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Publications of the Week

Massively Parallel Characterization of CYP2C9 Variant Enzyme Activity and Abundance

By August 20, 2021August 24th, 2021No Comments

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This week we profile a recent publication in The American Journal of Human Genetics from Dr. Clara Amorosi (pictured, right) and the laboratories of Drs. Maitreya Dunham (middle) and Douglas Fowler (left) at UW.

Can you provide a brief overview of your lab’s current research focus?

This project was a great collaboration that probably wouldn’t have worked out if just one of us had tackled it alone. The Fowler lab’s expertise is technology development for creating and measuring the consequences of thousands of genetic variants simultaneously. The Dunham lab has used those methods in the past in service of our main interests in genome evolution using yeast as a model system. The final important member of the team was Allan Rettie’s lab, who is an expert in pharmacogenomics. Combining us all together, we were able to do high throughput assessment of thousands of variants of an important pharmacogene, using yeast and human cell culture systems.

What is the significance of the findings in this publication?

The gene we studied is CYP2C9, which is important for drug metabolism. If you carry certain genetic variants in your CYP2C9 gene, you can get bad reactions to certain drugs, most notably for the blood thinner warfarin. For warfarin in particular, having the wrong dose for your genotype can lead to severe problems like excess bleeding. However, we only have accurate dosage advice for a small number of the most well studied genetic variants. In our project, we wanted to make all possible mutations in CYP2C9 so that we would be able to predict the right dosage for anyone, even someone with a new gene sequence that no one has ever seen before. We hope our data can improve personalized medicine and help people avoid adverse drug reactions.

What are the next steps for this research?

A large part of the work on this project was building a multiplexed yeast assay for human Cytochrome P450 genes. Now that we have this working, we are applying it to other Cytochrome P450s that metabolize other drugs. We are also expanding to other pharmacogenes.

If you’d like us to mention your funding sources, please list them.

We are grateful for support from NIH grants R24GM115277, R01GM132162, T32HG00035, and P01GM11669; an HHMI Faculty Scholar grant; and the Canadian Institute for Advanced Research.

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