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Population genetic structure of variable drug response.
J F Wilson1, M E Weale, A C Smith
1Galton Laboratory, Department of Biology, University College London, London, UK.
Nature Genetics
|October 31, 2001
Summary
Human genetic variation influences drug response. This study shows that drug-metabolizing enzyme profiles differ across genetic clusters, challenging ethnic labels and informing personalized medicine approaches.
Area of Science:
- Pharmacogenomics
- Population Genetics
- Human Genetic Variation
Background:
- Geographic patterns of genetic variation, particularly at drug metabolizing enzyme (DME) loci and drug targets, suggest frequent geographic structuring of inter-individual drug response variation.
- Evaluating drug safety and efficacy necessitates understanding how to represent and relate human population genetic structure to drug response.
Purpose of the Study:
- To infer genetic structure within a heterogeneous sample.
- To compare the distribution of DME variants across inferred genetic clusters.
- To establish a framework for relating genetic structure to drug response.
Main Methods:
- Inferred genetic structure from a heterogeneous sample.
- Compared the distribution of drug metabolizing enzyme (DME) variants across identified genetic clusters.
- Analyzed the drug-metabolizing profiles of these clusters.
Main Results:
- Commonly used ethnic labels are insufficient and inaccurate representations of inferred genetic clusters.
- Drug-metabolizing profiles differ significantly among the inferred genetic clusters.
- Human demographic complexity precludes obvious natural clustering schemes or resolution levels.
Conclusions:
- Genetic clusters reveal distinct drug-metabolizing profiles, highlighting limitations of ethnic labels in pharmacogenomics.
- A framework is established for assessing resolution in relating genetic structure to drug response.
- This research provides insights into optimizing drug safety and efficacy assessments by considering population genetic structure.