PharmVar GeneFocus: SLCO1B1.

The Pharmacogene Variation Consortium (PharmVar) is now providing star (*) allele nomenclature for the highly polymorphic human SLCO1B1 gene encoding the organic anion transporting polypeptide 1B1 (OATP1B1) drug transporter. Genetic variation within the SLCO1B1 gene locus impacts drug transport, which can lead to altered pharmacokinetic profiles of several commonly prescribed drugs. Variable OATP1B1 function is of particular importance regarding hepatic uptake of statins and the risk of statin-associated musculoskeletal symptoms. To introduce this important drug transporter gene into the PharmVar database and serve as a unified reference of haplotype variation moving forward, an international group of gene experts has performed an extensive review of all published SLCO1B1 star alleles. Previously published star alleles were self-assigned by authors and only loosely followed the star nomenclature system that was first developed for cytochrome P450 genes. This nomenclature system has been standardized by PharmVar and is now applied to other important pharmacogenes such as SLCO1B1. In addition, data from the 1000 Genomes Project and investigator-submitted data were utilized to confirm existing haplotypes, fill knowledge gaps, and/or define novel star alleles. The PharmVar-developed SLCO1B1 nomenclature has been incorporated by the Clinical Pharmacogenetics Implementation Consortium (CPIC) 2022 guideline on statin-associated musculoskeletal symptoms.

A pilot study of oral treprostinil pharmacogenomics and treatment persistence in patients with pulmonary arterial hypertension.

BACKGROUND AND AIMS: Treprostinil is a prostacyclin analog used to treat pulmonary arterial hypertension. Dosing is empiric and based on tolerability. Adverse effects are common and can affect treatment persistence. Pharmacogenomic variants that may affect treprostinil metabolism and transport have not been well-characterized. We aimed to investigate the pharmacogenomic sources of variability in treatment persistence and dosing. METHODS: Patients were prospectively recruited from an IRB approved biobank registry at a single pulmonary hypertension center. A cohort of patients who received oral treprostinil were screened for participation. Pharmacogenomic analysis was for variants in CYP2C8, CYP2C9, and ABCC4. A retrospective review was conducted for demographics, clinical status, dosing, and response. Fisher's exact test was used for categorical data and Kruskal-Wallis test or Wilcoxon rank sum were used for continuous data. RESULTS: A total of 15 patients received oral treprostinil and were consented. Their median age was 53 years, 73% were female, and 93% were White. The median total daily dose was 22.5 mg (13.5, 41) at last clinical observation. 40% of patients discontinued treatment with a majority due to adverse effects. Approximately 27% of patients had a loss-of-function variant in CYP2C8 (*1/*3 or *1/*4), whereas 47% of patients had a loss-of-function variant in CYP2C9 (*1/*2, *1/*3, or *2/*2). Minor allele frequencies for ABCC4 (rs1751034 and rs3742106) were 0.17 and 0.43, respectively. Survival analysis showed that increased CYP2C9 activity score was associated with decreased risk for treatment discontinuation [hazard ratio (HR): 0.13; 95% confidence interval (CI): 0.02, 0.91; p = 0.04]. Genetic variants were not significantly associated with dosing. CONCLUSION: Genetic variants responsible for the metabolism and transport of oral treprostinil were common. Increased CYP2C9 activity score was associated with decreased risk for treatment discontinuation. However, dosing was not associated with genetic variants in metabolizing enzymes for treprostinil. Our findings suggest significant variability in treatment persistence to oral treprostinil, with pharmacogenomics being a potentially important contributor.The reviews of this paper are available via the supplemental material section.

Genome Wide Epistasis Study of On-Statin Cardiovascular Events with Iterative Feature Reduction and Selection.

Predicting risk for major adverse cardiovascular events (MACE) is an evidence-based practice that incorporates lifestyle, history, and other risk factors. Statins reduce risk for MACE by decreasing lipids, but it is difficult to stratify risk following initiation of a statin. Genetic risk determinants for on-statin MACE are low-effect size and impossible to generalize. Our objective was to determine high-level epistatic risk factors for on-statin MACE with GWAS-scale data. Controlled-access data for 5890 subjects taking a statin collected from Vanderbilt University Medical Center's BioVU were obtained from dbGaP. We used Random Forest Iterative Feature Reduction and Selection (RF-IFRS) to select highly informative genetic and environmental features from a GWAS-scale dataset of patients taking statin medications. Variant-pairs were distilled into overlapping networks and assembled into individual decision trees to provide an interpretable set of variants and associated risk. 1718 cases who suffered MACE and 4172 controls were obtained from dbGaP. Pathway analysis showed that variants in genes related to vasculogenesis (FDR = 0.024), angiogenesis (FDR = 0.019), and carotid artery disease (FDR = 0.034) were related to risk for on-statin MACE. We identified six gene-variant networks that predicted odds of on-statin MACE. The most elevated risk was found in a small subset of patients carrying variants in COL4A2, TMEM178B, SZT2, and TBXAS1 (OR = 4.53, p < 0.001). The RF-IFRS method is a viable method for interpreting complex "black-box" findings from machine-learning. In this study, it identified epistatic networks that could be applied to risk estimation for on-statin MACE. Further study will seek to replicate these findings in other populations.

Membrane transporters in traumatic brain injury: Pathological, pharmacotherapeutic, and developmental implications.

Membrane transporters regulate the trafficking of endogenous and exogenous molecules across biological barriers and within the neurovascular unit. In traumatic brain injury (TBI), they moderate the dynamic movement of therapeutic drugs and injury mediators among neurons, endothelial cells and glial cells, thereby becoming important determinants of pathogenesis and effective pharmacotherapy after TBI. There are three ways transporters may impact outcomes in TBI. First, transporters likely play a key role in the clearance of injury mediators. Second, genetic association studies suggest transporters may be important in the transition of TBI from acute brain injury to a chronic neurological disease. Third, transporters dynamically control the brain penetration and efflux of many drugs and their distribution within and elimination from the brain, contributing to pharmacoresistance and possibly in some cases pharmacosensitivity. Understanding the nature of drugs or candidate drugs in development with respect to whether they are a transporter substrate or inhibitor is relevant to understand whether they distribute to their target in sufficient concentrations. Emerging data provide evidence of altered expression and function of transporters in humans after TBI. Genetic variability in expression and/or function of key transporters adds an additional dynamic, as shown in recent clinical studies. In this review, evidence supporting the role of individual membrane transporters in TBI are discussed as well as novel strategies for their modulation as possible therapeutic targets. Since data specifically targeting pediatric TBI are sparse, this review relies mainly on experimental studies using adult animals and clinical studies in adult patients.

Clinical Pharmacogenomics: Applications in Nephrology.

Pharmacogenomics is a tool for practitioners to provide precision pharmacotherapy using genomics. All providers are likely to encounter genomic data in practice with the expectation that they are able to successfully apply it to patient care. Pharmacogenomics tests for genetic variations in genes that are responsible for drug metabolism, transport, and targets of drug action. Variations can increase the risk for drug toxicity or poor efficacy. Pharmacogenomics can, therefore, be used to help select the best medication or aid in dosing. Nephrologists routinely treat cardiovascular disease and manage patients after kidney transplantation, two situations for which there are several high-evidence clinical recommendations for commonly used anticoagulants, antiplatelets, statins, and transplant medications. Successful use of pharmacogenomics in practice requires that providers are familiar with how to access and use pharmacogenomics resources. Similarly, clinical decision making related to whether to use existing data, whether to order testing, and if data should be used in practice is needed to deliver precision medicine. Pharmacogenomics is applicable to virtually every medical specialty, and nephrologists are well positioned to be implementation leaders.

ABCG2 c.421C>A Is Associated with Outcomes after Severe Traumatic Brain Injury.

Traumatic brain injury (TBI) is a leading cause of death with no pharmacological treatments that improve outcomes. Transporter proteins participate in TBI recovery by maintaining the central nervous system (CNS) biochemical milieu. Genetic variations in transporters that alter expression and/or function have been associated with TBI outcomes. The ATP-binding cassette transporter, ABCG2, is a uric acid (UA) transporter that effluxes UA from cells in the CNS and is responsible for systemic UA clearance. Uric acid is a CNS antioxidant and/or a biomarker that might support TBI recovery. Our objective was to investigate the impact of ABCG2 SNP: c.421C>A on TBI outcomes. Two cohorts (discovery [N = 270] and replication [N = 166]) were genotyped for ABCG2 c.421C>A. Glasgow Outcome Scale (GOS) scores were collected at 3, 6, 12, and 24 months post-injury and compared with mixed-effects multiple ordinal regression controlled for time post-injury, age, sex, time, post-injury imaging determined hemorrhage types, and Glasgow Coma Scale score. Variant alleles (genotype) were associated with better GOS scores (p = 0.01 [discovery] and p = 0.02 [replication]), whereas genotype*age interaction was associated with worse GOS scores (p = 0.03 [discovery] and p = 0.01 [replication]). Reversed coefficient directionality suggests variant allele(s) are protective up to approximately age 34 years. Overall, variant alleles at ABCG2 c.421C>A associate with better GOS scores post-injury in two independently sampled cohorts. This finding is mitigated by increasing subject age. This suggests that ABCG2 might have an age-dependent effect on TBI recovery and should be explored in future mechanistic studies.

The pharmacogenomics of severe traumatic brain injury.

Pharmacotherapy for traumatic brain injury (TBI) is focused on resuscitation, prevention of secondary injury, rehabilitation and recovery. Pharmacogenomics may play a role in TBI for predicting therapies for sedation, analgesia, seizure prevention, intracranial pressure-directed therapy and neurobehavioral/psychiatric symptoms. Research into genetic predictors of outcomes and susceptibility to complications may also help clinicians to tailor therapeutics for high-risk individuals. Additionally, the expanding use of genomics in the drug development pipeline has provided insight to novel investigational and repurposed medications that may be useful in the treatment of TBI and its complications. Genomics in the context of treatment and prognostication for patients with TBI is a promising area for clinical progress of pharmacogenomics.

Design and evaluation of a pharmacogenomics information resource for pharmacists.

OBJECTIVE: To develop and evaluate a pharmacogenomics information resource for pharmacists. MATERIALS AND METHODS: We built a pharmacogenomics information resource presenting Food and Drug Administration (FDA) drug product labelling information, refined it based on feedback from pharmacists, and conducted a comparative usability evaluation, measuring task completion time, task correctness and perceived usability. Tasks involved hypothetical clinical situations requiring interpretation of pharmacogenomics information to determine optimal prescribing for specific patients. RESULTS: Pharmacists were better able to perform certain tasks using the redesigned resource relative to the Pharmacogenomic Knowledgebase (PharmGKB) and the FDA Table of Pharmacogenomic Biomarkers in Drug Labeling. On average, participants completed tasks in 107.5 s using our resource, compared to 188.9 s using PharmGKB and 240.2 s using the FDA table. Using the System Usability Scale, participants rated our resource 79.62 on average, compared to 53.27 for PharmGKB and 50.77 for the FDA table. Participants found the correct answers for 100% of tasks using our resource, compared to 76.9% using PharmGKB and 69.2% using the FDA table. DISCUSSION: We present structured, clinically relevant pharmacogenomic FDA drug product label information with visualizations to help explain the relationships between gene variants, drugs, and phenotypes. The results from our evaluation suggest that user-centered interfaces for pharmacogenomics information can increase ease of access and comprehension. CONCLUSION: A clinician-focused pharmacogenomics information resource can answer pharmacogenomics-related medication questions faster, more correctly, and more easily than widely used alternatives, as perceived by pharmacists.

Advancing Pharmacogenomics Education in the Core PharmD Curriculum through Student Personal Genomic Testing.

OBJECTIVE: To develop, implement, and evaluate "Test2Learn" a program to enhance pharmacogenomics education through the use of personal genomic testing (PGT) and real genetic data. DESIGN: One hundred twenty-two second-year doctor of pharmacy (PharmD) students in a required course were offered PGT as part of a larger program approach to teach pharmacogenomics within a robust ethical framework. The program added novel learning objectives, lecture materials, analysis tools, and exercises using individual-level and population-level genetic data. Outcomes were assessed with objective measures and pre/post survey instruments. ASSESSMENT: One hundred students (82%) underwent PGT. Knowledge significantly improved on multiple assessments. Genotyped students reported a greater increase in confidence in understanding test results by the end of the course. Similarly, undergoing PGT improved student's self-perceived ability to empathize with patients compared to those not genotyped. Most students (71%) reported feeling PGT was an important part of the course, and 60% reported they had a better understanding of pharmacogenomics specifically because of the opportunity. CONCLUSION: Implementation of PGT in the core pharmacy curriculum was feasible, well-received, and enhanced student learning of pharmacogenomics.

Bringing clinical pharmacogenomics information to pharmacists: A qualitative study of information needs and resource requirements.

INTRODUCTION: As key experts in supporting medication-decision making, pharmacists are well-positioned to support the incorporation of pharmacogenomics into clinical care. However, there has been little study to date of pharmacists' information needs regarding pharmacogenomics. Understanding those needs is critical to design information resources that help pharmacists effectively apply pharmacogenomics information. OBJECTIVES: We sought to understand the pharmacogenomics information needs and resource requirements of pharmacists. METHODS: We conducted qualitative inquiries with 14 pharmacists representing 6 clinical environments, and used the results of those inquiries to develop a model of pharmacists' pharmacogenomics information needs and resource requirements. RESULTS: The inquiries identified 36 pharmacogenomics-specific and pharmacogenomics-related information needs that fit into four information needs themes: background information, patient information, medication information, and guidance information. The results of the inquiries informed a model of pharmacists' pharmacogenomics resource requirements, with 3 themes: structure of the resource, perceptions of the resource, and perceptions of the information. CONCLUSION: Responses suggest that pharmacists anticipate an imminently growing role for pharmacogenomics in their practice. Participants value information from trust-worthy resources like FDA product labels, but struggle to find relevant information quickly in labels. Specific information needs include clinically relevant guidance about genotypes, phenotypes, and how to care for their patients with known genotypes. Information resources supporting the goal of incorporating complicated genetic information into medication decision-making goals should be well-designed and trustworthy.