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A Genome-Wide Assoc...
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Kharazmi, MohammadUppsala universitet,Ortopedi,Uppsala Univ, Sweden
(författare)
A Genome-Wide Association Study of Bisphosphonate-Associated Atypical Femoral Fracture
- Artikel/kapitelEngelska2019
Förlag, utgivningsår, omfång ...
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2019-04-20
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SPRINGER,2019
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electronicrdacarrier
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LIBRIS-ID:oai:DiVA.org:uu-386428
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https://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-386428URI
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https://doi.org/10.1007/s00223-019-00546-9DOI
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https://urn.kb.se/resolve?urn=urn:nbn:se:liu:diva-158543URI
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Språk:engelska
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Sammanfattning på:engelska
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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
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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 p<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 p<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.
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Michaëlsson, Karl,1959-Uppsala universitet,Ortopedi,Uppsala Univ, Sweden(Swepub:uu)karlmich
(författare)
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Schilcher, JörgLinköpings universitet,Avdelningen för Kirurgi, Ortopedi och Onkologi,Medicinska fakulteten,Region Östergötland, Ortopedkliniken i Linköping(Swepub:liu)jorsc03
(författare)
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Eriksson, Niclas,1978-Uppsala universitet,Uppsala kliniska forskningscentrum (UCR),Institutionen för medicinska vetenskaper,Uppsala Univ, Sweden(Swepub:uu)nieri103
(författare)
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Melhus, HåkanUppsala universitet,Klinisk farmakogenomik och osteoporos,Uppsala Univ, Dept Med Sci, Uppsala, Sweden(Swepub:uu)hakamelh
(författare)
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Wadelius, MiaUppsala universitet,Klinisk farmakogenomik och osteoporos,Uppsala Univ, Sweden(Swepub:uu)miawadel
(författare)
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Hallberg, Pär,1974-Uppsala universitet,Klinisk farmakogenomik och osteoporos,Uppsala Univ, Sweden(Swepub:uu)pahal677
(författare)
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Uppsala universitetOrtopedi
(creator_code:org_t)
Sammanhörande titlar
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Ingår i:Calcified Tissue International: SPRINGER105:1, s. 51-670171-967X1432-0827
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