Translating pharmacogenomics into clinical decisions: do not let the perfect be the enemy of the good

Krebs, Kristi; Milani, Lili

doi:10.1186/s40246-019-0229-z

Cited by 137 publications

(114 citation statements)

References 84 publications

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“…Variations in genes that encode proteins involved in drug pharmacokinetics and pharmacodynamics lead to interindividual heterogeneity in drug response and can greatly affect clinical outcome. Dosage guidelines have been developed by organizations such as the Clinical Implementation of Pharmacogenetics Consortium (CPIC; cpicpgx.org) to aid physicians in incorporating pharmacogenetics into their practice, however the adoption of pharmacogenetics by practicing physicians has been slow 2,3 . Doctor's may not directly be using pharmacogenetics to inform practice, but genetics influences how patients respond to drugs nonetheless.…”

Section: Introductionmentioning

confidence: 99%

Drug Response Pharmacogenetics for 200,000 UK Biobank Participants

McInnes

Altman²

2020

Preprint

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Pharmacogenetics studies how genetic variation leads to variability in drug response. Guidelines for selecting the right drug and right dose to patients based on their genetics are clinically effective, but are still widely unused. For some drugs, the normal clinical decision making process may lead to the optimal dose of a drug that minimizes side effects and maximizes effectiveness. Without measurements of genotype, physicians and patients may observe and adjust dosage in a manner that reflects the underlying genetics. The emergence of genetic data linked to longitudinal clinical data in large biobanks offers an opportunity to confirm known pharmacogenetic interactions as well as discover novel associations by investigating outcomes from normal clinical practice. Here we use the UK Biobank to search for pharmacogenetic interactions among 200 drugs and 9 genes among 200,000 participants. We identify associations between pharmacogene phenotypes and drug maintenance dose as well as side effect incidence. We find support for several known drug-gene associations as well as novel pharmacogenetic interactions.

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Section: Introductionmentioning

confidence: 99%

Drug Response Pharmacogenetics for 200,000 UK Biobank Participants

McInnes

Altman²

2020

Preprint

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“…As accurate inference of metabolic activity of CYP2D6 cannot currently be done from GWAS chip data alone, the copy-number imputation method creates new opportunities for development towards and research of individualized medicine. When more data emerge, the pharmacogenetic decision algorithms can be then fine-tuned to reflect newest findings 54 . Hence, it is important that pharmacogenetic reports can be updated to maintain best possible dosing guidelines available for the patients.…”

Section: Discussionmentioning

confidence: 99%

Implementation of CYP2D6 copy-number imputation panel and frequency of key pharmacogenetic variants in Finnish individuals with a psychotic disorder

Häkkinen

Kiiski

Lähteenvuo

et al. 2020

Preprint

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PurposeWe constructed a CYP2D6 copy-number imputation panel by combining copy-number information to GWAS chip data. In addition, we report frequencies of key pharmacogenetic variants in individuals with a psychotic disorder from the genetically bottle-necked population of Finland.MethodsWe combined GWAS chip and CYP2D6 copy-number variation (CNV) data from the Breast Cancer Pain Genetics study (BrePainGen) to construct an imputation panel (N=902) for CYP2D6 CNV. The resulting data set was used as a CYP2D6 CNV imputation panel in 9,262 non-related individuals passing genotype data quality control procedures. The panel performance was evaluated by genotyping the CNV from a subset (N=297) of SUPER-Finland participants.ResultsCYP2D6 CNV was imputed correctly in 272 (92%) individuals. Sensitivity and specificity for detecting a duplication were 0.986 and 0.946, respectively. Sensitivity and specificity for detecting a deletion using imputation were 0.886 and 0.966, respectively. Based on imputation, the frequency of a CYP2D6 duplication and deletion in the whole SUPER-Finland sample with 9,262 non-related individuals passing quality control were 8.5% and 2.7%, respectively. We confirm the higher frequency of CYP2D6 ultrarapid metabolizers in Finland compared with non-Finnish Europeans. Additionally, we confirm a 21-fold enrichment of the UGT1A1 decreased function variant rs4148323 (also known as 211G>A, G71R or UGT1A1*6) in Finland compared with non-Finnish Europeans. Similarly, the NUDT15 variant rs116855232 was highly enriched in Finland.ConclusionOur results demonstrate that imputation of CYP2D6 CNV is possible. The methodology is not accurate enough to be used in clinical decision making, but it enables studying CYP2D6 in large biobanks with genome-wide data. In addition, it allows for researchers to recontact patients with certain pharmacogenetic variations through biobanks. We show that bottle-necked populations may have pharmacogenetically important variants with allele frequencies very different from the main ancestral group. Future studies should assess whether these differences are large enough to cause clinically significant changes in trial results across different ancestral groups.

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“…practice guidelines that can assist providers in applying the results of PGx testing to the management of medications used to treat mood disorders, cardiovascular disease, cancer, or other diseases among adults. 2,3 Previous research in adult populations has demonstrated the clinical utility [4][5][6][7][8] and cost-effectiveness 9,10 for both reactive PGx testing to guide current treatment and pre-emptive testing to guide future treatment decisions. However, the evidence base for PGx testing in pediatric patients and in treatment of diseases prevalent during childhood is less robust.…”

Section: Pharmacogenetic Testing In Childrenmentioning

confidence: 99%

Retrospective Review of Pharmacogenetic Testing at an Academic Children’s Hospital

Roberts

Wagner

Sandritter

et al. 2020

Clinical Translational Sci

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There is limited evidence to support pharmacogenetic (PGx) testing in children. We conducted a retrospective review of PGx testing among 452 patients at an academic children's hospital to determine the potential utility of PGx in diseases of childhood and to identify targets for future pediatric pharmacogenetic research. An actionable gene-drug pair associated with the 28 genes tested (Clinical Pharmacogenetics Implementation Consortium (CPIC) level A or B, Pharmacogenomics Knowledge Base (PharmGKB) level 1A or B, or US Food and Drug Administration (FDA) recommendation and a PharmGKB level) was present in 98.7% of patients. We identified 203 actionable gene-drug-diagnosis groups based on the indications for each actionable drug listed in Lexicomp. Among patients with an actionable gene-drug-diagnosis group, 49.3% had a diagnosis where the drug was a therapeutic option and PGx could be used to guide treatment selection. Among patients with an associated diagnosis, 30.9% had a prescription for the actionable drug allowing PGx guided dosing. Three genes (CYP2C19, CYP2D6, and CYP3A5) accounted for all the gene-drug-diagnosis groups with matching diagnoses and prescriptions. The most common gene-drug-diagnosis groups with matching diagnoses and prescriptions were CYP2C19-citalopram-escitalopram-depression 3.3% of patients tested; CYP2C19-dexlansoprazole-gastritis-esophagitis 3.1%; CYP2C19-omeprazole-gastritis-esophagitis 2.4%; CYP2D6-atomoxetine-attention deficit hyperactivity disorder 2.2%; and CYP2C19-citalopram-escitalopram-obsessivecompulsive disorder 1.5%. PGx could be used to guide selection of current treatment options or medication dosing in almost half (48.7%) of pediatric patients tested. Mood disorders and gastritis/esophagitis are promising targets for future study of PGx testing because of the high prevalence of these diagnoses and associated actionable gene-drug pairs in the pediatric population. Pharmacogenetic (PGx) testing, specifically the inquiry into genetic variants in pharmacokinetic or pharmacodynamic pathways involved in medication metabolism or response, is commercially available and being promoted to improve patient outcomes. 1 The level of evidence supporting the clinical utility of testing for variants in individual genes differs, and translation of the test results into clinical practice is complicated. Several organizations, including the Clinical Pharmacogenetics Implementation Consortium (CPIC) and the Royal Dutch Association for the Advancement of Pharmacy-Pharmacogenetics Working Group (DPWG), have created detailed, evidence-based, gene-drug clinical

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Translating pharmacogenomics into clinical decisions: do not let the perfect be the enemy of the good

Cited by 137 publications

References 84 publications

Drug Response Pharmacogenetics for 200,000 UK Biobank Participants

Drug Response Pharmacogenetics for 200,000 UK Biobank Participants

Implementation of CYP2D6 copy-number imputation panel and frequency of key pharmacogenetic variants in Finnish individuals with a psychotic disorder

Retrospective Review of Pharmacogenetic Testing at an Academic Children’s Hospital

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