A meta-analysis and a functional study support the influence of mtDNA variant m.16519C on the risk of rapid progression of knee osteoarthritis
Objectives To identify mitochondrial DNA (mtDNA) genetic variants associated with the risk of rapid progression of knee osteoarthritis (OA) and to characterise their functional significance using a cellular model of transmitochondrial cybrids. Methods Three prospective cohorts contributed participan...
| Autores: | , , , , , , , , , , , , , , , , |
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| Tipo de recurso: | artículo |
| Fecha de publicación: | 2023 |
| País: | España |
| Institución: | Servizo Galego de Saúde (SERGAS) |
| Repositorio: | RUNA. Repositorio da Consellería de Sanidade e Sergas |
| OAI Identifier: | oai:runa.sergas.gal:20.500.11940/20983 |
| Acceso en línea: | https://portalcientifico.sergas.gal//documentos/648600d6a219857f1d7895a0 http://hdl.handle.net/20.500.11940/20983 |
| Access Level: | acceso abierto |
| Palabra clave: | Humans DNA, Mitochondrial Osteoarthritis, Knee Reactive Oxygen Species Prospective Studies Mitochondria Inflammation AS A Coruña INIBIC CHUAC |
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| dc.title.none.fl_str_mv |
A meta-analysis and a functional study support the influence of mtDNA variant m.16519C on the risk of rapid progression of knee osteoarthritis |
| title |
A meta-analysis and a functional study support the influence of mtDNA variant m.16519C on the risk of rapid progression of knee osteoarthritis |
| spellingShingle |
A meta-analysis and a functional study support the influence of mtDNA variant m.16519C on the risk of rapid progression of knee osteoarthritis Duran Sotuela, Alejandro Humans DNA, Mitochondrial Osteoarthritis, Knee Reactive Oxygen Species Prospective Studies Mitochondria Inflammation AS A Coruña INIBIC AS A Coruña CHUAC AS A Coruña CHUAC AS A Coruña CHUAC AS A Coruña CHUAC AS A Coruña INIBIC AS A Coruña CHUAC AS A Coruña CHUAC AS A Coruña CHUAC AS A Coruña INIBIC AS A Coruña CHUAC AS A Coruña INIBIC AS A Coruña CHUAC AS A Coruña CHUAC |
| title_short |
A meta-analysis and a functional study support the influence of mtDNA variant m.16519C on the risk of rapid progression of knee osteoarthritis |
| title_full |
A meta-analysis and a functional study support the influence of mtDNA variant m.16519C on the risk of rapid progression of knee osteoarthritis |
| title_fullStr |
A meta-analysis and a functional study support the influence of mtDNA variant m.16519C on the risk of rapid progression of knee osteoarthritis |
| title_full_unstemmed |
A meta-analysis and a functional study support the influence of mtDNA variant m.16519C on the risk of rapid progression of knee osteoarthritis |
| title_sort |
A meta-analysis and a functional study support the influence of mtDNA variant m.16519C on the risk of rapid progression of knee osteoarthritis |
| dc.creator.none.fl_str_mv |
Duran Sotuela, Alejandro Fernández Moreno, Mercedes Suárez Ulloa, Victoria Vázquez-García, J. Relaño Fernández, Sara María Hermida Gómez, Tamara Balboa Barreiro, Vanesa Lourido-Salas, L. Calamia ., Valentina Fernández Puente, Patricia Ruiz Romero, Cristina Fernández Tajes, Juan Vaamonde García, Carlos De Andrés González, Mª Carmen Oreiro, N. Blanco García, Francisco Rego Pérez, Ignacio |
| author |
Duran Sotuela, Alejandro |
| author_facet |
Duran Sotuela, Alejandro Fernández Moreno, Mercedes Suárez Ulloa, Victoria Vázquez-García, J. Relaño Fernández, Sara María Hermida Gómez, Tamara Balboa Barreiro, Vanesa Lourido-Salas, L. Calamia ., Valentina Fernández Puente, Patricia Ruiz Romero, Cristina Fernández Tajes, Juan Vaamonde García, Carlos De Andrés González, Mª Carmen Oreiro, N. Blanco García, Francisco Rego Pérez, Ignacio |
| author_role |
author |
| author2 |
Fernández Moreno, Mercedes Suárez Ulloa, Victoria Vázquez-García, J. Relaño Fernández, Sara María Hermida Gómez, Tamara Balboa Barreiro, Vanesa Lourido-Salas, L. Calamia ., Valentina Fernández Puente, Patricia Ruiz Romero, Cristina Fernández Tajes, Juan Vaamonde García, Carlos De Andrés González, Mª Carmen Oreiro, N. Blanco García, Francisco Rego Pérez, Ignacio |
| author2_role |
author author author author author author author author author author author author author author author author |
| dc.subject.none.fl_str_mv |
Humans DNA, Mitochondrial Osteoarthritis, Knee Reactive Oxygen Species Prospective Studies Mitochondria Inflammation AS A Coruña INIBIC AS A Coruña CHUAC AS A Coruña CHUAC AS A Coruña CHUAC AS A Coruña CHUAC AS A Coruña INIBIC AS A Coruña CHUAC AS A Coruña CHUAC AS A Coruña CHUAC AS A Coruña INIBIC AS A Coruña CHUAC AS A Coruña INIBIC AS A Coruña CHUAC AS A Coruña CHUAC |
| topic |
Humans DNA, Mitochondrial Osteoarthritis, Knee Reactive Oxygen Species Prospective Studies Mitochondria Inflammation AS A Coruña INIBIC AS A Coruña CHUAC AS A Coruña CHUAC AS A Coruña CHUAC AS A Coruña CHUAC AS A Coruña INIBIC AS A Coruña CHUAC AS A Coruña CHUAC AS A Coruña CHUAC AS A Coruña INIBIC AS A Coruña CHUAC AS A Coruña INIBIC AS A Coruña CHUAC AS A Coruña CHUAC |
| description |
Objectives To identify mitochondrial DNA (mtDNA) genetic variants associated with the risk of rapid progression of knee osteoarthritis (OA) and to characterise their functional significance using a cellular model of transmitochondrial cybrids. Methods Three prospective cohorts contributed participants. The osteoarthritis initiative (OAI) included 1095 subjects, the Cohort Hip and Cohort Knee included 373 and 326 came from the PROspective Cohort of Osteoarthritis from A Coruña. mtDNA variants were screened in an initial subset of 450 subjects from the OAI by in-depth sequencing of mtDNA. A meta-analysis of the three cohorts was performed. A model of cybrids was constructed to study the functional consequences of harbouring the risk mtDNA variant by assessing: mtDNA copy number, mitochondrial biosynthesis, mitochondrial fission and fusion, mitochondrial reactive oxygen species (ROS), oxidative stress, autophagy and a whole transcriptome analysis by RNA-sequencing. Results mtDNA variant m.16519C is over-represented in rapid progressors (combined OR 1.546; 95% CI 1.163 to 2.054; p=0.0027). Cybrids with this variant show increased mtDNA copy number and decreased mitochondrial biosynthesis; they produce higher amounts of mitochondrial ROS, are less resistant to oxidative stress, show a lower expression of the mitochondrial fission-related gene fission mitochondrial 1 and an impairment of autophagic flux. In addition, its presence modulates the transcriptome of cybrids, especially in terms of inflammation, where interleukin 6 emerges as one of the most differentially expressed genes. Conclusions The presence of the mtDNA variant m.16519C increases the risk of rapid progression of knee OA. Among the most modulated biological processes associated with this variant, inflammation and negative regulation of cellular process stand out. The design of therapies based on the maintenance of mitochondrial function is recommended. |
| publishDate |
2023 |
| dc.date.none.fl_str_mv |
2023 |
| dc.type.none.fl_str_mv |
info:eu-repo/semantics/article |
| format |
article |
| dc.identifier.none.fl_str_mv |
https://portalcientifico.sergas.gal//documentos/648600d6a219857f1d7895a0 http://hdl.handle.net/20.500.11940/20983 |
| url |
https://portalcientifico.sergas.gal//documentos/648600d6a219857f1d7895a0 http://hdl.handle.net/20.500.11940/20983 |
| dc.language.none.fl_str_mv |
Inglés |
| language_invalid_str_mv |
Inglés |
| dc.rights.none.fl_str_mv |
http://creativecommons.org/licenses/by-nc/4.0/ info:eu-repo/semantics/openAccess |
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http://creativecommons.org/licenses/by-nc/4.0/ |
| eu_rights_str_mv |
openAccess |
| dc.source.none.fl_str_mv |
reponame:RUNA. Repositorio da Consellería de Sanidade e Sergas instname:Servizo Galego de Saúde (SERGAS) |
| instname_str |
Servizo Galego de Saúde (SERGAS) |
| reponame_str |
RUNA. Repositorio da Consellería de Sanidade e Sergas |
| collection |
RUNA. Repositorio da Consellería de Sanidade e Sergas |
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| _version_ |
1869403585426489344 |
| spelling |
A meta-analysis and a functional study support the influence of mtDNA variant m.16519C on the risk of rapid progression of knee osteoarthritisDuran Sotuela, AlejandroFernández Moreno, MercedesSuárez Ulloa, VictoriaVázquez-García, J.Relaño Fernández, Sara MaríaHermida Gómez, TamaraBalboa Barreiro, VanesaLourido-Salas, L.Calamia ., ValentinaFernández Puente, PatriciaRuiz Romero, CristinaFernández Tajes, JuanVaamonde García, CarlosDe Andrés González, Mª CarmenOreiro, N.Blanco García, FranciscoRego Pérez, IgnacioHumansDNA, MitochondrialOsteoarthritis, KneeReactive Oxygen SpeciesProspective StudiesMitochondriaInflammationAS A CoruñaINIBICAS A CoruñaCHUACAS A CoruñaCHUACAS A CoruñaCHUACAS A CoruñaCHUACAS A CoruñaINIBICAS A CoruñaCHUACAS A CoruñaCHUACAS A CoruñaCHUACAS A CoruñaINIBICAS A CoruñaCHUACAS A CoruñaINIBICAS A CoruñaCHUACAS A CoruñaCHUACObjectives To identify mitochondrial DNA (mtDNA) genetic variants associated with the risk of rapid progression of knee osteoarthritis (OA) and to characterise their functional significance using a cellular model of transmitochondrial cybrids. Methods Three prospective cohorts contributed participants. The osteoarthritis initiative (OAI) included 1095 subjects, the Cohort Hip and Cohort Knee included 373 and 326 came from the PROspective Cohort of Osteoarthritis from A Coruña. mtDNA variants were screened in an initial subset of 450 subjects from the OAI by in-depth sequencing of mtDNA. A meta-analysis of the three cohorts was performed. A model of cybrids was constructed to study the functional consequences of harbouring the risk mtDNA variant by assessing: mtDNA copy number, mitochondrial biosynthesis, mitochondrial fission and fusion, mitochondrial reactive oxygen species (ROS), oxidative stress, autophagy and a whole transcriptome analysis by RNA-sequencing. Results mtDNA variant m.16519C is over-represented in rapid progressors (combined OR 1.546; 95% CI 1.163 to 2.054; p=0.0027). Cybrids with this variant show increased mtDNA copy number and decreased mitochondrial biosynthesis; they produce higher amounts of mitochondrial ROS, are less resistant to oxidative stress, show a lower expression of the mitochondrial fission-related gene fission mitochondrial 1 and an impairment of autophagic flux. In addition, its presence modulates the transcriptome of cybrids, especially in terms of inflammation, where interleukin 6 emerges as one of the most differentially expressed genes. Conclusions The presence of the mtDNA variant m.16519C increases the risk of rapid progression of knee OA. Among the most modulated biological processes associated with this variant, inflammation and negative regulation of cellular process stand out. The design of therapies based on the maintenance of mitochondrial function is recommended.The Osteoarthritis Initiative (OAI) is a public- private partnership comprising five contracts (N01- AR- 2- 2258; N01- AR- 2- 2259; N01- AR- 2- 2260; N01- AR- 2- 2261; N01- AR- 2- 2262) funded by the National Institutes of Health, a branch of the Department of Health and Human Services, and conducted by the OAI Study Investigators. Private funding partners include Pfizer; Novartis Pharmaceuticals; Merck Research Laboratories and GlaxoSmithKline. Private sector funding for the OAI is managed by the Foundation for the National Institutes of Health. CHECK- cohort study is funded by the Dutch Arthritis Association. It is led by a steering committee comprising 16 members with expertise in different fields of OA. It is chaired by Professor J W J Bijlsma and coordinated by J Wesseling, MSc. The following institutions are involved: Erasmus Medical Center Rotterdam; Kennemer Gasthuis Haarlem; Leiden University Medical Center; Maastrich University Medical Center; Martini Hospital Groningen/Allied Health Care Center for Rheum and Rehabilitation Groningen; Medical Spectrum Twente Enschede/Ziekenhuisgroep Twente Almelo; Reade, formerly Jan van Breemen Institute/VU Medical Center Amsterdam; St Maartens- kliniek Nijmegen; University Medical Center Utrecht and Wilhelmina Hospital Assen. ISCIII ('PI17/00210', 'PI19/01206', 'PI19/01213', 'PI20/00614', 'RICORS RD21/0002/0009'), co- funded by ERDF/ESF, 'A way to make Europe'/'Investing in your future'). Xunta de Galicia ('IN607A2021/07'). IR- P is supported by Contrato Miguel Servet- II Fondo de Investigacion Sanitaria (CPII17/00026) estabilizado SERGAS. JV- G is supported by grant IN606A- 2022/048 from Xunta de Galicia, Spain. LL- S is supported by contrato Sara Borrell Fondo de Investigacion Sanitaria (CD19/00229). The Biomedical Research Networking Center (CIBER) is an initiative from ISCIII2023info:eu-repo/semantics/articlehttps://portalcientifico.sergas.gal//documentos/648600d6a219857f1d7895a0http://hdl.handle.net/20.500.11940/20983reponame:RUNA. Repositorio da Consellería de Sanidade e Sergasinstname:Servizo Galego de Saúde (SERGAS)Ingléshttp://creativecommons.org/licenses/by-nc/4.0/info:eu-repo/semantics/openAccessoai:runa.sergas.gal:20.500.11940/209832026-06-12T08:40:47Z |
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