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Pharmacogenomics: From Basic Research to Clinical Implementation

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A special issue of Journal of Personalized Medicine (ISSN 2075-4426). This special issue belongs to the section "Pharmacogenetics".

Deadline for manuscript submissions: closed (31 March 2021) | Viewed by 41439

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Special Issue Editor

Dr. Laura B. Scheinfeldt

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Guest Editor

Principal Investigator, NINDS (National Institute of Neurological Disorders and Stroke) Repository, Coriell Institute for Medical Research, 403 Haddon Avenue, Camden, NJ 08103, USA
Interests: personalized medicine; human genomics; human demography; human adaptation

Special Issue Information

Dear Colleagues,

This Special Issue focuses on the current state of pharmacogenomics (PGx) and the extensive translational process including the identification of functionally important PGx variation; the characterization of PGx haplotypes and metabolizer statuses, their clinical interpretation, clinical decision support, and the incorporation of PGx into clinical care.

Dr. Laura B. Scheinfeldt
Guest Editor

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Journal of Personalized Medicine is an international peer-reviewed open access monthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2600 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

pharmacogenetics
pharmacogenomics
clinical translation
clinical implementation
genetic education
genetic knowledge
clinical decision making
genetic counseling

Published Papers (11 papers)

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Editorial

Jump to: Research

2 pages, 162 KiB

Open AccessEditorial

Pharmacogenomics: From Basic Research to Clinical Implementation

by Laura B. Scheinfeldt

J. Pers. Med. 2021, 11(8), 800; https://0-doi-org.brum.beds.ac.uk/10.3390/jpm11080800 - 17 Aug 2021

Viewed by 1636

Abstract

The established contribution of genetic variation to drug response has the potential to improve drug efficacy and reduce drug toxicity [...] Full article

(This article belongs to the Special Issue Pharmacogenomics: From Basic Research to Clinical Implementation)

Research

Jump to: Editorial

18 pages, 2768 KiB

Open AccessArticle

Implementation of Pharmacogenomics and Artificial Intelligence Tools for Chronic Disease Management in Primary Care Setting

by Patrick Silva, David Jacobs, John Kriak, Asim Abu-Baker, George Udeani, Gabriel Neal and Kenneth Ramos

J. Pers. Med. 2021, 11(6), 443; https://0-doi-org.brum.beds.ac.uk/10.3390/jpm11060443 - 21 May 2021

Cited by 10 | Viewed by 4334

Abstract

Chronic disease management often requires use of multiple drug regimens that lead to polypharmacy challenges and suboptimal utilization of healthcare services. While the rising costs and healthcare utilization associated with polypharmacy and drug interactions have been well documented, effective tools to address these challenges remain elusive. Emerging evidence that proactive medication management, combined with pharmacogenomic testing, can lead to improved health outcomes and reduced cost burdens may help to address such gaps. In this report, we describe informatic and bioanalytic methodologies that integrate weak signals in symptoms and chief complaints with pharmacogenomic analysis of ~90 single nucleotide polymorphic variants, CYP2D6 copy number, and clinical pharmacokinetic profiles to monitor drug–gene pairs and drug–drug interactions for medications with significant pharmacogenomic profiles. The utility of the approach was validated in a virtual patient case showing detection of significant drug–gene and drug–drug interactions of clinical significance. This effort is being used to establish proof-of-concept for the creation of a regional database to track clinical outcomes in patients enrolled in a bioanalytically-informed medication management program. Our integrated informatic and bioanalytic platform can provide facile clinical decision support to inform and augment medication management in the primary care setting. Full article

(This article belongs to the Special Issue Pharmacogenomics: From Basic Research to Clinical Implementation)

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19 pages, 2561 KiB

Open AccessFeature PaperArticle

Implementing Pharmacogenomics Testing: Single Center Experience at Arkansas Children’s Hospital

by Pritmohinder S. Gill, Feliciano B. Yu, Patricia A. Porter-Gill, Bobby L. Boyanton, Judy C. Allen, Jason E. Farrar, Aravindhan Veerapandiyan, Parthak Prodhan, Kevin J. Bielamowicz, Elizabeth Sellars, Andrew Burrow, Joshua L. Kennedy, Jeffery L. Clothier, David L. Becton, Don Rule and G. Bradley Schaefer

J. Pers. Med. 2021, 11(5), 394; https://0-doi-org.brum.beds.ac.uk/10.3390/jpm11050394 - 11 May 2021

Cited by 15 | Viewed by 5807

Abstract

Pharmacogenomics (PGx) is a growing field within precision medicine. Testing can help predict adverse events and sub-therapeutic response risks of certain medications. To date, the US FDA lists over 280 drugs which provide biomarker-based dosing guidance for adults and children. At Arkansas Children’s Hospital (ACH), a clinical PGx laboratory-based test was developed and implemented to provide guidance on 66 pediatric medications for genotype-guided dosing. This PGx test consists of 174 single nucleotide polymorphisms (SNPs) targeting 23 clinically actionable PGx genes or gene variants. Individual genotypes are processed to provide per-gene discrete results in star-allele and phenotype format. These results are then integrated into EPIC- EHR. Genomic indicators built into EPIC-EHR provide the source for clinical decision support (CDS) for clinicians, providing genotype-guided dosing. Full article

(This article belongs to the Special Issue Pharmacogenomics: From Basic Research to Clinical Implementation)

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14 pages, 300 KiB

Open AccessArticle

Effects of CYP3A5 Polymorphism on Rapid Progression of Chronic Kidney Disease: A Prospective, Multicentre Study

by Fei Yee Lee, Farida Islahudin, Aina Yazrin Ali Nasiruddin, Abdul Halim Abdul Gafor, Hin-Seng Wong, Sunita Bavanandan, Shamin Mohd Saffian, Adyani Md Redzuan, Nurul Ain Mohd Tahir and Mohd Makmor-Bakry

J. Pers. Med. 2021, 11(4), 252; https://0-doi-org.brum.beds.ac.uk/10.3390/jpm11040252 - 30 Mar 2021

Cited by 5 | Viewed by 2645

Abstract

Personalised medicine is potentially useful to delay the progression of chronic kidney disease (CKD). The aim of this study was to determine the effects of CYP3A5 polymorphism in rapid CKD progression. This multicentre, observational, prospective cohort study was performed among adult CKD patients (≥18 years) with estimated glomerular filtration rate (eGFR) ≥30 mL/min/1.73 m², who had ≥4 outpatient, non-emergency eGFR values during the three-year study period. The blood samples collected were analysed for CYP3A5*3 polymorphism. Rapid CKD progression was defined as eGFR decline of >5 mL/min/1.73 m²/year. Multiple logistic regression was then performed to identify the factors associated with rapid CKD progression. A total of 124 subjects consented to participate. The distribution of the genotypes adhered to the Hardy–Weinberg equilibrium (X² = 0.237, p = 0.626). After adjusting for potential confounding factors via multiple logistic regression, the factors associated with rapid CKD progression were CYP3A5*3/*3 polymorphism (adjusted Odds Ratio [aOR] 4.190, 95% confidence interval [CI]: 1.268, 13.852), adjustments to antihypertensives, young age, dyslipidaemia, smoking and use of traditional/complementary medicine. CKD patients should be monitored closely for possible factors associated with rapid CKD progression to optimise clinical outcomes. The CYP3A5*3/*3 genotype could potentially be screened among CKD patients to offer more individualised management among these patients. Full article

(This article belongs to the Special Issue Pharmacogenomics: From Basic Research to Clinical Implementation)

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13 pages, 996 KiB

Open AccessArticle

Pharmacogenomic Biomarkers in US FDA-Approved Drug Labels (2000–2020)

by Jeeyun A. Kim, Rachel Ceccarelli and Christine Y. Lu

J. Pers. Med. 2021, 11(3), 179; https://0-doi-org.brum.beds.ac.uk/10.3390/jpm11030179 - 4 Mar 2021

Cited by 31 | Viewed by 5315

Abstract

Pharmacogenomics (PGx) is a key subset of precision medicine that relates genomic variation to individual response to pharmacotherapy. We assessed longitudinal trends in US FDA approval of new drugs labeled with PGx information. Drug labels containing PGx information were obtained from Drugs@FDA and guidelines from PharmGKB were used to compare the actionability of PGx information in drug labels across therapeutic areas. The annual proportion of new drug approvals with PGx labeling has increased by nearly threefold from 10.3% (n = 3) in 2000 to 28.2% (n = 11) in 2020. Inclusion of PGx information in drug labels has increased for all clinical areas over the last two decades but most prominently for cancer therapies, which comprise the largest proportion (75.5%) of biomarker–drug pairs for which PGx testing is required. Clinically actionable information was more frequently observed in biomarker–drug pairs associated with cancer drugs compared to those for other therapeutic areas (n = 92 (59.7%) vs. n = 62 (40.3%), p < 0.0051). These results suggest that further evidence is needed to support the clinical adoption of pharmacogenomics in non-cancer therapeutic areas. Full article

(This article belongs to the Special Issue Pharmacogenomics: From Basic Research to Clinical Implementation)

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13 pages, 1464 KiB

Open AccessArticle

Common Treatment, Common Variant: Evolutionary Prediction of Functional Pharmacogenomic Variants

by Laura B. Scheinfeldt, Andrew Brangan, Dara M. Kusic, Sudhir Kumar and Neda Gharani

J. Pers. Med. 2021, 11(2), 131; https://0-doi-org.brum.beds.ac.uk/10.3390/jpm11020131 - 16 Feb 2021

Cited by 7 | Viewed by 2259

Abstract

Pharmacogenomics holds the promise of personalized drug efficacy optimization and drug toxicity minimization. Much of the research conducted to date, however, suffers from an ascertainment bias towards European participants. Here, we leverage publicly available, whole genome sequencing data collected from global populations, evolutionary characteristics, and annotated protein features to construct a new in silico machine learning pharmacogenetic identification method called XGB-PGX. When applied to pharmacogenetic data, XGB-PGX outperformed all existing prediction methods and identified over 2000 new pharmacogenetic variants. While there are modest pharmacogenetic allele frequency distribution differences across global population samples, the most striking distinction is between the relatively rare putatively neutral pharmacogene variants and the relatively common established and newly predicted functional pharamacogenetic variants. Our findings therefore support a focus on individual patient pharmacogenetic testing rather than on clinical presumptions about patient race, ethnicity, or ancestral geographic residence. We further encourage more attention be given to the impact of common variation on drug response and propose a new ‘common treatment, common variant’ perspective for pharmacogenetic prediction that is distinct from the types of variation that underlie complex and Mendelian disease. XGB-PGX has identified many new pharmacovariants that are present across all global communities; however, communities that have been underrepresented in genomic research are likely to benefit the most from XGB-PGX’s in silico predictions. Full article

(This article belongs to the Special Issue Pharmacogenomics: From Basic Research to Clinical Implementation)

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11 pages, 2034 KiB

Open AccessArticle

Combination of Genome-Wide Polymorphisms and Copy Number Variations of Pharmacogenes in Koreans

by Nayoung Han, Jung Mi Oh and In-Wha Kim

J. Pers. Med. 2021, 11(1), 33; https://0-doi-org.brum.beds.ac.uk/10.3390/jpm11010033 - 7 Jan 2021

Cited by 3 | Viewed by 2432

Abstract

For predicting phenotypes and executing precision medicine, combination analysis of single nucleotide variants (SNVs) genotyping with copy number variations (CNVs) is required. The aim of this study was to discover SNVs or common copy CNVs and examine the combined frequencies of SNVs and CNVs in pharmacogenes using the Korean genome and epidemiology study (KoGES), a consortium project. The genotypes (N = 72,299) and CNV data (N = 1000) were provided by the Korean National Institute of Health, Korea Centers for Disease Control and Prevention. The allele frequencies of SNVs, CNVs, and combined SNVs with CNVs were calculated and haplotype analysis was performed. CYP2D6 rs1065852 (c.100C>T, p.P34S) was the most common variant allele (48.23%). A total of 8454 haplotype blocks in 18 pharmacogenes were estimated. DMD ranked the highest in frequency for gene gain (64.52%), while TPMT ranked the highest in frequency for gene loss (51.80%). Copy number gain of CYP4F2 was observed in 22 subjects; 13 of those subjects were carriers with CYP4F2*3 gain. In the case of TPMT, approximately one-half of the participants (N = 308) had loss of the TPMT*1*1 diplotype. The frequencies of SNVs and CNVs in pharmacogenes were determined using the Korean cohort-based genome-wide association study. Full article

(This article belongs to the Special Issue Pharmacogenomics: From Basic Research to Clinical Implementation)

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Graphical abstract

18 pages, 2913 KiB

Open AccessArticle

Pharmacogenomics at the Point of Care: A Community Pharmacy Project in British Columbia

by Samantha Breaux, Francis Arthur Derek Desrosiers, Mauricio Neira, Sunita Sinha and Corey Nislow

J. Pers. Med. 2021, 11(1), 11; https://0-doi-org.brum.beds.ac.uk/10.3390/jpm11010011 - 24 Dec 2020

Cited by 15 | Viewed by 3441

Abstract

In this study 180 patients were consented and enrolled for pharmacogenomic testing based on current antidepressant/antipsychotic usage. Samples from patients were genotyped by PCR, MassArray, and targeted next generation sequencing. We also conducted a quantitative, frequency-based analysis of participants’ perceptions using simple surveys. Pharmacogenomic information, including medication changes and altered dosing recommendations were returned to the pharmacists and used to direct patient therapy. Overwhelmingly, patients perceived pharmacists/pharmacies as an appropriate healthcare provider to deliver pharmacogenomic services. In total, 81 medication changes in 33 unique patients, representing 22% of all genotyped participants were recorded. We performed a simple drug cost analysis and found that medication adjustments and dosing changes across the entire cohort added $24.15CAD per patient per year for those that required an adjustment. Comparing different platforms, we uncovered a small number, 1.7%, of genotype discrepancies. We conclude that: (1). Pharmacists are competent providers of pharmacogenomic services. (2). The potential reduction in adverse drug responses and optimization of drug selection and dosing comes at a minimal cost to the health care system. (3). Changes in drug therapy, based on PGx tests, result in inconsequential changes in annual drug therapy cost with small cost increases just as likely as costs savings. (4). Pharmacogenomic services offered by pharmacists are ready for wide commercial implementation. Full article

(This article belongs to the Special Issue Pharmacogenomics: From Basic Research to Clinical Implementation)

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13 pages, 982 KiB

Open AccessArticle

Practical Barriers and Facilitators Experienced by Patients, Pharmacists and Physicians to the Implementation of Pharmacogenomic Screening in Dutch Outpatient Hospital Care—An Explorative Pilot Study

by Pauline Lanting, Evelien Drenth, Ludolf Boven, Amanda van Hoek, Annemiek Hijlkema, Ellen Poot, Gerben van der Vries, Robert Schoevers, Ernst Horwitz, Reinold Gans, Jos Kosterink, Mirjam Plantinga, Irene van Langen, Adelita Ranchor, Cisca Wijmenga, Lude Franke, Bob Wilffert and Rolf Sijmons

J. Pers. Med. 2020, 10(4), 293; https://0-doi-org.brum.beds.ac.uk/10.3390/jpm10040293 - 21 Dec 2020

Cited by 13 | Viewed by 4763

Abstract

Pharmacogenomics (PGx) can provide optimized treatment to individual patients while potentially reducing healthcare costs. However, widespread implementation remains absent. We performed a pilot study of PGx screening in Dutch outpatient hospital care to identify the barriers and facilitators to implementation experienced by patients (n = 165), pharmacists (n = 58) and physicians (n = 21). Our results indeed suggest that the current practical experience of healthcare practitioners with PGx is limited, that proper education is necessary, that patients want to know the exact implications of the results, that healthcare practitioners heavily rely on their computer systems, that healthcare practitioners encounter practical problems in the systems used, and a new barrier was identified, namely that there is an unclear allocation of responsibilities between healthcare practitioners about who should discuss PGx with patients and apply PGx results in healthcare. We observed a positive attitude toward PGx among all the stakeholders in our study, and among patients, this was independent of the occurrence of drug-gene interactions during their treatment. Facilitators included the availability of and adherence to Dutch Pharmacogenetics Working Group guidelines. While clinical decision support (CDS) is available and valued in our medical center, the lack of availability of CDS may be an important barrier within Dutch healthcare in general. Full article

(This article belongs to the Special Issue Pharmacogenomics: From Basic Research to Clinical Implementation)

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Graphical abstract

10 pages, 836 KiB

Open AccessArticle

Establishment of a Pharmacogenetics Service Focused on Optimizing Existing Pharmacogenetic Testing at a Large Academic Health Center

by Amy L. Pasternak, Kristen M. Ward, Mohammad B. Ateya, Hae Mi Choe, Amy N. Thompson, John S. Clark and Vicki Ellingrod

J. Pers. Med. 2020, 10(4), 154; https://0-doi-org.brum.beds.ac.uk/10.3390/jpm10040154 - 3 Oct 2020

Cited by 13 | Viewed by 2486

Abstract

Multiple groups have described strategies for clinical implementation of pharmacogenetics (PGx) that often include internal laboratory tests that are specifically developed for their implementation needs. However, many institutions are not able to follow this practice and instead must utilize external laboratories to obtain PGx testing results. As each external laboratory might have different ordering and reporting workflows, consistent reporting and storing of PGx results within the medical record can be a challenge. This might result in patient safety concerns as important PGx information might not be easily identifiable at the point of current or future prescribing. Herein, we describe initial PGx clinical implementation efforts at a large academic medical center, focusing on optimizing three different test ordering workflows and two distinct result reporting strategies. From this, we identified common issues such as variable reporting location and structure of PGx results, as well as duplicate PGx testing. We identified several opportunities to optimize our current processes, including—(1) PGx laboratory stewardship, (2) increasing visibility of PGx tests, and (3) clinician and patient education. Key to the success was the importance of engaging clinician, informatics, and pathology stakeholders, as we developed interventions to improve our PGX implementation processes. Full article

(This article belongs to the Special Issue Pharmacogenomics: From Basic Research to Clinical Implementation)

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15 pages, 1092 KiB

Open AccessFeature PaperArticle

Pharmacogenomic (PGx) Counseling: Exploring Participant Questions about PGx Test Results

by Tara Schmidlen, Amy C. Sturm and Laura B. Scheinfeldt

J. Pers. Med. 2020, 10(2), 29; https://0-doi-org.brum.beds.ac.uk/10.3390/jpm10020029 - 23 Apr 2020

Cited by 6 | Viewed by 4990

Abstract

As pharmacogenomic (PGx) use in healthcare increases, a better understanding of patient needs will be necessary to guide PGx result delivery. The Coriell Personalized Medicine Collaborative (CPMC) is a prospective study investigating the utility of personalized medicine. Participants received online genetic risk reports for 27 potentially actionable complex diseases and 7 drug–gene pairs and could request free, telephone-based genetic counseling (GC). To explore the needs of individuals receiving PGx results, we conducted a retrospective qualitative review of inquiries from CPMC participants who requested counseling from March 2009 to February 2017. Eighty out of 690 (12%) total GC inquiries were focused on the discussion of PGx results, and six salient themes emerged: “general help”, “issues with drugs”, “relevant disease experience”, “what do I do now?”, “sharing results”, and “other drugs”. The number of reported medications with a corresponding PGx result and participant engagement were significantly associated with PGx GC requests (p < 0.01 and p < 0.02, respectively). Our work illustrates a range of questions raised by study participants receiving PGx test results, most of which were addressed by a genetic counselor with few requiring referrals to prescribing providers or pharmacists. These results further support a role for genetic counselors in the team-based approach to optimal PGx result delivery. Full article

(This article belongs to the Special Issue Pharmacogenomics: From Basic Research to Clinical Implementation)

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