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A Genome-Wide Association Study of Bisphosphonate-Associated Atypical Femoral Fracture
Uppsala Univ, Sweden.
Uppsala Univ, Sweden.
Linköping University, Department of Clinical and Experimental Medicine, Division of Surgery, Orthopedics and Oncology. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Surgery, Orthopaedics and Cancer Treatment, Department of Orthopaedics in Linköping.ORCID iD: 0000-0003-0677-9265
Uppsala Univ, Sweden.
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2019 (English)In: Calcified Tissue International, ISSN 0171-967X, E-ISSN 1432-0827, Vol. 105, no 1, p. 51-67Article in journal (Refereed) Published
Abstract [en]

Atypical femoral fracture is a well-documented adverse reaction to bisphosphonates. It is strongly related to duration of bisphosphonate use, and the risk declines rapidly after drug withdrawal. The mechanism behind bisphosphonate-associated atypical femoral fracture is unclear, but a genetic predisposition has been suggested. With the aim to identify common genetic variants that could be used for preemptive genetic testing, we performed a genome-wide association study. Cases were recruited mainly through reports of adverse drug reactions sent to the Swedish Medical Products Agency on a nation-wide basis. We compared atypical femoral fracture cases (n=51) with population-based controls (n=4891), and to reduce the possibility of confounding by indication, we also compared with bisphosphonate-treated controls without a current diagnosis of cancer (n=324). The total number of single-nucleotide polymorphisms after imputation was 7,585,874. A genome-wide significance threshold of pamp;lt;5x10(-8) was used to correct for multiple testing. In addition, we performed candidate gene analyses for a panel of 29 genes previously implicated in atypical femoral fractures (significance threshold of pamp;lt;5.7x10(-6)). Compared with population controls, bisphosphonate-associated atypical femoral fracture was associated with four isolated, uncommon single-nucleotide polymorphisms. When cases were compared with bisphosphonate-treated controls, no statistically significant genome-wide association remained. We conclude that the detected associations were either false positives or related to the underlying disease, i.e., treatment indication. Furthermore, there was no significant association with single-nucleotide polymorphisms in the 29 candidate genes. In conclusion, this study found no evidence of a common genetic predisposition for bisphosphonate-associated atypical femoral fracture. Further studies of larger sample size to identify possible weakly associated genetic traits, as well as whole exome or whole-genome sequencing studies to identify possible rare genetic variation conferring a risk are warranted.

Place, publisher, year, edition, pages
SPRINGER , 2019. Vol. 105, no 1, p. 51-67
Keywords [en]
Genome-wide association study; Atypical fractures; Bisphosphonate; Drug-related side effects and adverse reactions; Pharmacogenetics
National Category
Orthopaedics
Identifiers
URN: urn:nbn:se:liu:diva-158543DOI: 10.1007/s00223-019-00546-9ISI: 000469477400005PubMedID: 31006051OAI: oai:DiVA.org:liu-158543DiVA, id: diva2:1334918
Note

Funding Agencies|Swedish Research Council [521-2011-2440, 521-2014-3370, 2015-03527]; Swedish Heart and Lung Foundation [20120557, 20140291, 20170711]; Selanders foundation; Thureus foundation; Swedish Medical Products Agency; Clinical Research Support (ALF) at Uppsala University; Ostergotland County Council [LIO-698411]; Science for Life Laboratory; Uppsala University; Research Council Swedish [2017-00641]; Swedish Research Council

Available from: 2019-07-03 Created: 2019-07-03 Last updated: 2019-07-03

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Division of Surgery, Orthopedics and OncologyFaculty of Medicine and Health SciencesDepartment of Orthopaedics in Linköping
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