into clinical pharmacogenetic recommendations: challenges and - PowerPoint PPT Presentation

Translating genotype data of 44,000 biobank participants into clinical pharmacogenetic recommendations: challenges and solutions Published in Genetics in Medicine. 2019 Jun;21(6):1345. ICPerMed 2nd Workshop Madrid 2019 On behalf of all authors Dr. Sulev Reisberg INSTITUTE OF COMPUTER SCIENCE UNIVERSITY OF TARTU, ESTONIA 1

How we are built DNA Proteins, enzymes Body 2

Inactive drug Drug concentration in blood Pharmacogenetic phenotype Normal Time Dose Dose Normal gene Functional enzyme Active drug

Inactive drug Drug concentration in blood Pharmacogenetic phenotype Normal Time Dose Dose Normal gene Functional enzyme Active drug Poor Gene with Inactive drug Non-functional enzyme loss-of-function Time Dose Dose mutation

Inactive drug Drug concentration in blood Pharmacogenetic phenotype Normal Time Dose Dose Normal gene Functional enzyme Active drug Poor Gene with Inactive drug Non-functional enzyme loss-of-function Time Dose Dose mutation Rapid Gene with mutation that increases the level Increased Increased level of Time of produced enzymes metabolism of active functional enzyme Dose Dose drug

Pharmacogenetic phenotype Normal Normal gene Pharmaco- Information in Poor genetic drug leaflets Gene with loss-of-function knowledge mutation Rapid Gene with mutation that increases the level of produced enzymes

Pharmacogenetic Pharmacogenetic phenotype recommendations Normal Normal gene Pharmaco- Information in Poor genetic drug leaflets Gene with loss-of-function knowledge mutation Rapid Gene with mutation that increases the level of produced enzymes

Normal Pharmaco- Poor genetic Rapid knowledge (and others) Predicted “phenotypes” 11 pharmacogenomic genes for 11 genes of 44,000 biobank for 44,000 participants of participants Estonian Biobank

Whole genome Exome Genotyping sequencing sequencing arrays

Whole genome Exome Genotyping sequencing sequencing arrays

Fraction of high risk phenotypic predictions by gene and method. High risk phenotypes are defined as those that differ from normal and unknown phenotypes and would require a different drug dosing or recommendation. 11

Genotyping arrays (with imputation) are cost-effective alternatives for pharmacogenetic testing 99.8% of biobank participants need a dosage adjustment for at least one of the medications 12

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Next steps • Align with MDR and IVDR regulations, obtain CE Marking • GenMed project (2019-2022): Integrate pharmacogenetic recommendations to national online digital prescription system 15

Acknowledgements Kristi Krebs University of Tartu Maarja Lepamets STACC Mart Kals Quretec Reedik Mägi Kristjan Metsalu Volker M. Lauschke Jaak Vilo Lili Milani 16

Thank you! sulev.reisberg@ut.ee 17