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Gene network of susceptibility to atypical femoral fractures related to bisphosphonate treatment

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dc.contributor.author Garcia Giralt, Natàlia
dc.contributor.author Roca Ayats, Neus
dc.contributor.author Abril Ferrando, Josep Francesc
dc.contributor.author Martínez-Gil, Núria
dc.contributor.author Ovejero Crespo, Diana
dc.contributor.author Castañeda, Santos
dc.contributor.author Nogués Solan, Francesc Xavier
dc.contributor.author Grinberg, Daniel
dc.contributor.author Balcells, Susana
dc.contributor.author Rabionet, Raquel
dc.date.accessioned 2022-09-21T06:12:46Z
dc.date.available 2022-09-21T06:12:46Z
dc.date.issued 2022
dc.identifier.citation Garcia-Giralt N, Roca-Ayats N, Abril JF, Martinez-Gil N, Ovejero D, Castañeda S, Nogues X, Grinberg D, Balcells S, Rabionet R. Gene network of susceptibility to atypical femoral fractures related to bisphosphonate treatment. Genes (Basel). 2022 Jan 14;13(1):146. DOI: 10.3390/genes13010146
dc.identifier.issn 2073-4425
dc.identifier.uri http://hdl.handle.net/10230/54124
dc.description.abstract Atypical femoral fractures (AFF) are rare fragility fractures in the subtrocantheric or diaphysis femoral region associated with long-term bisphosphonate (BP) treatment. The etiology of AFF is still unclear even though a genetic basis is suggested. We performed whole exome sequencing (WES) analysis of 12 patients receiving BPs for at least 5 years who sustained AFFs and 4 controls, also long-term treated with BPs but without any fracture. After filtration and prioritization of rare variants predicted to be damaging and present in genes shared among at least two patients, a total of 272 variants in 132 genes were identified. Twelve of these genes were known to be involved in bone metabolism and/or AFF, highlighting DAAM2 and LRP5, both involved in the Wnt pathway, as the most representative. Afterwards, we intersected all mutated genes with a list of 34 genes obtained from a previous study of three sisters with BP-related AFF, identifying nine genes. One of these (MEX3D) harbored damaging variants in two AFF patients from the present study and one shared among the three sisters. Gene interaction analysis using the AFFNET web suggested a complex network among bone-related genes as well as with other mutated genes. BinGO biological function analysis highlighted cytoskeleton and cilium organization. In conclusion, several genes and their interactions could provide genetic susceptibility to AFF, that along with BPs treatment and in some cases with glucocorticoids may trigger this so feared complication.
dc.description.sponsorship This research was funded by MCIN/AEI/10.13039/501100011033, Project PID2019-107188RB-C21. The research was also supported by Centro de Investigación Biomédica en Red de Fragilidad y Envejecimiento Saludable (grants number CB16/10/00245); Fundación Española de Investigación Ósea y del Metabolismo Mineral (FEIOMM); Formación en Investigación en Salud (grant number PI19/00033) from Instituto de Salud Carlos III (ISCIII); and European Regional Development Fund. DO is recipient of a Sara Borrell grant from ISCIII.
dc.format.mimetype application/pdf
dc.language.iso eng
dc.publisher MDPI
dc.relation.ispartof Genes (Basel). 2022 Jan 14;13(1):146
dc.rights © 2022 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).
dc.rights.uri https://creativecommons.org/licenses/by/4.0/
dc.title Gene network of susceptibility to atypical femoral fractures related to bisphosphonate treatment
dc.type info:eu-repo/semantics/article
dc.identifier.doi http://dx.doi.org/10.3390/genes13010146
dc.subject.keyword WES
dc.subject.keyword Atypical femoral fractures
dc.subject.keyword Bisphosphonates
dc.relation.projectID info:eu-repo/grantAgreement/ES/2PE/PID2019-107188RB-C21
dc.rights.accessRights info:eu-repo/semantics/openAccess
dc.type.version info:eu-repo/semantics/publishedVersion


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