On 27 August at 11:15 Kristi Krebs will defend her doctoral thesis molecular biomedicine “Exploring the genetics of adverse events in pharmacotherapy using Biobanks and Electronic Health Records”
Supervisors: Leading Scientist Lili Milani, the Institute of Genomics and Professor Andres Metspalu, the Institute of Molecular and Cell Biology and the Institute of Genomics, University of Tartu
Oponent: Professor Sir Munir Pirmohamed, University of Liverpool (United Kingdom)
Individual genetic variants may influence pharmacotherapy by affecting the efficacy and safety of a drug. The aim of the field of pharmacogenomics (PGx) is to find these predisposing genetic risk factors to help personalize treatment towards a desired outcome. Although there are various studies indicating the role of genetic variants in drug efficacy, there are less studies on drugs adverse events (ADEs). The rarer nature of ADEs has made the collection of sufficiently large sample sizes more challenging. Coupling population-based biobanks with electronic health records (EHRs) provides the opportunity to retrospectively retrieve specific phenotypes for thousands of individuals simultaneously, thereby bringing a potential asset to studies in different routes of PGx research. We explored here the genetic data of over 15,000 participants of the Estonian biobank (EstBB) with the information on ADEs imbedded in their EHRs for the discovery of potential genetic risk factors for such events. We identified a strongly significant association between penicillin allergy and an allele of the human leukocyte antigen (HLA) gene and validated this result in two additional cohorts involving a total of 1.14 million individuals. Our work further revealed an association between adverse cardiovascular events and genetic variants that mimic the therapeutic effect of a drug in clinical development for the treatment of osteoporosis, thus illustrating the potential of human genetics studies for the guidance of drug development processes. Finally, we show a potential cost-effective and comprehensive alternative for the detection of genetic variants with drug treatment recommendations based on the EstBB and highlight the large proportion of individuals who are anticipated to benefit from genetic testing prior to treatment. In conclusion, with our work we contribute to the field of pharmacogenomics by bringing new knowledge in pharmacotherapy that with further in-depth research has the potential to yield more clinically actionable recommendations.