Dr Gaedigk is a Professor of Pediatrics at the Children’s Mercy Research Institute in Kansas City where she directs the Pharmacogenetics Core Laboratory in the Division of Clinical Pharmacology and Therapeutic Innovation. Her work focuses on variation in pharmacogenes in diverse adult and pediatric populations in clinical and basic research which has led to over 245 peer-reviewed publications. She is also directing the Pharmacogene Variation Consortium and closely works with the Pharmacogenomics KnowledgeBase, the Clinical Pharmacogenetics Implementation Consortium and other organizations and groups to promote the implementation of pharmacogenetics into clinical practice. Dr Gaedigk is a collaborator on many internal, national, and international research projects.  

Dr Gaedigk. a distinguished researcher and professor, has made significant contributions to the field of pharmacogenomics. Her work which has led to over 245 peer-reviewed publications has been instrumental in advancing our understanding of drug metabolism and its implications for personalized medicine. She has characterized the CYP2D6 gene locus across ethnically diverse populations discovering numerous allelic variants, enhancing our understanding of genetic diversity and its impact on drug response. Dr. Gaedigk has also developed the activity score system, a method facilitating genotype interpretation, which has been adopted in Clinical Pharmacogenetics Implementation Consortium (CPIC) guidelines and is widely used in pharmacogenomics implementation. This innovative approach has significantly improved the accuracy of pharmacogenomic testing, enabling more precise predictions of individual drug responses. In addition to her research, Dr. Gaedigk serves as the Director of the Pharmacogene Variation Consortium (PharmVar), a pharmacogene data repository. Under her leadership, PharmVar provides pharmacogenomics gene nomenclature, serving as a vital resource for researchers and clinicians worldwide.

Pharmacogenetics of CYP2D6: why you should care about this gene and PharmVar

Cytochrome P450 CYP2D6 plays a crucial role in the metabolism of over 20% of drugs prescribed to children and adults. CYP2D6 genetic variation leads to phenotypic differences among individuals and across populations. Patients with a metabolic status at the extreme ends of the variability distribution have an increased risk of having adverse events or fail to respond to treatment. Thus, knowing a patient’s CYP2D6 genotype preemptively allows prescribers to individualize drug treatment by adjusting the dose or prescribe a different drug while retrospective testing may explain therapeutic failure or side effects. The Clinical Pharmacogenetic Implementation Consortium (CPIC) and Dutch Pharmacogenetic Working Groups (DPWG), among others, have published several practice guidelines for CYP2D6/drug pairs including SSRIs, tricyclic antidepressants, opioids, and the estrogen receptor modulator tamoxifen.

A myriad of SNPs and indels, as well as extensive structural variation (gene deletions and duplications) and rearrangements with the CYP2D7 pseudogene (hybrid genes) have been discovered to date. Their frequencies may vary considerably across world populations and function remains unknown or uncertain for many, especially rare allelic variants. Consequently, CYP2D6 genetic testing, characterization of novel haplotypes, and translation of genotype to phenotype require a deep understanding of this rather complex gene locus. Although next generation sequencing (NGS) technologies and analysis pipelines including specialized tools for star allele calling have vastly improved during over the years, obtaining accurate CYP2D6 genotype calls from short read exome and whole genome data remains challenging. To date, over 160 distinct haplotypes, or star alleles, have been described for CYP2D6 and catalogued by the  Pharmacogenetic Variation Consortium (PharmVar). The PharmVar database serves as a central repository for pharmacogene variation that focuses on haplotype structure, which is crucial for basic and clinical research, and essential for the clinical interpretation of pharmacogenetic (PGx) test results. PharmVar works closely with the Pharmacogenomics Knowledgebase (PharmGKB), CPIC, the Genetic testing Reference Materials Coordinating Program (GeT-RM), and others to provide “star allele” nomenclature of clinically relevant pharmacogenes. Standardized reporting and data interpretation are integral for clinical implementation of PGx, as well as research efforts that aim to further our understanding of how genetic variation contributes to drug metabolism and response.