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A Genome-Wide Assoc...
A Genome-Wide Association Study of Bisphosphonate-Associated Atypical Femoral Fracture
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- Kharazmi, Mohammad (author)
- Uppsala universitet,Ortopedi,Uppsala Univ, Sweden
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- Michaëlsson, Karl, 1959- (author)
- Uppsala universitet,Ortopedi,Uppsala Univ, Sweden
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- Schilcher, Jörg (author)
- Linköpings universitet,Avdelningen för Kirurgi, Ortopedi och Onkologi,Medicinska fakulteten,Region Östergötland, Ortopedkliniken i Linköping
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- Eriksson, Niclas, 1978- (author)
- Uppsala universitet,Uppsala kliniska forskningscentrum (UCR),Institutionen för medicinska vetenskaper,Uppsala Univ, Sweden
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- Melhus, Håkan (author)
- Uppsala universitet,Klinisk farmakogenomik och osteoporos,Uppsala Univ, Dept Med Sci, Uppsala, Sweden
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- Wadelius, Mia (author)
- Uppsala universitet,Klinisk farmakogenomik och osteoporos,Uppsala Univ, Sweden
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- Hallberg, Pär, 1974- (author)
- Uppsala universitet,Klinisk farmakogenomik och osteoporos,Uppsala Univ, Sweden
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(creator_code:org_t)
- 2019-04-20
- 2019
- English.
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In: Calcified Tissue International. - : SPRINGER. - 0171-967X .- 1432-0827. ; 105:1, s. 51-67
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Abstract
Subject headings
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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.
Subject headings
- MEDICIN OCH HÄLSOVETENSKAP -- Klinisk medicin -- Ortopedi (hsv//swe)
- MEDICAL AND HEALTH SCIENCES -- Clinical Medicine -- Orthopaedics (hsv//eng)
- MEDICIN OCH HÄLSOVETENSKAP -- Klinisk medicin -- Endokrinologi och diabetes (hsv//swe)
- MEDICAL AND HEALTH SCIENCES -- Clinical Medicine -- Endocrinology and Diabetes (hsv//eng)
Keyword
- Genome-wide association study
- Atypical fractures
- Bisphosphonate
- Drug-related side effects and adverse reactions
- Pharmacogenetics
Publication and Content Type
- ref (subject category)
- art (subject category)
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