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Susanne B Haga, Rachel Mills, Jivan Moaddeb, Yiling Liu, Deepak Voora Center for Applied Genomics & Precision Medicine, Duke University School of Medicine, Durham, NC, 27708, USACorrespondence: Susanne B Haga Email Susanne.haga@duke.eduObjective: The delivery of pharmacogenetic (PGx) testing has primarily been through clinical and hospital settings. We conducted a study to explore the feasibility of delivering PGx testing through community pharmacies, a less-studied setting.Methods: We conducted a cluster randomized trial of community pharmacies in North Carolina through two approaches: the provision of PGx testing alone or PGx testing with medication therapy management (MTM).Results: A total of 150 patient participants were enrolled at 17 pharmacies and reported high satisfaction with their testing experience. Participants in the PGx plus MTM arm were more likely to recall a higher number of results (p=0.04) and more likely to clearly understand their choices for prevention or early detection of side effects (p=0.01). A medication or dose change based on the PGx results was made for 8.7% of participants.Conclusion: Limited differences were observed in the provision of PGx testing as a standalone test or combined with MTM. A limited number of treatment changes were made based on PGx test results. Patient acceptance of PGx testing offered through the community pharmacy was very high, but the addition of MTM did not impact patient-reported perceptions about PGx testing or medication adherence.Keywords: pharmacy, pharmacogenetic testing, feasibility, patient experience

Susanne B Haga, Rachel Mills, Jivan Moaddeb, Yiling Liu, Deepak Voora Center for Applied Genomics & Precision Medicine, Durham, NC, 27708, USACorrespondence: Susanne B HagaCenter for Applied Genomics & Precision Medicine, 101 Science Drive, Box 3382, Durham, NC, 27708 Tel +919-684-0325Email susanne.haga@duke.eduObjective: This study assessed pharmacist experiences with delivering pharmacogenetic (PGx) testing in independent community pharmacies.Methods: We conducted a cluster randomized trial of independent community pharmacies in North Carolina randomized to provide either PGx testing as a standalone service or integrated into medication therapy management (MTM) services. Surveys and pharmacist data about the delivery of PGx testing were collected. Semi-structured interviews were also conducted.Results: A total of 36 pharmacists participated in the study from 22 pharmacies. Sixteen pharmacists completed the pre-study and post-study surveys, and four pharmacists completed the semi-structured interviews. Thirty-one percent (11/36) of pharmacists had had some education in personalized medicine or PGx prior to the study. The only outcome that differed by study arm was the use of educational resources, with significantly higher utilization in the PGx testing only arm (p=0.007). Overall, compared to the pre-study assessment, pharmacists’ knowledge about PGx significantly improved post-study (p=0.018). In the post-study survey, almost all pharmacists indicated that they felt qualified/able to provide PGx testing at their pharmacy. While 75% of pharmacists indicated that they may continue to provide PGx testing at their pharmacy after the study, the major concerns were lack of reimbursement for PGx counseling and consultation given the necessary time required.Conclusion: Our findings demonstrated a positive experience with delivering PGx testing in the community pharmacy setting with little difference in pharmacists’ experiences in providing PGx testing with or without MTM. Pharmacists were confident in their ability to provide PGx testing and were interested in continuing to offer testing, though sustained delivery may be challenged by lack of prescribing provider engagement and reimbursement.Keywords: pharmacy, pharmacogenetic testing, feasibility, pharmacist experience

Amber L Beitelshees,1,* Deepak Voora,2,* Joshua P Lewis,1,* 1Program for Personalized and Genomic Medicine and Division of Endocrinology, Diabetes, and Nutrition, University of Maryland School of Medicine, Baltimore, MD, USA; 2Center for Applied Genomics & Precision Medicine, Department of Medicine, Duke School of Medicine, Durham, NC, USA*All authors contributed equally to this work Abstract: In recent years, substantial effort has been made to better understand the influence of genetic factors on the efficacy and safety of numerous medications. These investigations suggest that the use of pharmacogenetic data to inform physician decision-making has great potential to enhance patient care by reducing on-treatment clinical events, adverse drug reactions, and health care-related costs. In fact, integration of such information into the clinical setting may be particularly applicable for antiplatelet and anticoagulation therapeutics, given the increasing body of evidence implicating genetic variation in variable drug response. In this review, we summarize currently available pharmacogenetic information for the most commonly used antiplatelet (ie, clopidogrel and aspirin) and anticoagulation (ie, warfarin) medications. Furthermore, we highlight the currently known role of genetic variability in response to next-generation antiplatelet (prasugrel and ticagrelor) and anticoagulant (dabigatran) agents. While compelling evidence suggests that genetic variants are important determinants of antiplatelet and anticoagulation therapy response, significant barriers to clinical implementation of pharmacogenetic testing exist and are described herein. In addition, we briefly discuss development of new diagnostic targets and therapeutic strategies as well as implications for enhanced patient care. In conclusion, pharmacogenetic testing can provide important information to assist clinicians with prescribing the most personalized and effective antiplatelet and anticoagulation therapy. However, several factors may limit its usefulness and should be considered. Keywords: pharmacogenetics, clopidogrel, warfarin, anticoagulant, aspirin, precision medicine

Rachel Mills,1 Deepak Voora,1,2 Bruce Peyser,3 Susanne B Haga1,2 1Duke Institute for Genome Sciences and Policy, 2Duke Center for Personalized and Precision Medicine, 3Duke University Medical Center, Pickett Road Primary Care Clinic, Duke University, Durham, NC, USA Abstract: Pharmacogenetic testing refers to a type of genetic test to predict a patient's likelihood to experience an adverse event or not respond to a given drug. Despite revision to several labels of commonly prescribed drugs regarding the impact of genetic variation, the use of this testing has been limited in many settings due to a number of factors. In the primary care setting, the limited office time as well as the limited knowledge and experience of primary care practitioners have likely attributed to the slow uptake of pharmacogenetic testing. This paper provides talking points for primary care physicians to discuss with patients when pharmacogenetic testing is warranted. As patients and physicians become more familiar and accepting of pharmacogenetic testing, it is anticipated that discussion time will be comparable to that of other clinical tests. Keywords: pharmacogenetics, primary care, pharmacogenetic testing, patient education

The role of lipoprotein (a) (Lp[a]) in the development of obstructive coronary artery disease (CAD) and high-risk plaque (HRP) in primary prevention patients with stable chest pain is unknown. We sought to evaluate the relation of Lp(a), independent of low-density lipoprotein cholesterol (LDL-C), with the presence of obstructive CAD and HRP to improve understanding of the residual risk imparted by Lp(a) on CAD. We performed a secondary analysis in Prospective Multicenter Imaging Study for Evaluation of Chest Pain (PROMISE) Trial participants who had coronary computed tomographic angiography (CTA) performed and Lp(a) data available. Lp(a) concentration was analyzed as a binary variable, with elevated Lp(a) defined as ≥50 mg/100 ml. "Stenosis ≥50%" was defined as ≥50% coronary artery stenosis in any epicardial vessel, and "stenosis ≥70%" was defined as ≥70% coronary artery stenosis in any epicardial vessel and/or ≥50% left main coronary artery stenosis. HRP was defined as presence of plaque on CTA imaging with evidence of positive remodeling, low computed tomography attenuation, or napkin-ring sign. Multivariate logistic regression models were constructed to evaluate the association between Lp(a) and the outcomes of obstructive CAD and HRP stratified by LDL-C ≥100 versus <100 mg/100 ml. Of the 1,815 patients who underwent CTA and had Lp(a) data available, those with elevated Lp(a) were more commonly women and Black than those with lower Lp(a). Elevated Lp(a) was associated with stenosis ≥50% (odds ratio 1.57, 95% confidence interval 1.14 to 2.15, p = 0.005) and stenosis ≥70% (odds ratio 2.05, 95% confidence interval 1.34 to 3.11, p = 0.0008) in the multivariate models, and this relation was not modified by LDL-C ≥100 versus <100 mg/100 ml (interaction p >0.4). Elevated Lp(a) was not associated with HRP when adjusted for obstructive CAD. This study of patients without known CAD found that elevated Lp(a) ≥50 mg/100 ml was independently associated with the presence of obstructive CAD regardless of controlled versus uncontrolled LDL-C but was not independently associated with HRP when stenosis ≥50% or ≥70% was accounted for. Further research is warranted to delineate the role of Lp(a) in the residual risk for atherosclerotic cardiovascular disease that patients may have despite optimal LDL-C lowering., Competing Interests: Declaration of competing interest Dr. Shah reports research grants from Amgen, Janssen, Eli Lily, Novartis, and National Institutes of Health, and service as a consultant/advisor for Merck, Amgen, Norvartis, and New Amsterdam Pharma. Dr. Ferencik reports consulting fees from Cleerly, HeartFlow, Elucid, Siemens Healthineers, and BioMarin, and stock options from Elucid, and is a member of an advisory board for Cleerly. Dr. Lu reports research funding to his institution from the American Heart Association, AstraZeneca, Ionis, Johnson & Johnson Innovation, Kowa Pharmaceuticals America, MedImmune, National Academy of Medicine, National Heart, Lung, and Blood Institute, and Risk Management Foundation of the Harvard Medical Institutions outside the submitted work. Dr. Foldyna reports research grants from National Institutes of Health/National Heart, Lung, and Blood Institute (R01HL170877, 5P30DK040561), AstraZeneca, Cleerly Health, MedImmune, and MedTrace. Dr. Pagidipati reports research support from Alnylam, Amgen, Bayer, Boehringer Ingelheim (Ingelheim, Germany), Eggland's Best, Eli Lilly (Esperion), Novartis, Novo Nordisk, Merck; service on consultation/advisory panels for Amgen, Bayer, Boehringer Ingelheim, CRISPR Therapeutics, Eli Lilly, AstraZeneca, Merck, Novartis, and Novo Nordisk; service as an Executive Committee member for trials sponsored by Novo Nordisk and by Amgen and by AstraZeneca; service on a Data and Safety Monitoring Board for trials sponsored by Johnson & Johnson and Novartis; and service on a medical advisory board for Miga Health. The remaining authors have no competing interests to declare., (Copyright © 2024 Elsevier Inc. All rights reserved.)

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 healthcare system where 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. A conditional logistic model was used to identify factors associated with a PGx order receipt and estimate odds ratios and 95% confidence intervals., Results: The following patient factors predicted receipt of a PGx test order: younger age, married status, rural residence, non-Hispanic Black or Hispanic race/ethnicity, PGx educational mailer receipt, depression diagnosis, allergy to a drug on the panel, prescriptions for drugs on the panel, and specialty care visits (p<0.05). Additionally, patients whose providers were female, younger, a nurse practitioner/physician assistant or pharmacist, or participated in an educational mailer program were more likely to receive an order (p<0.05)., Conclusion: This study highlights factors that may facilitate or hinder the widespread and equitable implementation of PGx testing in a large national healthcare system. The information is being used to further refine the program., (Copyright © 2024. Published by Elsevier Inc.)

Aim: To survey Veterans Health Administration providers who prescribed tramadol or codeine to patients with known genotyping for cytochrome 2D6 ( CYP2D6 ) to ascertain awareness of their patient's pharmacogenetic (PGx) test status, whether these results influenced prescribing, perceived benefit of PGx testing, and resources needed to obtain and deliver PGx testing information. Materials & methods: A provider survey was conducted of those who prescribed tramadol or codeine in a patient genotyped for CYP2D6 . Results: Of 876 eligible providers, 220 completed the survey. Ten percent were aware that their patient received a PGx test, 64% had not ordered any PGx test related to any medication in the prior year, 55% strongly agreed or agreed that PGx testing is or will be valuable to guide pain medication prescriptions, 29% felt that the evidence base for PGx testing is very strong or moderately strong, 22% responded likely or extremely likely to order a future PGx test, and 51% felt that it would be either very important or fairly important to have a local subject matter expert as a resource for PGx testing. Conclusion: There are modifiable factors that the Veterans Health Administration could address to optimize PGx testing for pain management.

Background: Hematopoietic transcription factor RUNX1 is expressed from proximal P2 and distal P1 promoters 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., Methods: We performed studies on RUNX1 isoforms in megakaryocytic human erythroleukemia (HEL) cells and HeLa cells (lack endogenous RUNX1), in platelets from 85 healthy volunteers administered aspirin or ticagrelor, and on the association of RUNX1 target genes with acute events in 587 patients with cardiovascular disease (CVD)., Results: In chromatin immunoprecipitation and luciferase promoter assays, RUNX1 isoforms B and C bound and regulated P1 and P2 promoters. In HeLa cells, RUNX1B decreased and RUNX1C increased P1 and P2 activities, respectively. In HEL cells, RUNX1B overexpression decreased RUNX1C and RUNX1A expression; RUNX1C increased RUNX1B and RUNX1A. RUNX1B and RUNX1C regulated target genes (MYL9, F13A1, PCTP, PDE5A, and others) differentially in HEL cells. In platelets, RUNX1B transcripts (by RNA sequencing) correlated negatively with RUNX1C and RUNX1A; RUNX1C correlated positively with RUNX1A. RUNX1B correlated positively with F13A1, PCTP, PDE5A, RAB1B, and others, and negatively with MYL9. In our previous studies, RUNX1C transcripts in whole blood were protective against acute events in CVD patients. We found that higher expression of RUNX1 targets F13A1 and RAB31 associated with acute events., Conclusion: RUNX1 isoforms B and C autoregulate RUNX1 and regulate downstream genes in a differential manner, and this is associated with acute events in CVD., Competing Interests: Declaration of competing interests There are no competing interests to disclose., (Copyright © 2024 International Society on Thrombosis and Haemostasis. Published by Elsevier Inc. All rights reserved.)

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 0.4 µM epinephrine had a higher incidence of the 30 day primary cardiovascular endpoint (37.2% vs. 15.3% in those without hyperreactivity, adjusted HR 2.76, 95% CI 1.5-5.1, p = 0.002). PRESS performs well in identifying a hyperreactive phenotype in patients with PAD (AUC [cross-validation] 0.81, 95% CI 0.68 -0.94, n = 84) and in an independent cohort of healthy participants (AUC [validation] 0.77, 95% CI 0.75 -0.79, n = 35). Following multivariable adjustment, PAD individuals with a PRESS score above the median are at higher risk for a future cardiovascular event (adjusted HR 1.90, CI 1.07-3.36; p = 0.027, n = 129, NCT02106429). This study derives and validates the ability of PRESS to discriminate platelet hyperreactivity and identify those at increased cardiovascular risk. Future studies in a larger independent cohort are warranted for further validation. The development of a platelet reactivity expression score opens the possibility for a personalized approach to antithrombotic therapy for cardiovascular risk reduction., (© 2024. The Author(s).)

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. The objective of this narrative review is to describe the current status of pharmacogenetic testing recommendations within clinical practice guidelines in the US., Summary: Guidelines were reviewed for pharmacogenetic testing recommendations for 21 gene-drug pairs that have well-established drug response associations and all of which are categorized as clinically actionable by the Clinical Pharmacogenetics Implementation Consortium. The degree of consistency within and between organizations in pharmacogenetic testing recommendations was assessed. Relatively few clinical practice guidelines that provide a pharmacogenetic testing recommendation were identified. Testing recommendations for HLA-B*57:01 before initiation of abacavir and G6PD before initiation of rasburicase, both of which are included in drug labeling, were mostly consistent across guidelines. Gene-drug pairs with at least one clinical practice guideline recommending testing or stating that testing could be considered included CYP2C19-clopidogrel, CYP2D6-codeine, CYP2D6-tramadol, CYP2B6-efavirenz, TPMT-thiopurines, and NUDT15-thiopurines. Testing recommendations for the same gene-drug pair were often inconsistent between organizations and sometimes inconsistent between different guidelines from the same organization., Conclusion: A standardized approach to evaluating the evidence of clinical utility for pharmacogenetic testing may increase the inclusion and consistency of pharmacogenetic testing recommendations in clinical practice guidelines, which could benefit patients and society by increasing clinical use of pharmacogenetic testing., (© American Society of Health-System Pharmacists 2024. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.)

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. We quantified prescriptions active or recently expired at the time of PGx testing. We constructed two co-primary polypharmacy (≥10 medications) end points: (i) based on all medications and (ii) requiring that at least one medication was affected by a pharmacogene of interest. Pharmacogenes and actionable phenotypes of interest included poor and ultrarapid metabolizers for CYP2D6, CYP2C9, and CYP2C19 and intermediate and normal metabolizers for CYP3A5. Patients were classified as having 0, 1, and 2+ total phenotypes across all genes. Of the 15,144 patients screened, 13,116 met eligibility criteria. Across phenotype cohorts, there was no significant association with polypharmacy using all medications, number of total medications, or number of medications affected by phenotypes. However, there was a significant difference in patients with polypharmacy prescribed ≥1 medication impacted by PGx across phenotype groups: 2,514/4,949 (51%), 1,349/2,595 (52%), 204/350 (58%) (P = 0.03, OR 1.31, 95% CI 1.02-1.67). The median number of medications affected by PGx phenotypes with ≥1 PGx-impacted medication across phenotype groups was a median of 0 (IQR 0, 0), 0 (IQR 0, 0), and 1 (IQR 0, 1) (P < 0.001). In patients prescribed ≥1 medication impacted by PGx, those with more actionable pharmacogenomic phenotypes were more likely to meet polypharmacy criteria., (Published 2024. This article is a U.S. Government work and is in the public domain in the USA.)

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. However, CYP2D6 is rarely used in clinical practice due in part to the demand for additional clinical trial evidence. Thus, we designed the ADOPT-PGx (A Depression and Opioid Pragmatic Trial in Pharmacogenetics) chronic pain study, a multicenter, pragmatic, randomized controlled clinical trial, to assess the effect of CYP2D6 testing on pain management. The study enrolled 1048 participants who are taking or being considered for treatment with CYP2D6-impacted opioids for their chronic pain. Participants were randomized to receive immediate or delayed (by 6 months) genotyping of CYP2D6 with clinical decision support (CDS). CDS encouraged the providers to follow the CYP2D6-guided trial recommendations. The primary study outcome is the 3-month absolute change in the composite pain intensity score assessed using Patient-Reported Outcomes Measurement Information System (PROMIS) measures. Follow-up will be completed in July 2024. Herein, we describe the design of this trial along with challenges encountered during enrollment., (© 2024 The Author(s). Clinical and Translational Science published by Wiley Periodicals LLC on behalf of American Society for Clinical Pharmacology and Therapeutics.)

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 12 inhibitor, platelets from healthy volunteers receiving aspirin or P2Y 12 inhibition, and platelets from patients with systemic lupus erythematosus (SLE). P2Y 12 inhibition reduced gene expression and inflammatory pathways in MKs and platelets. In SLE, the interferon (IFN) pathway was elevated. In vitro experiments demonstrated the role of P2Y 12 inhibition in reducing IFNα-induced platelet-leukocyte interactions and IFN signaling pathways. These results suggest that P2Y 12 inhibition may have therapeutic potential for proinflammatory and autoimmune conditions like SLE., Competing Interests: This work was supported by National Institutes of Health grants R01HL139909 (to Drs Berger and Buyon), R35HL144993 (to Dr Berger), 1OT2HL156812-01 (to Dr Berger), R01HL167917 (to Dr Barrett), and R01HL118049 (to Dr Voora). The authors have reported that they have no relationships relevant to the contents of this paper to disclose.PerspectivesCOMPETENCY IN MEDICAL KNOWLEDGE: The comprehensive analysis of MK and platelet transcriptomes suppressed by P2Y12 inhibitors and their role in modulating immune reactions adds insights into understanding immune-mediated disorders and their therapeutic potential. P2Y12 inhibitors might synergize with existing treatments to provide more comprehensive control over immune dysregulation and thrombotic tendencies. TRANSLATIONAL OUTLOOK: Further investigation into the precise molecular mechanisms linking P2Y12 inhibition, platelet function, and immune modulation would provide a deeper understanding of the nonhemostatic effects of platelet directed therapies. This knowledge could uncover novel drug targets within platelet-mediated pathways. In addition to SLE, the role of platelet activation and its modulation by P2Y12 inhibitors could be investigated in other inflammatory conditions, expanding the potential applications of these agents., (© 2024 Published by Elsevier on behalf of the American College of Cardiology Foundation.)

Specific selective serotonin reuptake inhibitors (SSRIs) metabolism is strongly influenced by two pharmacogenes, CYP2D6 and CYP2C19. However, the effectiveness of prospectively using pharmacogenetic variants to select or dose SSRIs for depression is uncertain in routine clinical practice. The objective of this prospective, multicenter, pragmatic randomized controlled trial is to determine the effectiveness of genotype-guided selection and dosing of antidepressants on control of depression in participants who are 8 years or older with ≥3 months of depressive symptoms who require new or revised therapy. Those randomized to the intervention arm undergo pharmacogenetic testing at baseline and receive a pharmacy consult and/or automated clinical decision support intervention based on an actionable phenotype, while those randomized to the control arm have pharmacogenetic testing at the end of 6-months. In both groups, depression and drug tolerability outcomes are assessed at baseline, 1 month, 3 months (primary), and 6 months. The primary end point is defined by change in Patient-Reported Outcomes Measurement Information System (PROMIS) Depression score assessed at 3 months versus baseline. Secondary end points include change inpatient health questionnaire (PHQ-8) measure of depression severity, remission rates defined by PROMIS score < 16, medication adherence, and medication side effects. The primary analysis will compare the PROMIS score difference between trial arms among those with an actionable CYP2D6 or CYP2C19 genetic result or a CYP2D6 drug-drug interaction. The trial has completed accrual of 1461 participants, of which 562 were found to have an actionable phenotype to date, and follow-up will be complete in April of 2024., (© 2024 The Author(s). Clinical and Translational Science published by Wiley Periodicals LLC on behalf of American Society for Clinical Pharmacology and Therapeutics.)

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. Lipoprotein particle size/number were measured by nuclear magnetic resonance spectroscopy. Principal components analysis (PCA) was used for dimensionality reduction. The association of PCA factors and individual lipoprotein particle size/number with HS were assessed in multivariable regression models. Associations were validated in an independent cohort of 59 individuals with histopathology defined HS., Results: Individuals with HS (n=410/1,509) vs those without (n=1,099/1,509), were younger (59±8 vs 61±8 years) and less often females (47.6 % vs 55.9 %). All PCA factors were associated with HS: factor 1 (OR:1.36, 95 %CI:1.21-1.53), factor 3 (OR:1.75, 95 %CI:1.53-2.02) and factor 4 (OR:1.49; 95 %CI:1.32-1.68) were weighted heavily with small low density lipoprotein (LDL) and triglyceride-rich (TRL) particles, while factor 2 (OR:0.86, 95 %CI:0.77-0.97) and factor 5 (OR:0.74, 95 %CI:0.65-0.84) were heavily loaded with high density lipoprotein (HDL) and larger LDL particles. These observations were confirmed with the analysis of individual lipoprotein particles in PROMISE. In the validation cohort, association between HS and large TRL (OR: 8.16, 95 %CI:1.82-61.98), and mean sizes of TRL- (OR: 2.82, 95 %CI:1.14-9.29) and HDL (OR:0.35, 95 %CI:0.13-0.72) were confirmed., Conclusions: Large TRL, mean sizes of TRL-, and HDL were associated with radiographic and histopathologic HS. The use of lipoprotein particle size/number could improve cardiovascular risk assessment in HS., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2024 Published by Elsevier B.V.)

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. RNA sequencing was used to discover platelet genes affected by ticagrelor, and a subset of the most informative was summarized into a composite score and tested for validation. This score was further analyzed (1) in CD34+ megakaryocytes exposed to an P2Y12 inhibitor in vitro, (2) with baseline platelet function in healthy controls, (3) in peripheral artery disease patients (n=139) versus patient controls (n=30) without atherosclerosis, and (4) in patients with peripheral artery disease for correlation with atherosclerosis severity and risk of incident major adverse cardiovascular and limb events., Results: Ticagrelor exposure differentially expressed 3409 platelet transcripts. Of these, 111 were prioritized to calculate a Ticagrelor Exposure Signature score, which ticagrelor reproducibly increased in discovery and validation cohorts. Ticagrelor's effects on platelets transcripts positively correlated with effects of P2Y12 inhibition in primary megakaryocytes. In healthy controls, higher baseline scores correlated with lower baseline platelet function and with minor bleeding while receiving ticagrelor. In patients, lower scores independently associated with both the presence and extent of atherosclerosis and incident ischemic events., Conclusions: Ticagrelor-responsive platelet transcripts are a biomarker for platelet function and cardiovascular risk and may have clinical utility for selecting patients with optimal risk:benefit for ticagrelor use., Competing Interests: Disclosures Coauthors (R.A. Myers, G.S. Ginsburg, and D. Voora) are listed as coinventors on an invention disclosure related to use of platelet RNA biomarkers to predict bleeding due to platelet P2Y12 inhibitors. This article was prepared while G.S. Ginsburg was employed at Duke University. The opinions expressed in this article are the author’s own and do not reflect the view of the National Institutes of Health, the Department of Health and Human Services, or the United States government.

Aim: Understanding barriers and facilitators to pharmacogenomics (PGx) implementation and how to structure a clinical program with the Veterans Health Administration (VA). Materials & methods: 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. Results: 186 (12% response rate) surveyed believed PGx informs drug efficacy (74.7%) and adverse events (71.0%). Low confidence in knowledge (43.0%) and ability to implement (35.4-43.5%). 23 (60.5% response rate) interviewees supported a nationally program to oversee VA education, consultation and IT resources. Prescribing HCPs should be directing local activities. Conclusion: HCPs recognize PGx value but are not prepared to implement. Healthcare systems should build system-wide programs for implementation education and support.