Osteoarthritis genetic risk acting on the galactosyltransferase gene COLGALT2 has opposing functional effects in articulating joint tissues
Abstract Background Investigation of cartilage and chondrocytes has revealed that the osteoarthritis risk marked by the independent DNA variants rs11583641 and rs1046934 mediate their effects by decreasing the methylation status of CpG dinucleotides in enhancers and increasing the expression of sha...
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| Format: | Article |
| Language: | English |
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BMC
2023-05-01
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| Series: | Arthritis Research & Therapy |
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| Online Access: | https://doi.org/10.1186/s13075-023-03066-y |
| _version_ | 1797822764948652032 |
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| author | Yulia S. Kehayova J. Mark Wilkinson Sarah J. Rice John Loughlin |
| author_facet | Yulia S. Kehayova J. Mark Wilkinson Sarah J. Rice John Loughlin |
| author_sort | Yulia S. Kehayova |
| collection | DOAJ |
| description | Abstract Background Investigation of cartilage and chondrocytes has revealed that the osteoarthritis risk marked by the independent DNA variants rs11583641 and rs1046934 mediate their effects by decreasing the methylation status of CpG dinucleotides in enhancers and increasing the expression of shared target gene COLGALT2. We set out to investigate if these functional effects operate in a non-cartilaginous joint tissue. Methods Nucleic acids were extracted from the synovium of osteoarthritis patients. Samples were genotyped, and DNA methylation was quantified by pyrosequencing at CpGs within the COLGALT2 enhancers. CpGs were tested for enhancer effects using a synovial cell line and a reporter gene assay. DNA methylation was altered using epigenetic editing, with the impact on gene expression determined using quantitative polymerase chain reaction. In silico analysis complemented laboratory experiments. Results The rs1046934 genotype did not associate with DNA methylation or COLGALT2 expression in the synovium, whereas the rs11583641 genotype did. Surprisingly, the effects for rs11583641 were opposite to those previously observed in cartilage. Epigenetic editing in synovial cells revealed that enhancer methylation is causally linked to COLGALT2 expression. Conclusions This is the first direct demonstration for osteoarthritis genetic risk of a functional link between DNA methylation and gene expression operating in opposite directions between articular joint tissues. It highlights pleiotropy in the action of osteoarthritis risk and provides a cautionary note in the application of future genetically based osteoarthritis therapies: an intervention that decreases the detrimental effect of a risk allele in one joint tissue may inadvertently increase its detrimental effect in another joint tissue. |
| first_indexed | 2024-03-13T10:13:59Z |
| format | Article |
| id | doaj.art-d3db7e5027b6495781391d28190ee6fc |
| institution | Directory Open Access Journal |
| issn | 1478-6362 |
| language | English |
| last_indexed | 2024-03-13T10:13:59Z |
| publishDate | 2023-05-01 |
| publisher | BMC |
| record_format | Article |
| series | Arthritis Research & Therapy |
| spelling | doaj.art-d3db7e5027b6495781391d28190ee6fc2023-05-21T11:22:35ZengBMCArthritis Research & Therapy1478-63622023-05-0125111310.1186/s13075-023-03066-yOsteoarthritis genetic risk acting on the galactosyltransferase gene COLGALT2 has opposing functional effects in articulating joint tissuesYulia S. Kehayova0J. Mark Wilkinson1Sarah J. Rice2John Loughlin3Newcastle University, Biosciences Institute, International Centre for LifeDepartment of Oncology and Metabolism, University of SheffieldNewcastle University, Biosciences Institute, International Centre for LifeNewcastle University, Biosciences Institute, International Centre for LifeAbstract Background Investigation of cartilage and chondrocytes has revealed that the osteoarthritis risk marked by the independent DNA variants rs11583641 and rs1046934 mediate their effects by decreasing the methylation status of CpG dinucleotides in enhancers and increasing the expression of shared target gene COLGALT2. We set out to investigate if these functional effects operate in a non-cartilaginous joint tissue. Methods Nucleic acids were extracted from the synovium of osteoarthritis patients. Samples were genotyped, and DNA methylation was quantified by pyrosequencing at CpGs within the COLGALT2 enhancers. CpGs were tested for enhancer effects using a synovial cell line and a reporter gene assay. DNA methylation was altered using epigenetic editing, with the impact on gene expression determined using quantitative polymerase chain reaction. In silico analysis complemented laboratory experiments. Results The rs1046934 genotype did not associate with DNA methylation or COLGALT2 expression in the synovium, whereas the rs11583641 genotype did. Surprisingly, the effects for rs11583641 were opposite to those previously observed in cartilage. Epigenetic editing in synovial cells revealed that enhancer methylation is causally linked to COLGALT2 expression. Conclusions This is the first direct demonstration for osteoarthritis genetic risk of a functional link between DNA methylation and gene expression operating in opposite directions between articular joint tissues. It highlights pleiotropy in the action of osteoarthritis risk and provides a cautionary note in the application of future genetically based osteoarthritis therapies: an intervention that decreases the detrimental effect of a risk allele in one joint tissue may inadvertently increase its detrimental effect in another joint tissue.https://doi.org/10.1186/s13075-023-03066-yGeneticsEpigeneticsDNA methylationCOLGALT2Synovium |
| spellingShingle | Yulia S. Kehayova J. Mark Wilkinson Sarah J. Rice John Loughlin Osteoarthritis genetic risk acting on the galactosyltransferase gene COLGALT2 has opposing functional effects in articulating joint tissues Arthritis Research & Therapy Genetics Epigenetics DNA methylation COLGALT2 Synovium |
| title | Osteoarthritis genetic risk acting on the galactosyltransferase gene COLGALT2 has opposing functional effects in articulating joint tissues |
| title_full | Osteoarthritis genetic risk acting on the galactosyltransferase gene COLGALT2 has opposing functional effects in articulating joint tissues |
| title_fullStr | Osteoarthritis genetic risk acting on the galactosyltransferase gene COLGALT2 has opposing functional effects in articulating joint tissues |
| title_full_unstemmed | Osteoarthritis genetic risk acting on the galactosyltransferase gene COLGALT2 has opposing functional effects in articulating joint tissues |
| title_short | Osteoarthritis genetic risk acting on the galactosyltransferase gene COLGALT2 has opposing functional effects in articulating joint tissues |
| title_sort | osteoarthritis genetic risk acting on the galactosyltransferase gene colgalt2 has opposing functional effects in articulating joint tissues |
| topic | Genetics Epigenetics DNA methylation COLGALT2 Synovium |
| url | https://doi.org/10.1186/s13075-023-03066-y |
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