GDF5 , TGFB1 ), extracellular calcium regulator ( MGP ), intracellular enzyme ( ALDH1A2 ), transcription factor ( RUNX2 ) and cytoskeletal protein ( PLEC ), indicating that OA genetic risk is operating on a broad range of biological functions.…”

Section: Introductionmentioning

confidence: 99%

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Genetics of osteoarthritis

Aubourg

Rice

Bruce-Wootton

et al. 2022

Osteoarthritis and Cartilage

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Osteoarthritis genetics has been transformed in the past decade through the application of large-scale genome-wide association scans. So far, over 100 polymorphic DNA variants have been associated with this common and complex disease. These genetic risk variants account for over 20% of osteoarthritis heritability and the vast majority map to non-protein coding regions of the genome where they are presumed to act by regulating the expression of target genes. Statistical fine mapping, in silico analyses of genomics data, and laboratory-based functional studies have enabled the identification of some of these targets, which encode proteins with diverse roles, including extracellular signaling molecules, intracellular enzymes, transcription factors, and cytoskeletal proteins. A large number of the risk variants correlate with epigenetic factors, in particular cartilage DNA methylation changes in cis, implying that epigenetics may be a conduit through which genetic effects on gene expression are mediated. Some of the variants also appear to have been selected as humans adapted to bipedalism, suggesting that a proportion of osteoarthritis genetic susceptibility results from antagonistic pleiotropy, with risk variants having a positive role in joint formation but a negative role in the long-term health of the joint. Although data from an osteoarthritis genetic study has not yet directly led to a novel treatment, some of the osteoarthritis associated genes code for proteins that have available therapeutics. Genetic investigations are therefore revealing fascinating fundamental insights into osteoarthritis and can expose options for translational intervention.

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