Evaluating the frequency and the impact of pharmacogenetic alleles in an ancestrally diverse Biobank population

Abstract

Background Pharmacogenomics (PGx) aims to utilize a patient’s genetic data to enable safer and more effective prescribing of medications. The Clinical Pharmacogenetics Implementation Consortium (CPIC) provides guidelines with strong evidence for 24 genes that affect 72 medications. Despite strong evidence linking PGx alleles to drug response, there is a large gap in the implementation and return of actionable pharmacogenetic findings to patients in standard clinical practice. In this study, we evaluated opportunities for genetically guided medication prescribing in a diverse health system and determined the frequencies of actionable PGx alleles in an ancestrally diverse biobank population. Methods A retrospective analysis of the Penn Medicine electronic health records (EHRs), which includes ~ 3.3 million patients between 2012 and 2020, provides a snapshot of the trends in prescriptions for drugs with genotype-based prescribing guidelines (‘CPIC level A or B’) in the Penn Medicine health system. The Penn Medicine BioBank (PMBB) consists of a diverse group of 43,359 participants whose EHRs are linked to genome-wide SNP array and whole exome sequencing (WES) data. We used the Pharmacogenomics Clinical Annotation Tool (PharmCAT), to annotate PGx alleles from PMBB variant call format (VCF) files and identify samples with actionable PGx alleles. Results We identified ~ 316.000 unique patients that were prescribed at least 2 drugs with CPIC Level A or B guidelines. Genetic analysis in PMBB identified that 98.9% of participants carry one or more PGx actionable alleles where treatment modification would be recommended. After linking the genetic data with prescription data from the EHR, 14.2% of participants (n = 6157) were prescribed medications that could be impacted by their genotype (as indicated by their PharmCAT report). For example, 856 participants received clopidogrel who carried CYP2C19 reduced function alleles, placing them at increased risk for major adverse cardiovascular events. When we stratified by genetic ancestry, we found disparities in PGx allele frequencies and clinical burden. Clopidogrel users of Asian ancestry in PMBB had significantly higher rates of CYP2C19 actionable alleles than European ancestry users of clopidrogrel (p < 0.0001, OR = 3.68). Conclusions Clinically actionable PGx alleles are highly prevalent in our health system and many patients were prescribed medications that could be affected by PGx alleles. These results illustrate the potential utility of preemptive genotyping for tailoring of medications and implementation of PGx into routine clinical care.

Establishing a patient‐centered, multidisciplinary pharmacogenomics clinic in an academic health system: Successes, challenges, and future direction

“…In our clinic, all patients who received genetic testing had at least one actionable pharmacogenetic variant. This is similar to previously reported findings from the Mayo Clinic and the Penn Medicine Biobank, which both found that approximately 99% of participants had at least one actionable variant 12,31 . However, we found that a higher percentage of our patients had three or more actionable variants compared to what has been previously reported (74% vs. 58%) 31 .…”

“…10 Several real-world studies have reported that 20%-50% of patients are taking medications impacted by PGx variants. 9,11,12 Translation of PGx into the clinic has been facilitated by evidencebased guidelines published by the Clinical Pharmacogenetics Implementation Consortium (CPIC) and FDA-approved package labeling that provide genotype-guided medication recommendations, however PGx testing has not been widely adopted across clinical settings. 13 The University of Pennsylvania Health System (Penn Medicine) began PGx testing within a research setting for specific use cases such as cytochrome P450 2C19 (CYP2C19) testing for percutaneous coronary intervention 14 and dihydropyrimidine dehydrogenase (DPYD) variant testing for gastrointestinal cancers.…”

“…and >200 Food and Drug Administration (FDA) approved medications include PGx information in the label 10 . Several real‐world studies have reported that 20%–50% of patients are taking medications impacted by PGx variants 9,11,12 . Translation of PGx into the clinic has been facilitated by evidence‐based guidelines published by the Clinical Pharmacogenetics Implementation Consortium (CPIC) and FDA‐approved package labeling that provide genotype‐guided medication recommendations, however PGx testing has not been widely adopted across clinical settings 13 …”

Empowering Personalized Pharmacogenomics with Generative AI Solutions

“…[6] This is especially important in pharmacogenomics where there is a high proportion of actionable results and broad application beyond specialty clinics. [7,8]…”

Assessing the Occurrence and Influence of Cancer Chemotherapy-Related Pharmacogenetic Alleles in the Chilean Population

“…On the other hand, multiple studies have demonstrated ancestry-specific patterns in these pharmacogenes [ 13 , 14 , 15 ], therefore, understanding the prevalence of these variants in multiple populations would help to target efforts in the implementation of pharmacogenetic testing with the greatest possible impact. In this context, the origin of the Chilean population is intricately intertwined with the Mapuche and Huilliche Amerindian communities, which has greatly enriched the nation’s cultural heritage.…”