Progress in Pharmacogenomics Implementation in the United States: Barrier Erosion and Remaining Challenges.

Barriers to incorporating pharmacogenetics into routine clinical practice in the United States are well documented. Initial surveys by the Clinical Pharmacogenetics Implementation Consortium (CPIC) in 2009 and 2010 identified barriers across four key domains that have hindered the widespread adoption of clinical pharmacogenetic testing. These are presented verbatim as: (i) absence of a definition of the processes required to interpret genotype information and to translate genetic information into clinical actions; (ii) need for recommended drug/gene pairs to implement clinically now; (iii) clinician resistance to consider pharmacogenetic information at the bedside; and (iv) concerns about test costs and reimbursement.

CYP2C19 Polymorphisms and Clinical Outcomes Following Percutaneous Coronary Intervention in the Million Veteran Program.

CYP2C19 loss-of-function (LOF) alleles decrease the antiplatelet effect of clopidogrel following percutaneous coronary intervention (PCI) in patients presenting with acute coronary syndrome (ACS). The impact of genotype in patients undergoing PCI for stable ischemic heart disease (SIHD) in real-world populations is less clear. We determined time to major adverse cardiac event (MACE), defined as the composite of cardiovascular death, stroke, or myocardial infarction, within 12 months following PCI in the VA Million Veteran Program (MVP) participants treated with clopidogrel from 1/1/2009 to 9/30/2017.

Can Pharmacogenetics Be Used to Predict the Response to Fesoterodine Fumarate?

Importance: Pharmacogenetics could address the challenge of predicting an individual's response to anticholinergic medications for urgency urinary incontinence (UUI).

Objectives: Our objectives were to evaluate whether the metabolizer status of cytochrome p450 2D6 (CYP2D6), the drug metabolizing enzyme for fesoterodine, is associated with effectiveness or moderate/severe adverse events (AEs) from fesoterodine fumarate in women with UUI.

Study Design: In this pilot pharmacogenetics study, 58 women aged ≥50 with ≥3 UUI episodes on a 3-day bladder diary were treated with fesoterodine.

Trends in and predictors of patient pharmacogenomic test uptake in a national health care system.

Purpose: Better understanding patient uptake of pharmacogenomic (PGx) testing may inform its implementation and maximize the benefits that such testing can confer. This study examined patient and provider factors associated with PGx test ordering in a national health care system in which panel-based testing was implemented as part of routine care.

Methods: We used a retrospective matched cohort design and data from the Veterans Health Administration Corporate Data Warehouse.

Inhibiting the P2Y Receptor in Megakaryocytes and Platelets Suppresses Interferon-Associated Responses.

The authors investigated the impact of antiplatelet therapy on the megakaryocyte (MK) and platelet transcriptome. RNA-sequencing was performed on MKs treated with aspirin or P2Y inhibitor, platelets from healthy volunteers receiving aspirin or P2Y inhibition, and platelets from patients with systemic lupus erythematosus (SLE). P2Y inhibition reduced gene expression and inflammatory pathways in MKs and platelets.

Implementing a pragmatic clinical trial to tailor opioids for chronic pain on behalf of the IGNITE ADOPT PGx investigators.

Chronic pain is a prevalent condition with enormous economic burden. Opioids such as tramadol, codeine, and hydrocodone are commonly used to treat chronic pain; these drugs are activated to more potent opioid receptor agonists by the hepatic CYP2D6 enzyme. Results from clinical studies and mechanistic understandings suggest that CYP2D6-guided therapy will improve pain control and reduce adverse drug events.

A Platelet Reactivity ExpreSsion Score derived from patients with peripheral artery disease predicts cardiovascular risk.

Platelets are key mediators of atherothrombosis, yet, limited tools exist to identify individuals with a hyperreactive platelet phenotype. In this study, we investigate the association of platelet hyperreactivity and cardiovascular events, and introduce a tool, the Platelet Reactivity ExpreSsion Score (PRESS), which integrates platelet aggregation responses and RNA sequencing. Among patients with peripheral artery disease (PAD), those with a hyperreactive platelet response (>60% aggregation) to 0.

RUNX1 Isoforms Regulate RUNX1 and Target-Genes Differentially in Platelets-Megakaryocytes: Association with Clinical Cardiovascular Events.

Background: Hematopoietic transcription factor RUNX1 is expressed from proximal P2 and distal P1 promoter to yield isoforms RUNX1 B and C, respectively. The roles of these isoforms in RUNX1 autoregulation and downstream-gene regulation in megakaryocytes and platelets are unknown.

Objectives: To understand the regulation of RUNX1 and its target genes by RUNX1 isoforms.

Association of Pharmacogenomic Phenotypes in CYP2D6, CYP2C9, CYP2C19, and CYP3A5 on Polypharmacy in Veterans.

The Department of Veterans Affairs (VA) utilizes a pharmacogenomic (PGx) program that analyzes specific "pharmacogenes." This study evaluates the effect that pharmacogenes may have on prevalence of polypharmacy. This retrospective cohort study included patients with VA prescriptions who underwent PGx testing.

Lipoprotein subclasses are associated with Hepatic steatosis: insights from the prospective multicenter imaging study for the evaluation of chest pain (PROMISE) clinical trial.

Objectives: To determine the relationship between lipoprotein particle size/number with hepatic steatosis (HS), given its association with traditional lipoproteins and coronary atherosclerosis.

Methods: Individuals with available CT data and blood samples enrolled in the PROMISE trial were studied. HS was defined based on CT attenuation.

LXR signaling pathways link cholesterol metabolism with risk for prediabetes and diabetes.

BACKGROUNDPreclinical studies suggest that cholesterol accumulation leads to insulin resistance. We previously reported that alterations in a monocyte cholesterol metabolism transcriptional network (CMTN) - suggestive of cellular cholesterol accumulation - were cross-sectionally associated with obesity and type 2 diabetes (T2D). Here, we sought to determine whether the CMTN alterations independently predict incident prediabetes/T2D risk, and correlate with cellular cholesterol accumulation.

Recommendations for pharmacogenetic testing in clinical practice guidelines in the US.

Purpose: Pharmacogenetic testing can identify patients who may benefit from personalized drug treatment. However, clinical uptake of pharmacogenetic testing has been limited. Clinical practice guidelines recommend biomarker tests that the guideline authors deem to have demonstrated clinical utility, meaning that testing improves treatment outcomes.

Workforce readiness for pharmacogenomics and key elements for sustainment within the Veterans Health Administration.

Understanding barriers and facilitators to pharmacogenomics (PGx) implementation and how to structure a clinical program with the Veterans Health Administration (VA). Healthcare provider (HCP) survey at 20 VA facilities assessing PGx knowledge/acceptance and qualitative interviews to understand how best to design and sustain a national program. 186 (12% response rate) surveyed believed PGx informs drug efficacy (74.

Pharmacogenetic testing and monitoring of complete blood counts among Veterans newly prescribed thiopurine treatments: a retrospective cohort study.

Pharmacogenetic (PGx) testing before initiation of thiopurine treatment and CBC monitoring post-initiation helps avoid adverse events and ensure patient safety. This study aims to evaluate trends in PGx testing and CBC monitoring among Veterans prescribed azathioprine, thioguanine, or mercaptopurine to demonstrate VA's efforts to improve medication safety after an adverse event. To assess testing patterns, we used VA electronic health report data to identify 20,524 Veterans who first began thiopurine treatment between January 1, 2010, to December 31, 2021.

Platelet RNA Biomarker of Ticagrelor-Responsive Genes Is Associated With Platelet Function and Cardiovascular Events.

Background: Identifying patients with the optimal risk:benefit for ticagrelor is challenging. The aim was to identify ticagrelor-responsive platelet transcripts as biomarkers of platelet function and cardiovascular risk.

Methods: Healthy volunteers (n=58, discovery; n=49, validation) were exposed to 4 weeks of ticagrelor with platelet RNA data, platelet function, and self-reported bleeding measured pre-/post-ticagrelor.

Patient Perspectives of Barriers and Facilitators for the Uptake of Pharmacogenomic Testing in Veterans Affairs' Pharmacogenomic Testing for the Veterans (PHASER) Program.

We applied implementation science frameworks to identify barriers and facilitators to veterans' acceptance of pharmacogenomic testing (PGx), which was made available as a part of clinical care at 25 VA medical centers. We conducted 30 min interviews with veterans who accepted ( = 14), declined ( = 9), or were contemplating ( = 8) PGx testing. Six team members coded one transcript from each participant group to develop the codebook and finalize definitions.

An Introductory Tutorial on Cardiovascular Pharmacogenetics for Healthcare Providers.

Pharmacogenetics can improve clinical outcomes by reducing adverse drug effects and enhancing therapeutic efficacy for commonly used drugs that treat a wide range of cardiovascular diseases. One of the major barriers to the clinical implementation of cardiovascular pharmacogenetics is limited education on this field for current healthcare providers and students. The abundance of pharmacogenetic literature underscores its promise, but it can also be challenging to learn such a wealth of information.

Branched-Chain Amino Acids in Computed Tomography-Defined Adipose Depots and Coronary Artery Disease: A PROMISE Trial Biomarker Substudy.

Background The interplay between branched-chain amino acid (BCAA) metabolism, an important pathway in adiposity and cardiometabolic disease, and visceral adipose depots such as hepatic steatosis (HS) and epicardial adipose tissue is unknown. We leveraged the PROMISE clinical trial with centrally adjudicated coronary computed tomography angiography imaging to determine relationships between adipose depots, BCAA dysregulation, and coronary artery disease (CAD). Methods and Results The PROMISE (Prospective Multicenter Imaging Study for Evaluation of Chest Pain) trial randomized 10 003 outpatients with stable chest pain to computed tomography angiography versus standard-of-care diagnostics.

Veterans Health Administration: Implementation of pharmacogenomic clinical decision support with statin medications and the SLCO1B1 gene as an exemplar.

Purpose: To describe the implementation of clinical decision support tools for alerting prescribers of actionable drug-gene interactions in the Veterans Health Administration (VHA).

Summary: Drug-gene interactions have been the focus of clinicians for years. Interactions between SCLO1B1 genotype and statin medications are of particular interest as these can inform risk for statin-associated muscle symptoms (SAMS).