into clinical pharmacogenetic recommendations: challenges and - - PowerPoint PPT Presentation

Translating genotype data of 44,000 biobank participants into clinical pharmacogenetic recommendations: challenges and solutions

• Dr. Sulev Reisberg

INSTITUTE OF COMPUTER SCIENCE UNIVERSITY OF TARTU, ESTONIA

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On behalf of all authors

Published in Genetics in Medicine. 2019 Jun;21(6):1345. ICPerMed 2nd Workshop Madrid 2019

How we are built

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DNA Proteins, enzymes Body

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

Normal

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

Normal Poor

Inactive drug Functional enzyme Active drug Non-functional enzyme Inactive drug Normal gene Gene with loss-of-function mutation Drug concentration in blood Time Dose Dose Dose Dose Increased level of functional enzyme Gene with mutation that increases the level

• f produced enzymes

Increased metabolism of active drug Time Dose Dose Time Pharmacogenetic phenotype

Normal Poor Rapid

Normal gene Gene with loss-of-function mutation Gene with mutation that increases the level

• f produced enzymes

Pharmacogenetic phenotype

Normal Poor Rapid

Pharmaco- genetic knowledge Information in drug leaflets

Pharmaco- genetic knowledge

Normal gene Gene with loss-of-function mutation Gene with mutation that increases the level

• f produced enzymes

Pharmacogenetic phenotype

Normal Poor Rapid

Pharmacogenetic recommendations

Information in drug leaflets

Pharmaco- genetic knowledge 11 pharmacogenomic genes

• f 44,000 biobank

participants

Normal Poor Rapid

Predicted “phenotypes” for 11 genes for 44,000 participants of Estonian Biobank

(and others)

Whole genome sequencing Exome sequencing Genotyping arrays

Whole genome sequencing Exome sequencing Genotyping 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.

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• f biobank participants

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

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99.8%

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Next steps

• Align with MDR and IVDR

regulations, obtain CE Marking

• GenMed project (2019-2022):

Integrate pharmacogenetic recommendations to national

• nline digital prescription

system

Acknowledgements

Kristi Krebs Maarja Lepamets Mart Kals Reedik Mägi Kristjan Metsalu Volker M. Lauschke Jaak Vilo Lili Milani

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University of Tartu STACC Quretec

Thank you!

sulev.reisberg@ut.ee

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