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Genetic variation in human drug-related genes

Charlotta P.I. Schärfe, Roman Tremmel, Matthias Schwab, Oliver Kohlbacher, Debora S. Marks
doi: https://doi.org/10.1101/147108
Charlotta P.I. Schärfe
1Department of Systems Biology, Harvard Medical School, Boston, 02115 Massachusetts, USA
2Center for Bioinformatics, University of Tübingen, 72076 Tübingen, Germany
3Applied Bioinformatics, Dept. of Computer Science, 72076 Tübingen, Germany
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Roman Tremmel
4Dr. Margarete Fischer-Bosch Institute of Clinical Pharmacology, Stuttgart, Germany
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Matthias Schwab
4Dr. Margarete Fischer-Bosch Institute of Clinical Pharmacology, Stuttgart, Germany
5Department of Clinical Pharmacology, University Hospital Tübingen, Germany
6Department of Pharmacy and Biochemistry, University of Tübingen, Tübingen, Germany
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Oliver Kohlbacher
2Center for Bioinformatics, University of Tübingen, 72076 Tübingen, Germany
3Applied Bioinformatics, Dept. of Computer Science, 72076 Tübingen, Germany
7Quantitative Biology Center, 72076 Tübingen, Germany
8Faculty of Medicine, University of Tübingen, 72076 Tübingen, Germany
9Biomolecular Interactions, Max Planck Institute for Developmental Biology, 72076 Tübingen, Germany
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  • For correspondence: oliver.kohlbacher@uni-tuebingen.de debbie@hms.harvard.edu
Debora S. Marks
1Department of Systems Biology, Harvard Medical School, Boston, 02115 Massachusetts, USA
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  • For correspondence: oliver.kohlbacher@uni-tuebingen.de debbie@hms.harvard.edu
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Abstract

Variability in drug efficacy and adverse effects are observed in clinical practice. While the extent of genetic variability in classical pharmacokinetic genes is rather well understood, the role of genetic variation in drug targets is typically less studied. Based on 60,706 human exomes from the ExAC dataset, we performed an in-depth computational analysis of the prevalence of functional-variants in in 806 drug-related genes, including 628 known drug targets. We find that most genetic variants in these genes are very rare (f < 0.1%) and thus likely not observed in clinical trials. Overall, however, four in five patients are likely to carry a functional-variant in a target for commonly prescribed drugs and many of these might alter drug efficacy. We further computed the likelihood of 1,236 FDA approved drugs to be affected by functional-variants in their targets and show that the patient-risk varies for many drugs with respect to geographic ancestry. A focused analysis of oncological drug targets indicates that the probability of a patient carrying germline variants in oncological drug targets is with 44% high enough to suggest that not only somatic alterations, but also germline variants carried over into the tumor genome should be included in therapeutic decision-making.

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Posted June 07, 2017.
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Genetic variation in human drug-related genes
Charlotta P.I. Schärfe, Roman Tremmel, Matthias Schwab, Oliver Kohlbacher, Debora S. Marks
bioRxiv 147108; doi: https://doi.org/10.1101/147108
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Genetic variation in human drug-related genes
Charlotta P.I. Schärfe, Roman Tremmel, Matthias Schwab, Oliver Kohlbacher, Debora S. Marks
bioRxiv 147108; doi: https://doi.org/10.1101/147108

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