Publications by authors named "Nita A Limdi"

82 Publications

Multisite evaluation of institutional processes and implementation determinants for pharmacogenetic testing to guide antidepressant therapy.

Clin Transl Sci 2021 Sep 25. Epub 2021 Sep 25.

University of Minnesota Medical School, Minneapolis, Minnesota, USA.

There is growing interest in utilizing pharmacogenetic (PGx) testing to guide antidepressant use, but there is lack of clarity on how to implement testing into clinical practice. We administered two surveys at 17 sites that had implemented or were in the process of implementing PGx testing for antidepressants. Survey 1 collected data on the process and logistics of testing. Survey 2 asked sites to rank the importance of Consolidated Framework for Implementation Research (CFIR) constructs using best-worst scaling choice experiments. Of the 17 sites, 13 had implemented testing and four were in the planning stage. Thirteen offered testing in the outpatient setting, and nine in both outpatient/inpatient settings. PGx tests were mainly ordered by psychiatry (92%) and primary care (69%) providers. CYP2C19 and CYP2D6 were the most commonly tested genes. The justification for antidepressants selected for PGx guidance was based on Clinical Pharmacogenetics Implementation Consortium guidelines (94%) and US Food and Drug Administration (FDA; 75.6%) guidance. Both institutional (53%) and commercial laboratories (53%) were used for testing. Sites varied on the methods for returning results to providers and patients. Sites were consistent in ranking CFIR constructs and identified patient needs/resources, leadership engagement, intervention knowledge/beliefs, evidence strength and quality, and the identification of champions as most important for implementation. Sites deployed similar implementation strategies and measured similar outcomes. The process of implementing PGx testing to guide antidepressant therapy varied across sites, but key drivers for successful implementation were similar and may help guide other institutions interested in providing PGx-guided pharmacotherapy for antidepressant management.
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http://dx.doi.org/10.1111/cts.13154DOI Listing
September 2021

Pharmacogenetic Predictors of Cannabidiol Response and Tolerability in Treatment-Resistant Epilepsy.

Clin Pharmacol Ther 2021 Nov 22;110(5):1368-1380. Epub 2021 Sep 22.

Department of Neurology, University of Alabama at Birmingham, Birmingham, Alabama, USA.

In patients with treatment-resistant epilepsy (TRE), cannabidiol (CBD) produces variable improvement in seizure control. Patients in the University of Alabama at Birmingham CBD Expanded Access Program (EAP) were enrolled in the genomic study and genotyped using the Affymetrix Drug Metabolizing Enzymes and Transporters plus array. Associations between variants and CBD response (≥50% seizure reduction) and tolerability (diarrhea, sedation, and abnormal liver function) was evaluated under dominant and recessive models. Expression quantitative trait loci (eQTL) influencing potential CBD targets was evaluated in the UK Brain Expression Consortium data set (Braineac), and genetic co-expression examined. Of 169 EAP patients, 112 (54.5% pediatric and 50.0% female) were included in the genetic analyses. Patients with AOX1 rs6729738 CC (aldehyde oxidase; odds ratio (OR) 6.69, 95% confidence interval (CI) 2.19-20.41, P = 0.001) or ABP1 rs12539 (diamine oxidase; OR 3.96, 95% CI 1.62-9.73, P = 0.002) were more likely to respond. Conversely, patients with SLC15A1 rs1339067 TT had lower odds of response (OR 0.06, 95% CI 0.01-0.56, P = 0.001). ABCC5 rs3749442 was associated with lower likelihood of response and abnormal liver function tests, and higher likelihood of sedation. The eQTL revealed that rs1339067 decreased GPR18 expression (endocannabinoid receptor) in white matter (P = 5.6 × 10 ), and rs3749442 decreased hippocampal HTR3E expression (serotonin 5-HT ; P = 8.5 × 10 ). Furthermore, 75% of genes associated with lower likelihood of response were co-expressed. Pharmacogenetic variation is associated with CBD response and influences expression of CBD targets in TRE. Implicated pathways, including cholesterol metabolism and glutathione conjugation, demonstrate potential interactions between CBD and common medications (e.g., statins and acetaminophen) that may require closer monitoring. These results highlight the role of pharmacogenes in fundamental biologic processes and potential genetic underpinnings of treatment-resistance.
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http://dx.doi.org/10.1002/cpt.2408DOI Listing
November 2021

Translational Pharmacogenomics: Discovery, Evidence Synthesis and Delivery of Race-Conscious Medicine.

Clin Pharmacol Ther 2021 10 29;110(4):909-925. Epub 2021 Jul 29.

Department of Neurology, School of Medicine, University of Alabama at Birmingham, Birmingham, Alabama, USA.

Response to medications, the principal treatment modality for acute and chronic diseases, is highly variable, with 40-70% of patients exhibiting lack of efficacy or adverse drug reactions. With ~ 15-30% of this variability explained by genetic variants, pharmacogenomics has become a valuable tool in our armamentarium for optimizing treatments and is poised to play an increasing role in clinical care. This review presents the progress made toward elucidating genetic underpinnings of drug response including discovery of race/ancestry-specific pharmacogenetic variants and discusses the current evidence and evidence framework for actionability. The review is framed in the context of changing demographics and evolving views related to race and ancestry. Finally, it highlights the vital role played by cohort studies in elucidating genetic differences in drug response across race and ancestry and the informal collaborations that have enabled the field to bridge the "bench to bedside" translational gap.
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http://dx.doi.org/10.1002/cpt.2357DOI Listing
October 2021

Evaluation of population-level pharmacogenetic actionability in Alabama.

Clin Transl Sci 2021 Jun 13. Epub 2021 Jun 13.

Department of Neurology, School of Medicine, University of Alabama at Birmingham, Birmingham, Alabama, USA.

The evolution of evidence and availability of Clinical Pharmacogenetic Implementation Consortium (CPIC) guidelines have enabled assessment of pharmacogenetic (PGx) actionability and clinical implementation. However, population-level actionability is not well-characterized. We leveraged the Alabama Genomic Health Initiative (AGHI) to evaluate population-level PGx actionability. Participants (>18 years), representing all 67 Alabama counties, were genotyped using the Illumina Global Screening array. Using CPIC guidelines, actionability was evaluated using (1) genotype data and genetic ancestry, (2) prescribing data, and (3) combined genotype and medication data. Of 6,331 participants, 4230 had genotype data and 3386 had genotype and prescription data (76% women; 76% White/18% Black [self-reported]). Genetic ancestry was concordant with self-reported race. For CPIC level A genes, 98.6% had an actionable genotype (99.4% Blacks/African; 98.5% White/European). With the exception of DPYD and CYP2C19, the prevalence of actionable genotypes by gene differed significantly by race. Based on prescribing, actionability was highest for CYP2D6 (70.9%), G6PD (54.1%), CYP2C19 (53.5%), and CYP2C9 (47.5%). Among participants prescribed atenolol, carvedilol, or metoprolol, ~ 50% had an actionable ADRB1 genotype, associated with decreased therapeutic response, with higher actionability among Blacks compared to Whites (62.5% vs. 47.4%; p < 0.0001). Based on both genotype and prescribing frequencies, no significant differences in actionability were observed between men and women. This statewide effort highlights PGx population-level impact to help optimize pharmacotherapy. Almost all Alabamians harbor an actionable genotype, and a significant proportion are prescribed affected medications. Statewide efforts, such as AGHI, lay the foundation for translational research and evaluate "real-world" outcomes of PGx.
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http://dx.doi.org/10.1111/cts.13097DOI Listing
June 2021

Opportunity for Genotype-Guided Prescribing Among Adult Patients in 11 US Health Systems.

Clin Pharmacol Ther 2021 07 16;110(1):179-188. Epub 2021 Feb 16.

Department of Biomedical Informatics, Vanderbilt University Medical Center, Nashville, Tennessee, USA.

The value of utilizing a multigene pharmacogenetic panel to tailor pharmacotherapy is contingent on the prevalence of prescribed medications with an actionable pharmacogenetic association. The Clinical Pharmacogenetics Implementation Consortium (CPIC) has categorized over 35 gene-drug pairs as "level A," for which there is sufficiently strong evidence to recommend that genetic information be used to guide drug prescribing. The opportunity to use genetic information to tailor pharmacotherapy among adult patients was determined by elucidating the exposure to CPIC level A drugs among 11 Implementing Genomics In Practice Network (IGNITE)-affiliated health systems across the US. Inpatient and/or outpatient electronic-prescribing data were collected between January 1, 2011 and December 31, 2016 for patients ≥ 18 years of age who had at least one medical encounter that was eligible for drug prescribing in a calendar year. A median of ~ 7.2 million adult patients was available for assessment of drug prescribing per year. From 2011 to 2016, the annual estimated prevalence of exposure to at least one CPIC level A drug prescribed to unique patients ranged between 15,719 (95% confidence interval (CI): 15,658-15,781) in 2011 to 17,335 (CI: 17,283-17,386) in 2016 per 100,000 patients. The estimated annual exposure to at least 2 drugs was above 7,200 per 100,000 patients in most years of the study, reaching an apex of 7,660 (CI: 7,632-7,687) per 100,000 patients in 2014. An estimated 4,748 per 100,000 prescribing events were potentially eligible for a genotype-guided intervention. Results from this study show that a significant portion of adults treated at medical institutions across the United States is exposed to medications for which genetic information, if available, should be used to guide prescribing.
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http://dx.doi.org/10.1002/cpt.2161DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8217370PMC
July 2021

Prescribing Prevalence of Medications With Potential Genotype-Guided Dosing in Pediatric Patients.

JAMA Netw Open 2020 12 1;3(12):e2029411. Epub 2020 Dec 1.

Personalized Medicine Initiative, Nicklaus Children's Health System, Miami, Florida.

Importance: Genotype-guided prescribing in pediatrics could prevent adverse drug reactions and improve therapeutic response. Clinical pharmacogenetic implementation guidelines are available for many medications commonly prescribed to children. Frequencies of medication prescription and actionable genotypes (genotypes where a prescribing change may be indicated) inform the potential value of pharmacogenetic implementation.

Objective: To assess potential opportunities for genotype-guided prescribing in pediatric populations among multiple health systems by examining the prevalence of prescriptions for each drug with the highest level of evidence (Clinical Pharmacogenetics Implementation Consortium level A) and estimating the prevalence of potential actionable prescribing decisions.

Design, Setting, And Participants: This serial cross-sectional study of prescribing prevalences in 16 health systems included electronic health records data from pediatric inpatient and outpatient encounters from January 1, 2011, to December 31, 2017. The health systems included academic medical centers with free-standing children's hospitals and community hospitals that were part of an adult health care system. Participants included approximately 2.9 million patients younger than 21 years observed per year. Data were analyzed from June 5, 2018, to April 14, 2020.

Exposures: Prescription of 38 level A medications based on electronic health records.

Main Outcomes And Measures: Annual prevalence of level A medication prescribing and estimated actionable exposures, calculated by combining estimated site-year prevalences across sites with each site weighted equally.

Results: Data from approximately 2.9 million pediatric patients (median age, 8 [interquartile range, 2-16] years; 50.7% female, 62.3% White) were analyzed for a typical calendar year. The annual prescribing prevalence of at least 1 level A drug ranged from 7987 to 10 629 per 100 000 patients with increasing trends from 2011 to 2014. The most prescribed level A drug was the antiemetic ondansetron (annual prevalence of exposure, 8107 [95% CI, 8077-8137] per 100 000 children). Among commonly prescribed opioids, annual prevalence per 100 000 patients was 295 (95% CI, 273-317) for tramadol, 571 (95% CI, 557-586) for codeine, and 2116 (95% CI, 2097-2135) for oxycodone. The antidepressants citalopram, escitalopram, and amitriptyline were also commonly prescribed (annual prevalence, approximately 250 per 100 000 patients for each). Estimated prevalences of actionable exposures were highest for oxycodone and ondansetron (>300 per 100 000 patients annually). CYP2D6 and CYP2C19 substrates were more frequently prescribed than medications influenced by other genes.

Conclusions And Relevance: These findings suggest that opportunities for pharmacogenetic implementation among pediatric patients in the US are abundant. As expected, the greatest opportunity exists with implementing CYP2D6 and CYP2C19 pharmacogenetic guidance for commonly prescribed antiemetics, analgesics, and antidepressants.
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http://dx.doi.org/10.1001/jamanetworkopen.2020.29411DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7737091PMC
December 2020

Thromboembolic and Hemorrhagic Outcomes in the Direct Oral Anticoagulant Trials Across the Spectrum of Kidney Function.

Clin Pharmacol Ther 2021 06 19;109(6):1593-1605. Epub 2021 Jan 19.

Office of Clinical Pharmacology, Office of Translational Sciences, Center for Drug Evaluation and Research, US Food and Drug Administration, Silver Spring, Maryland, USA.

Chronic kidney disease is a common comorbidity among patients taking direct-acting oral anticoagulants (DOACs). Herein, we evaluate the influence of kidney function on stroke or systemic embolism (SEE), hemorrhage, and composite end points (stroke/SEE/hemorrhage/death and stroke/SEE/death) among patients on DOACs and warfarin. Baseline kidney function was categorized as glomerular filtration rate (GFR) ≥ 60 (reference), 45-59, and < 45mL/min/1.73 m for participants in the Randomized Evaluation of Long-Term Anticoagulant Therapy (RE-LY) (n = 18,049), Apixaban for Reduction in Stroke and Other Thromboembolic Events (ARISTOTLE) (n = 18,187), and The Effective Anticoagulation with Factor Xa Next Generation in AF (ENGAGE AF) (n = 20,798) trials. Incidence of events was compared across GFR categories. Hazard ratios for events were estimated using Cox regression using intention-to-treat analysis adjusting for known predictors. A large proportion of participants had GFR < 60 (25-29% had 45 ≤ GFR < 60 and 9.5-12.6% with GFR < 45). Compared with patients with GFR ≥ 60, warfarin users across the trials with GFR ≥ 45-59 and GFR < 45 had a higher incidence of hemorrhage (P values < 0.0001) and warfarin users in the ARISTOTLE and ENGAGE trials had higher incidence of stroke/SEE (P values ≤ 0.05). Compared with patients with GFR ≥ 60, dabigatran users with GFR ≥ 45-59 and GFR < 45 had a higher incidence of stroke/SEE (P ≤ 0.02), hemorrhage (P < 0.001), and both composite end points (P < 0.0001). Compared with patients with GFR ≥ 60, apixaban and edoxaban users with GFR ≥ 45-59 and GFR < 45 had a higher incidence of hemorrhage (P values ≤ 0.05) and composite end points (P values ≤ 0.05). After adjustment, compared with patients with GFR ≥ 60, warfarin users with GFR < 60 in the ARISTOTLE and RE-LY trials had a higher risk of hemorrhage (P < 0.05), as did dabigatran (P < 0.001) and edoxaban (P ≤ 0.005) users, while apixaban users did not exhibit an increased risk (P = 0.08 GFR ≥ 45-59; P = 0.71 GFR < 45). Kidney function significantly influences the safety and efficacy of oral anticoagulants.
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http://dx.doi.org/10.1002/cpt.2131DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8159869PMC
June 2021

Impact of the CYP2C19*17 Allele on Outcomes in Patients Receiving Genotype-Guided Antiplatelet Therapy After Percutaneous Coronary Intervention.

Clin Pharmacol Ther 2021 03 2;109(3):705-715. Epub 2020 Oct 2.

Department of Pharmacotherapy and Translational Research, Center for Pharmacogenomics and Precision Medicine, University of Florida, Gainesville, Florida, USA.

Genotyping for CYP2C19 no function alleles to guide antiplatelet therapy after percutaneous coronary intervention (PCI) improves clinical outcomes. Although results for the increased function CYP2C19*17 allele are also reported, its clinical relevance in this setting remains unclear. A collaboration across nine sites examined antiplatelet therapy prescribing and clinical outcomes in 3,342 patients after implementation of CYP2C19-guided antiplatelet therapy. Risk of major atherothrombotic and bleeding events over 12 months after PCI were compared across cytochrome P450 2C19 isozyme (CYP2C19) metabolizer phenotype and antiplatelet therapy groups by proportional hazards regression. Clopidogrel was prescribed to a similar proportion of CYP2C19 normal (84.5%), rapid (82.9%), and ultrarapid metabolizers (80.6%) (P = 0.360). Clopidogrel-treated normal metabolizers (20.4 events/100 patient-years; adjusted hazard ratio (HR) 1.00, 95% confidence interval (CI), 0.75-1.33, P = 0.993) and clopidogrel-treated rapid or ultrarapid metabolizers (19.1 events/100 patient-years; adjusted HR 0.95, 95% CI, 0.69-1.30, P = 0.734) exhibited no difference in major atherothrombotic events compared with patients treated with prasugrel or ticagrelor (17.6 events/100 patient-years). In contrast, clopidogrel-treated intermediate and poor metabolizers exhibited significantly higher atherothrombotic event risk compared with prasugrel/ticagrelor-treated patients (adjusted HR 1.56, 95% CI, 1.12-2.16, P = 0.008). When comparing clopidogrel-treated rapid or ultrarapid metabolizers to normal metabolizers, no difference in atherothrombotic (adjusted HR 0.97, 95% CI, 0.73-1.29, P = 0.808) or bleeding events (adjusted HR 1.34, 95% CI, 0.83-2.17, P = 0.224) were observed. In a real-world setting of genotype-guided antiplatelet therapy, the CYP2C19*17 allele did not significantly impact post-PCI prescribing decisions or clinical outcomes. These results suggest the CYP2C19 *1/*17 and *17/*17 genotypes have limited clinical utility to guide antiplatelet therapy after PCI.
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http://dx.doi.org/10.1002/cpt.2039DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7902344PMC
March 2021

Development of Customizable Implementation Guides to Support Clinical Adoption of Pharmacogenomics: Experiences of the Implementing GeNomics In pracTicE (IGNITE) Network.

Pharmgenomics Pers Med 2020 17;13:217-226. Epub 2020 Jul 17.

Department of Pharmacotherapy and Translational Research and Center for Pharmacogenomics & Precision Medicine, University of Florida College of Pharmacy, Gainesville, FL, USA.

Introduction: Clinical adoption of genomic medicine has lagged behind the pace of scientific discovery. Practice-based resources can help overcome implementation challenges.

Methods: In 2015, the IGNITE (Implementing GeNomics In pracTicE) Network created an online genomic medicine implementation resource toolbox that was expanded in 2017 to incorporate the ability for users to create targeted implementation guides. This expansion was led by a multidisciplinary team that developed an evidence-based, structured framework for the guides, oversaw the technical process/build, and pilot tested the first guide, -Clopidogrel Testing Implementation.

Results: Sixty-five resources were collected from 12 institutions and categorized according to a seven-step implementation framework for the pilot -Clopidogrel Testing Implementation Guide. Five months after its launch, 96 -Clopidogrel Testing Implementation Guides had been created. Eighty percent of the resources most frequently selected by users were created by IGNITE to fill an identified resource gap. Resources most often included in guides were from the test reimbursement (22%), Implementation support gathering (22%), EHR integration (17%), and genetic testing workflow steps (17%).

Conclusion: Lessons learned from this implementation guide development process provide insight for prioritizing development of future resources and support the value of collaborative efforts to create resources for genomic medicine implementation.
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http://dx.doi.org/10.2147/PGPM.S241599DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7373415PMC
July 2020

Correction: Evaluating the extent of reusability of CYP2C19 genotype data among patients genotyped for antiplatelet therapy selection.

Genet Med 2020 Nov;22(11):1919

University of Florida College of Pharmacy, Department of Pharmacotherapy and Translational Research and Center for Pharmacogenomics and Precision Medicine, Gainesville, FL, USA.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.
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http://dx.doi.org/10.1038/s41436-020-0931-1DOI Listing
November 2020

Evaluating the extent of reusability of CYP2C19 genotype data among patients genotyped for antiplatelet therapy selection.

Genet Med 2020 11 17;22(11):1898-1902. Epub 2020 Jul 17.

University of Florida College of Pharmacy, Department of Pharmacotherapy and Translational Research and Center for Pharmacogenomics and Precision Medicine, Gainesville, FL, USA.

Purpose: Genotype-guided antiplatelet therapy is increasingly being incorporated into clinical care. The purpose of this study is to determine the extent to which patients initially genotyped for CYP2C19 to guide antiplatelet therapy were prescribed additional medications affected by CYP2C19.

Methods: We assembled a cohort of patients from eight sites performingCYP2C19 genotyping to inform antiplatelet therapy. Medication orders were evaluated from time of genotyping through one year. The primary endpoint was the proportion of patients prescribed two or more CYP2C19 substrates. Secondary endpoints were the proportion of patients with a drug-genotype interaction and time to receiving a CYP2C19 substrate.

Results: Nine thousand one hundred ninety-one genotyped patients (17% nonwhite) with a mean age of 68 ± 3 years were evaluated; 4701 (51%) of patients received two or more CYP2C19 substrates and 3835 (42%) of patients had a drug-genotype interaction. The average time between genotyping and CYP2C19 substrate other than antiplatelet therapy was 25 ± 10 days.

Conclusions: More than half of patients genotyped in the setting of CYP2C19-guided antiplatelet therapy received another medication impacted by CYP2C19 in the following year. Given that genotype is stable for a patient's lifetime, this finding has implications for cost effectiveness, patient care, and treatment outcomes beyond the indication for which it was originally performed.
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http://dx.doi.org/10.1038/s41436-020-0894-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7606808PMC
November 2020

Race-based and sex-based differences in bioactive lipid mediators after myocardial infarction.

ESC Heart Fail 2020 08 4;7(4):1700-1710. Epub 2020 May 4.

Department of Neurology, University of Alabama at Birmingham, Birmingham, AL, 35294, USA.

Aims: Leucocyte-directed specialized pro-resolving mediators (SPMs) are essential for cardiac repair, and their biosynthesis coincides with the expression of pro-inflammatory mediators; however, the precise quantitation during an acute myocardial infarction (MI) event is poorly understood in race-specific and sex-specific manner. Coronary heart disease is the leading cause of death and disability in the USA. Although the prevalence of coronary heart disease is similar between Black and White patients, cardiovascular events (including MI), rehospitalization, and mortality are disproportionately higher in Black patients. Therefore, understanding differences in inflammation and resolution can enable the development of predictive, personalized, and precise treatment and attenuate sex/racial disparities. Thus, herein, we assess differences in bioactive lipids and SPMs, between Black and White patients experiencing an acute MI.

Methods And Results: From the PRiME-GGAT cohort, we collected plasma after MI within 24-48 h from 22 Black (15 male and 7 female) and 31 White (23 male and 8 female) subjects for a comparative race-based and sex-based analyses. MI was confirmed using a biochemical measurement of plasma troponin and ST elevation. Plasma levels of three essential polyunsaturated fatty acids [arachidonic acid (AA), docosahexaenoic acid (DHA), and eicosapentaenoic acid (EPA)] and a set of 40 bioactive lipid mediators with major emphasis on SPMs were quantified by liquid chromatography-mass spectrometry. AA and DHA were higher in White male and female patients, and EPA was noted higher only in White male patients compared with White female and Black male and female patients. Lipoxygenase-mediated AA-derived 12-hydroxyeicosatetraenoic acid (29-63%) and 15-hydroxyeicosatetraenoic acid (3-9%) and DHA-derived 17-hydroxydocosahexaenoic acid (3-22%) and 14-hydroxydocosahexaenoic acid (7-10%) were major bioactive lipid mediators in plasma. The SPM signature resolvin E1 was significantly lower in Black patients compared with White male and female patients, whereas protectin D1 was lower in White male patients compared with White female and Black male and female patients.

Conclusion: Our comparative analyses of fatty acids and respective cyclooxygenase-derived and lipoxygenase-derived SPM signatures capture the heterogeneity of disease pathology and elucidate potential mechanisms underlying sex-based and race-based differences following MI.
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http://dx.doi.org/10.1002/ehf2.12730DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7373890PMC
August 2020

Cost-effectiveness of CYP2C19-guided antiplatelet therapy in patients with acute coronary syndrome and percutaneous coronary intervention informed by real-world data.

Pharmacogenomics J 2020 10 11;20(5):724-735. Epub 2020 Feb 11.

Department of Biomedical Informatics, Vanderbilt University Medical Center, Nashville, TN, USA.

Current guidelines recommend dual antiplatelet therapy (DAPT) consisting of aspirin and a P2Y12 inhibitors following percutaneous coronary intervention (PCI). CYP2C19 genotype can guide DAPT selection, prescribing ticagrelor or prasugrel for loss-of-function (LOF) allele carriers (genotype-guided escalation). Cost-effectiveness analyses (CEA) are traditionally grounded in clinical trial data. We conduct a CEA using real-world data using a 1-year decision-analytic model comparing primary strategies: universal empiric clopidogrel (base case), universal ticagrelor, and genotype-guided escalation. We also explore secondary strategies commonly implemented in practice, wherein all patients are prescribed ticagrelor for 30 days post PCI. After 30 days, all patients are switched to clopidogrel irrespective of genotype (nonguided de-escalation) or to clopidogrel only if patients do not harbor an LOF allele (genotype-guided de-escalation). Compared with universal clopidogrel, both universal ticagrelor and genotype-guided escalation were superior with improvement in quality-adjusted life years (QALY's). Only genotype-guided escalation was cost-effective ($42,365/QALY) and demonstrated the highest probability of being cost-effective across conventional willingness-to-pay thresholds. In the secondary analysis, compared with the nonguided de-escalation strategy, although genotype-guided de-escalation and universal ticagrelor were more effective, with ICER of $188,680/QALY and $678,215/QALY, respectively, they were not cost-effective. CYP2C19 genotype-guided antiplatelet prescribing is cost-effective compared with either universal clopidogrel or universal ticagrelor using real-world implementation data. The secondary analysis suggests genotype-guided and nonguided de-escalation may be viable strategies, needing further evaluation.
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http://dx.doi.org/10.1038/s41397-020-0162-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7417282PMC
October 2020

Genetic Factors Influencing Warfarin Dose in Black-African Patients: A Systematic Review and Meta-Analysis.

Clin Pharmacol Ther 2020 06 28;107(6):1420-1433. Epub 2020 Jan 28.

Department of Molecular and Clinical Pharmacology, The Wolfson Centre for Personalized Medicine, MRC Centre for Drug Safety Science, University of Liverpool, Liverpool, UK.

Warfarin is the most commonly used oral anticoagulant in sub-Saharan Africa. Dosing is challenging due to a narrow therapeutic index and high interindividual variability in dose requirements. To evaluate the genetic factors affecting warfarin dosing in black-Africans, we performed a meta-analysis of 48 studies (2,336 patients). Significant predictors for CYP2C9 and stable dose included rs1799853 (CYP2C9*2), rs1057910 (CYP2C9*3), rs28371686 (CYP2C9*5), rs9332131 (CYP2C9*6), and rs28371685 (CYP2C9*11) reducing dose by 6.8, 12.5, 13.4, 8.1, and 5.3 mg/week, respectively. VKORC1 variants rs9923231 (-1639G>A), rs9934438 (1173C>T), rs2359612 (2255C>T), rs8050894 (1542G>C), and rs2884737 (497T>G) decreased dose by 18.1, 21.6, 17.3, 11.7, and 19.6 mg/week, respectively, whereas rs7294 (3730G>A) increased dose by 6.9 mg/week. Finally, rs12777823 (CYP2C gene cluster) was associated with a dose reduction of 12.7 mg/week. Few studies were conducted in Africa, and patient numbers were small, highlighting the need for further work in black-Africans to evaluate genetic factors determining warfarin response.
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http://dx.doi.org/10.1002/cpt.1755DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7217737PMC
June 2020

Severity of Hypertension Mediates the Association of Hyperuricemia With Stroke in the REGARDS Case Cohort Study.

Hypertension 2020 01 2;75(1):246-256. Epub 2019 Dec 2.

Division of Clinical Immunology and Rheumatology (S.L.B., K.G.S., E.J.R., J.R.C., A.G., R.J.R., J.A.S.), University of Alabama at Birmingham.

Previous studies do not widely support hyperuricemia as a risk factor for stroke and other cardiovascular diseases. We assessed the relationship between hyperuricemia and ischemic stroke (≈900 cases) using a large data set from the REGARDS study (Reasons for Geographic and Racial Differences in Stroke). We employed a case-cohort design (incident stroke cases and randomly selected cohort participants) and weighted Cox-proportional hazard models to estimate the association of serum urate level ≥6.8 mg/dL (ie, hyperuricemia) and 6.0 to <6.8 mg/dL versus <6.0 mg/dL (reference) with incident stroke. Analyses were stratified by race, gender, and age. Mediation of cardiovascular disease comorbidities on the serum urate-stroke association was tested. Hyperuricemia was associated with stroke (hazard ratio, 1.40 [95% CI, 1.10-1.78]) after adjustment for demographic variables and systolic and diastolic blood pressure. This association was substantially attenuated (hazard ratio, 1.17 [95% CI, 0.90-1.51]) by additional covariate adjustment. In particular, apparent treatment-resistant hypertension (systolic blood pressure ≥140 mm Hg or diastolic blood pressure ≥90 mm Hg on 3 antihypertensive medications or use of ≥4 antihypertensive medications) and the count of antihypertensive medication classes significantly reduced the effect of hyperuricemia on ischemic stroke. Specifically, apparent treatment-resistant hypertension and number of antihypertensive, respectively, mediate 45% and 43% of the association. There was no effect modification in the association between hyperuricemia and stroke by age, race, or gender. We conclude that hyperuricemia may be a risk factor for stroke. The substantial attenuation of this association by apparent treatment-resistant hypertension and number of antihypertensive suggests that severe hypertension may be a mediator.
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http://dx.doi.org/10.1161/HYPERTENSIONAHA.119.13580DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7122733PMC
January 2020

Risk of Major Adverse Cardiovascular Events and Major Hemorrhage Among White and Black Patients Undergoing Percutaneous Coronary Intervention.

J Am Heart Assoc 2019 11 8;8(22):e012874. Epub 2019 Nov 8.

Department of Neurology University of Alabama at Birmingham AL.

Background Data on racial disparities in major adverse cardiovascular events (MACE) and major hemorrhage (HEM) after percutaneous coronary intervention are limited. Factors contributing to these disparities are unknown. Methods and Results PRiME-GGAT (Pharmacogenomic Resource to Improve Medication Effectiveness-Genotype-Guided Antiplatelet Therapy) is a prospective cohort. Patients aged ≥18 years undergoing percutaneous coronary intervention were enrolled and followed for up to 1 year. Racial disparities in risk of MACE and HEM were assessed using an incident rate ratio. Sequential cumulative adjustment analyses were performed to identify factors contributing to these disparities. Data from 919 patients were included in the analysis. Compared with white patients, black patients (n=203; 22.1% of the cohort) were younger and were more likely to be female, to be a smoker, and to have higher body mass index, lower socioeconomic status, higher prevalence of diabetes mellitus and moderate to severe chronic kidney disease, and presentation with acute coronary syndrome and to undergo urgent percutaneous coronary intervention. The incident rates of MACE (34.1% versus 18.2% per 100 person-years, <0.001) and HEM (17.7% versus 10.3% per 100 person-years, =0.02) were higher in black patients. The incident rate ratio was 1.9 (95% CI, 1.3-2.6; <0.001) for MACE and 1.7 (95% CI, 1.1-2. 7; =0.02) for HEM. After adjustment for nonclinical and clinical factors, black race was not significantly associated with outcomes. Rather, differences in socioeconomic status, comorbidities, and coronary heart disease severity were attributed to racial disparities in outcomes. Conclusions Despite receiving similar treatment, racial disparities in MACE and HEM still exist. Opportunities exist to narrow these disparities by mitigating the identified contributors.
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http://dx.doi.org/10.1161/JAHA.119.012874DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6915255PMC
November 2019

Validation of the Spartan RXCYP2C19 Genotyping Assay Utilizing Blood Samples.

Clin Transl Sci 2020 03 29;13(2):260-264. Epub 2019 Nov 29.

Department of Pathology, University of Alabama at Birmingham, Birmingham, Alabama, USA.

The antiplatelet agent clopidogrel, a prodrug that requires bioactivation through the cytochrome P450 2C19 (CYP2C19) enzyme, is commonly prescribed post-percutaneous coronary intervention (PCI). Genetic variation in CYP2C19 contributes to individual variability in clopidogrel response, and can lead to adverse cardiovascular events. Incorporating CYP2C19 testing during routine clinical care helps identify high-risk patients, and provides the opportunity for pharmacotherapeutic interventions in the early post-PCI period. The Spartan RX CYP2C19 System has emerged as an optimal genotyping assay for use in clinical care due to ease of use, utilization of buccal swabs, and rapid turnaround time. However, workflow constraints related to sample collection and processing, storage, time, and personnel were encountered when integrating testing into clinical care. To improve clinical workflow and successfully implement CYP2C19 genotyping at our institution, we validated the Spartan RX System to return genotype utilizing blood samples. Our Molecular Diagnostic Laboratory tested 26 known reference materials and both blood and buccal swab samples from 23 patients and volunteers using the Spartan RX Assay. Genotype results were 100% concordant between DNA from blood and buccal swabs for all patients or volunteers, and consistent with expected results for the 26 reference materials. For reproducibility, three samples were tested in at least four separate runs, with all resulting genotypes in agreement between runs. Post-validation, the laboratory began offering CYP2C19 testing during clinical care. DNA extracted from blood can serve as a genomic DNA source for the Spartan RX Assay. Alteration of the methodology allowed for clinical implementation to support genotype-guided therapy.
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http://dx.doi.org/10.1111/cts.12714DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7070822PMC
March 2020

Racial differences in adult-onset MRI-negative temporal lobe epilepsy.

Epilepsy Behav 2019 11 28;100(Pt A):106501. Epub 2019 Sep 28.

University of California San Francisco, Department of Neurology, United States of America. Electronic address:

Objective: We recently detected a significant racial difference in our population with temporal lobe epilepsy (TLE) at the University of Alabama at Birmingham (UAB) seizure monitoring unit. We found that Black patients were more likely than their White counterparts to carry a TLE diagnosis. Using this same patient population, we focus on the patients with TLE to better describe the relationship between race and epidemiology in this population.

Methods: We analyzed the data from patients diagnosed with TLE admitted to the UAB seizure monitoring unit between January 2000 and December 2011. For patients with a video electroencephalography (EEG) confirmed diagnosis of TLE (n = 385), basic demographic information including race and magnetic resonance imaging (MRI) findings were collected. Descriptive statistics and multivariate logistic regression were used to explore the relationship between MRI findings, demographic data, and race.

Results: For Black patients with TLE, we found that they were more likely to be female (odds ratio [OR] = 1.91, 95% confidence interval [CI]: 1.14-3.19), have seizure onset in adulthood (OR = 2.39, 95% CI: 1.43-3.19), and have normal MRIs (OR = 1.69, 95% CI: 1.04-2.77) compared to White counterparts with TLE after adjusting for covariates.

Conclusions: These data suggest that Black race (compared to White) is associated with higher expression of adult-onset MRI-negative TLE, an important subtype of epilepsy with unique implications for evaluation, treatment, and prognosis. If validated in other cohorts, the findings may explain the lower reported rates of epilepsy surgery utilization among Blacks. The racial differences in surgical utilization could be due to a greater prevalence of an epilepsy that is less amenable to surgical resection rather than to cultural differences or access to care.
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http://dx.doi.org/10.1016/j.yebeh.2019.106501DOI Listing
November 2019

CYP3A5 genotype affects time to therapeutic tacrolimus level in pediatric kidney transplant recipients.

Pediatr Transplant 2019 08 24;23(5):e13494. Epub 2019 May 24.

Department of Neurology, University of Alabama at Birmingham, Birmingham, Alabama.

Background: Optimal management of immunosuppression in kidney transplantation requires a delicate balance of efficacy and toxicity. Tacrolimus (TAC) dose requirements are significantly impacted by genetic variation in CYP3A5 polymorphisms, however the impact that genotype has on clinical outcomes in the pediatric kidney transplant population remains unclear.

Methods: We evaluated a retrospective cohort of 98 pediatric kidney transplant recipients. The primary exposure was CYP3A5 genotype, which classified each recipient into the expresser (at least one CYP3A5*1 allele) or non-expresser group (only CYP3A5*3 alleles). The primary outcome was time to achieve a steady therapeutic TAC concentration. Secondary outcomes include incidence of early allograft rejection and calcineurin inhibitor (CNI) nephrotoxicity during the first year post-transplant.

Results: The study cohort included 55 (56%) expressers and 43 (44%) non-expressers of the CYP3A5*1 allele. Expressers had a significantly longer time to achieve a steady therapeutic TAC concentration than non-expressers (log rank, P = 0.03). Expressers had a trend for higher incidence of early allograft rejection (29.1% vs 16.3%, log rank, P = 0.16). Early biopsy-proven CNI nephrotoxicity was seen in 60% of recipients, with no differences in the rate between expressers and non-expressers.

Conclusions: Pediatric kidney transplant recipients with the CYP3A5*1 allele (expressers) take a longer time to achieve therapeutic TAC levels than those with the CYP3A5*3 allele (non-expressers). However, we observed no significant differences in acute rejection or CNI nephrotoxicity based on CYP3A5 genotype. Thus CYP3A5 genotype was not observed to have an immediate impact on early transplant outcomes.
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http://dx.doi.org/10.1111/petr.13494DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8009482PMC
August 2019

Between a rock and a hard place: a high-risk patient with resistance to multiple P2Y antagonists.

Pharmacogenomics 2019 05;20(7):475-481

Department of Neurology, School of Medicine, University of Alabama at Birmingham, Birmingham, AL, USA 35294.

Impaired response to P2Y receptor antagonists, such as clopidogrel and prasugrel, can have devastating consequences for patients that require prolonged or indefinite therapy with these agents, including those with a left ventricular assist device (LVAD). While loss-of-function (LOF) alleles in have been elucidated as contributing to high on treatment platelet reactivity (HTPR) during clopidogrel therapy, genetic variations in the metabolic pathway of prasugrel have not been shown to elicit this same effect. Moreover, limited studies have assessed the effect of coexisting genetic variations in pharmacokinetic and pharmacodynamic pathways. Herein, we report a left ventricular assist device patient exhibiting high on treatment platelet reactivity during clopidogrel and prasugrel therapy. Genotyping revealed variants in pharmacokinetic (), and pharmacodynamic pathways, with multiple variants in P2Y, the target receptor.
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http://dx.doi.org/10.2217/pgs-2018-0201DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6563016PMC
May 2019

Multi-site investigation of strategies for the clinical implementation of CYP2D6 genotyping to guide drug prescribing.

Genet Med 2019 10 21;21(10):2255-2263. Epub 2019 Mar 21.

Department of Medicine, Division of Clinical Pharmacology, Indiana University School of Medicine, Indianapolis, IN, USA.

Purpose: A number of institutions have clinically implemented CYP2D6 genotyping to guide drug prescribing. We compared implementation strategies of early adopters of CYP2D6 testing, barriers faced by both early adopters and institutions in the process of implementing CYP2D6 testing, and approaches taken to overcome these barriers.

Methods: We surveyed eight early adopters of CYP2D6 genotyping and eight institutions in the process of adoption. Data were collected on testing approaches, return of results procedures, applications of genotype results, challenges faced, and lessons learned.

Results: Among early adopters, CYP2D6 testing was most commonly ordered to assist with opioid and antidepressant prescribing. Key differences among programs included test ordering and genotyping approaches, result reporting, and clinical decision support. However, all sites tested for copy-number variation and nine common variants, and reported results in the medical record. Most sites provided automatic consultation and had designated personnel to assist with genotype-informed therapy recommendations. Primary challenges were related to stakeholder support, CYP2D6 gene complexity, phenotype assignment, and sustainability.

Conclusion: There are specific challenges unique to CYP2D6 testing given the complexity of the gene and its relevance to multiple medications. Consensus lessons learned may guide those interested in pursuing similar clinical pharmacogenetic programs.
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http://dx.doi.org/10.1038/s41436-019-0484-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6754805PMC
October 2019

Improvement in Kidney Function After Ventricular Assist Device Implantation and Its Influence on Thromboembolism, Hemorrhage, and Mortality.

ASAIO J 2020 03;66(3):268-276

From the Department of Neurology, Department of Medicine, University of Alabama at Birmingham, Birmingham, Alabama.

Although heart transplantation remains the gold standard for management of heart failure, ventricular assist devices (VAD) have emerged as viable alternatives. VAD implantation improves kidney function. However, whether the improvement is sustained or associated with improved outcomes is unclear. Herein we assess kidney function improvement, predictors of improvement, and associations with thromboembolism, hemorrhage, and mortality in VAD patients. Kidney function was defined using chronic kidney disease (CKD) stages: stage 1 (glomerular filtration rate [eGFR] ≥ 90 ml/min/1.73 m), stage 2 (eGFR 60-90 ml/min/1.73 m), stage 3a (eGFR 45-59 ml/min/1.73 m), stage 3b (eGFR 30-44 ml/min/1.73 m), stage 4 (eGFR 15-30 ml/min/1.73 m), and stage 5 (eGFR < 15 ml/min/1.73 m). Improvement in kidney function was defined as an improvement in eGFR that resulted in a CKD stage change to one of lesser severity. Kidney function improved post implant, and was maintained over 1 year for all patients, except those with baseline stage 5 CKD. Younger age at implantation (OR 0.93, 95% CI: 0.90-0.96, P < 0.0001) was associated with sustained improvement in kidney function. Poor kidney function was associated increased mortality but not with thromboembolism or hemorrhage. Compared to patients with baseline eGFR > 45 ml/min/1.73 m; patients with eGFR < 45 ml/min/1.73 m had a higher mortality risk (HR 3.32, 95% CI: 1.10-9.98, p = 0.03 for stage 3b; HR 4.07, 95% CI: 1.27-13.1, p = 0.02 for stage 4; and HR 4.01, 95% CI: 1.17-13.7, p = 0.03 for stage 5 CKD). Kidney function was not associated with thromboembolism or hemorrhage, and sustained improvement was not associated with lower risk of death. However, poor kidney function at implantation was associated with an increased risk of mortality.
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http://dx.doi.org/10.1097/MAT.0000000000000989DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6744354PMC
March 2020

Circulating myocardial microRNAs from infarcted hearts are carried in exosomes and mobilise bone marrow progenitor cells.

Nat Commun 2019 02 27;10(1):959. Epub 2019 Feb 27.

Department of Biomedical Engineering, University of Alabama at Birmingham, School of Medicine and School of Engineering, 35294, Birmingham, AL, USA.

Myocardial microRNAs (myo-miRs) are released into the circulation after acute myocardial infarction (AMI). How they impact remote organs is however largely unknown. Here we show that circulating myo-miRs are carried in exosomes and mediate functional crosstalk between the ischemic heart and the bone marrow (BM). In mice, we find that AMI is accompanied by an increase in circulating levels of myo-miRs, with miR-1, 208, and 499 predominantly in circulating exosomes and miR-133 in the non-exosomal component. Myo-miRs are imported selectively to peripheral organs and preferentially to the BM. Exosomes mediate the transfer of myo-miRs to BM mononuclear cells (MNCs), where myo-miRs downregulate CXCR4 expression. Injection of exosomes isolated from AMI mice into wild-type mice downregulates CXCR4 expression in BM-MNCs and increases the number of circulating progenitor cells. Thus, we propose that myo-miRs carried in circulating exosomes allow a systemic response to cardiac injury that may be leveraged for cardiac repair.
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http://dx.doi.org/10.1038/s41467-019-08895-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6393447PMC
February 2019

Effect of CYP4F2, VKORC1, and CYP2C9 in Influencing Coumarin Dose: A Single-Patient Data Meta-Analysis in More Than 15,000 Individuals.

Clin Pharmacol Ther 2019 06 17;105(6):1477-1491. Epub 2019 Feb 17.

Department of Clinical Pharmacology & Genetics, School of Pharmaceutical Sciences, University of Shizuoka, Shizuoka, Japan.

The cytochrome P450 (CYP)4F2 gene is known to influence mean coumarin dose. The aim of the present study was to undertake a meta-analysis at the individual patients level to capture the possible effect of ethnicity, gene-gene interaction, or other drugs on the association and to verify if inclusion of CYP4F2*3 variant into dosing algorithms improves the prediction of mean coumarin dose. We asked the authors of our previous meta-analysis (30 articles) and of 38 new articles retrieved by a systematic review to send us individual patients' data. The final collection consists of 15,754 patients split into a derivation and validation cohort. The CYP4F2*3 polymorphism was consistently associated with an increase in mean coumarin dose (+9% (95% confidence interval (CI) 7-10%), with a higher effect in women, in patients taking acenocoumarol, and in white patients. The inclusion of the CYP4F2*3 in dosing algorithms slightly improved the prediction of stable coumarin dose. New pharmacogenetic equations potentially useful for clinical practice were derived.
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http://dx.doi.org/10.1002/cpt.1323DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6542461PMC
June 2019

Pharmacogenetics of warfarin dosing in patients of African and European ancestry.

Pharmacogenomics 2018 11 22;19(17):1357-1371. Epub 2018 Oct 22.

Department of Neurology, School of Medicine, University of Alabama at Birmingham, AL 35294, USA.

Despite the introduction of direct acting oral anticoagulants, warfarin remains the most commonly prescribed oral anticoagulant. However, warfarin therapy is plagued by the large inter- and intrapatient variability. The variability in dosing fueled research to identify clinical and genetic predictors and develop more accurate dosing algorithms. Observational studies have demonstrated the significant impact of single nucleotide polymorphisms in CYP2C9 and VKORC1 on warfarin dose in patients of European ancestry and African-Americans. This evidence supported the design and conduct of clinical trials to assess whether genotype-guided dosing results in improved anticoagulation control and outcomes. The trial results have shown discordance by race, with pharmacogenetic algorithms improving dose and anticoagulation control among European ancestry patients compared with African-American patients. Herein, we review the evidence from observational and interventional studies, highlight the need for inclusion of minority race groups and propose the need to develop race specific dosing algorithms.
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http://dx.doi.org/10.2217/pgs-2018-0146DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6562764PMC
November 2018

Genome-wide meta-analysis of SNP-by9-ACEI/ARB and SNP-by-thiazide diuretic and effect on serum potassium in cohorts of European and African ancestry.

Pharmacogenomics J 2019 02 1;19(1):97-108. Epub 2018 Jun 1.

Division of Biomedical Informatics and Personalized Medicine, Department of Medicine, University of Colorado Anschutz Medical Campus, Aurora, CO, USA.

We evaluated interactions of SNP-by-ACE-I/ARB and SNP-by-TD on serum potassium (K+) among users of antihypertensive treatments (anti-HTN). Our study included seven European-ancestry (EA) (N = 4835) and four African-ancestry (AA) cohorts (N = 2016). We performed race-stratified, fixed-effect, inverse-variance-weighted meta-analyses of 2.5 million SNP-by-drug interaction estimates; race-combined meta-analysis; and trans-ethnic fine-mapping. Among EAs, we identified 11 significant SNPs (P < 5 × 10) for SNP-ACE-I/ARB interactions on serum K+ that were located between NR2F1-AS1 and ARRDC3-AS1 on chromosome 5 (top SNP rs6878413 P = 1.7 × 10; ratio of serum K+ in ACE-I/ARB exposed compared to unexposed is 1.0476, 1.0280, 1.0088 for the TT, AT, and AA genotypes, respectively). Trans-ethnic fine mapping identified the same group of SNPs on chromosome 5 as genome-wide significant for the ACE-I/ARB analysis. In conclusion, SNP-by-ACE-I /ARB interaction analyses uncovered loci that, if replicated, could have future implications for the prevention of arrhythmias due to anti-HTN treatment-related hyperkalemia. Before these loci can be identified as clinically relevant, future validation studies of equal or greater size in comparison to our discovery effort are needed.
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http://dx.doi.org/10.1038/s41397-018-0021-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6274589PMC
February 2019

Genetic deletion of 12/15 lipoxygenase promotes effective resolution of inflammation following myocardial infarction.

J Mol Cell Cardiol 2018 05 8;118:70-80. Epub 2018 Mar 8.

Division of Cardiovascular Disease, Department of Medicine, The University of Alabama at Birmingham, AL, USA. Electronic address:

12/15 lipoxygenase (LOX) directs inflammation and lipid remodeling. However, the role of 12/15LOX in post-myocardial infarction (MI) left ventricular remodeling is unclear. To determine the role of 12/15LOX, 8-12 week-old C57BL/6 J wild-type (WT; n = 93) and 12/15LOX (n = 97) mice were subjected to permanent coronary artery ligation and monitored at day (d)1 and d5 post-operatively. Post-MI d28 survival was measured in male and female mice. No-MI surgery mice were maintained as d0 naïve controls. 12/15LOX mice exhibited higher survival rates with lower cardiac rupture and improved LV function as compared with WT post-MI. Compared to WT, neutrophils and macrophages in 12/15LOX mice were polarized towards N2 and M2 phenotypes, respectively, with increased of expression mrc-1, ym-1, and arg-1 post-MI. 12/15LOX mice exhibited lower levels of pro-inflammatory 12-(S)-hydroperoxyeicosatetraenoic acid (12(S)-HETE) and higher CYP2J-derived epoxyeicosatrienoic acids (EETs) levels. CYP2J-derived 5,6-, 8,9-, 11,12-, and 14,15-EETs activated macrophage-specific hemeoxygenase (HO)-1 marked with increases in F4/80/Ly6C and F4/80/CD206 cells at d5 post-MI in 12/15LOX mice. In contrast, inhibition of HO-1 led to total mortality in 12/15LOX mice by post-MI d5. 12/15LOX mice exhibited reduced collagen density and lower α-smooth muscle actin (SMA) expression at d5 post-MI, indicating delayed or limited fibroblast-to-myofibroblast differentiation. In conclusion, genetic deletion of 12/15LOX reduces 12(S)-HETE and activates CYP2J-derived EETs to promote effective resolution of inflammation post-MI leading to reduced cardiac rupture, improved LV function, and better survival.
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http://dx.doi.org/10.1016/j.yjmcc.2018.03.004DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5940552PMC
May 2018

Influence of Age on Warfarin Dose, Anticoagulation Control, and Risk of Hemorrhage.

Pharmacotherapy 2018 06 27;38(6):588-596. Epub 2018 Feb 27.

Department of Neurology, School of Medicine, University of Alabama at Birmingham, Birmingham, Alabama.

Objective: We assessed the influence of age on warfarin dose, percentage time in target range (PTTR), and risk of major hemorrhage.

Design: Warfarin users recruited into a large prospective inception cohort study were categorized into three age groups: young (younger than 50 yrs), middle aged (50-70 yrs), and elderly (older than 70 yrs). The influence of age on warfarin dose and PTTR was assessed using regression analysis; risk of major hemorrhage was assessed using proportional hazards analysis. Models were adjusted for demographic, clinical, and genetic factors.

Setting: Two outpatient anticoagulation clinics.

Participants: A total of 1498 anticoagulated patients.

Outcomes: Warfarin dose (mg/day), PTTR, major hemorrhage.

Results: Of the 1498 patients, 22.8% were young, 44.1% were middle aged, and 33.1% were elderly. After accounting for clinical and genetic factors, compared with young warfarin users, warfarin dose requirements were 10.6% lower among the middle aged and an additional 10.6% lower for the elderly. Compared with young patients, middle-aged and elderly patients spent more time in target international normalized ratio (INR) range (p<0.0001), despite having fewer INR assessments (p<0.0001). Compared with young warfarin users, absolute risk of hemorrhage was marginally higher among the middle aged (p=0.08) and significantly higher among the elderly (p=0.016). Compared with young warfarin users, after adjustment, the relative risk of hemorrhage increased by 31% for each age category (p=0.026).

Conclusions: In a real-world setting, despite achieving better anticoagulation control, elderly patients had a higher risk of major hemorrhagic events. As the population ages and the candidacy for oral anticoagulation increases, strategies that mitigate the elevated risk of hemorrhage need to be identified.
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http://dx.doi.org/10.1002/phar.2089DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6014885PMC
June 2018

Multisite Investigation of Strategies for the Implementation of CYP2C19 Genotype-Guided Antiplatelet Therapy.

Clin Pharmacol Ther 2018 10 30;104(4):664-674. Epub 2018 Jan 30.

Division of Pharmacotherapy and Experimental Therapeutics, Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA.

CYP2C19 genotype-guided antiplatelet therapy following percutaneous coronary intervention is increasingly implemented in clinical practice. However, challenges such as selecting a testing platform, communicating test results, building clinical decision support processes, providing patient and provider education, and integrating methods to support the translation of emerging evidence to clinical practice are barriers to broad adoption. In this report, we compare and contrast implementation strategies of 12 early adopters, describing solutions to common problems and initial performance metrics for each program. Key differences between programs included the test result turnaround time and timing of therapy changes, which are both related to the CYP2C19 testing model and platform used. Sites reported the need for new informatics infrastructure, expert clinicians such as pharmacists to interpret results, physician champions, and ongoing education. Consensus lessons learned are presented to provide a path forward for those seeking to implement similar clinical pharmacogenomics programs within their institutions.
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http://dx.doi.org/10.1002/cpt.1006DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6019555PMC
October 2018
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