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1.  Symptom Frequency, Severity, and Quality of Life among Persons with Three Disease Trajectories: Cancer, ALS, and CHF 
Applied nursing research : ANR  2015;28(4):311-315.
Purpose
National reports on end-of-life symptom management reveal a gap in the evidence regarding symptoms other than pain and studies of diseases other than cancer. This study examines the frequency and severity of symptoms and quality of life (QOL) in persons with advanced cancer, amyotrophic lateral sclerosis (ALS), and congestive heart failure (CHF).
Methods
The present study is a cross-sectional examination of symptoms and QOL measured using the McGill QOL Questionnaire, among 147 participants.
Results
Forty one percent of participants had advanced cancer, 22% had ALS, and 37% had advanced CHF. A total of 266 symptoms were reported, with the common symptom categories being discomfort/pain, weakness/fatigue/sleep, and respiratory. Participants with CHF had the highest mean symptom severity and the lowest QOL.
Conclusion
Clinicians should be aware and attentive for symptoms other than pain in patients with advanced illness. Studies on diseases other than cancer, such as CHF and ALS, are important to improve symptom management in all disease groups.
doi:10.1016/j.apnr.2015.03.005
PMCID: PMC4661438  PMID: 26608431
Chronic Disease; End of Life; Symptoms; Quality of Life
2.  PTPRD gene associated with blood pressure response to atenolol and resistant hypertension 
Journal of hypertension  2015;33(11):2278-2285.
Objective
The aim of this study is to identify single-nucleotide polymorphisms (SNPs) influencing blood pressure (BP) response to the β-blocker atenolol.
Methods
Genome-wide association analysis of BP response to atenolol monotherapy was performed in 233 white participants with uncomplicated hypertension in the pharmacogenomic evaluation of antihypertensive responses study. Forty-two polymorphisms with P less than 10−5 for association with either diastolic or systolic response to atenolol monotherapy were validated in four independent groups of hypertensive individuals (total n = 2114).
Results
In whites, two polymorphisms near the gene PTPRD (rs12346562 and rs1104514) were associated with DBP response to atenolol (P = 3.2 × 10−6 and P = 5.9 × 10−6, respectively) with directionally opposite association for response to hydrochlorothiazide in another group of 228 whites (P = 0.0018 and P = 0.00012). A different polymorphism (rs10739150) near PTPRD was associated with response to atenolol in 150 black hypertensive individuals (P = 8.25 ×10−6). rs12346562 had a similar trend in association with response to bisoprolol (a different β-blocker) in 207 Finnish men in the genetics of drug responsiveness in essential hypertension study. In addition, an intronic single-nucleotide polymorphism (rs4742610) in the PTPRD gene was associated with resistant hypertension in whites and Hispanics in the international verapamil SR trandolapril study (meta-analysis P = 3.2 × 10−5).
Conclusion
PTPRD was identified as a novel locus potentially associated with BP response to atenolol and resistant hypertension in multiple ethnic groups.
doi:10.1097/HJH.0000000000000714
PMCID: PMC4788379  PMID: 26425837
atenolol; blood pressure response; genome-wide association study; pharmacogenomic evaluation of antihypertensive responses; pharmacogenomics; PTPRD; resistant hypertension
3.  “URM Candidates Are Encouraged to Apply”: A National Study to Identify Effective Strategies to Enhance Racial and Ethnic Faculty Diversity in Academic Departments of Medicine 
Purpose
There is little evidence regarding which factors and strategies are associated with high proportions of underrepresented minority (URM) faculty in academic medicine. The authors conducted a national study of U.S. academic medicine departments to better understand the challenges, successful strategies, and predictive factors for enhancing racial and ethnic diversity among faculty (i.e., physicians with an academic position or rank).
Method
This was a mixed-methods study using quantitative and qualitative methods. The authors conducted a cross-sectional study of eligible departments of medicine in 125 accredited U.S. medical schools, dichotomized into low-URM (bottom 50%) versus high-URM rank (top 50%). They used t tests and chi-squared tests to compare departments by geographic region, academic school rank, city type, and composite measures of “diversity best practices.” The authors also conducted semistructured in-depth interviews with a subsample from the highest-and lowest-quartile medical schools in terms of URM rank.
Results
Eighty-two medical schools responded (66%). Geographic region and academic rank were statistically associated with URM rank, but not city type or composite measures of diversity best practices. Key themes emerged from interviews regarding successful strategies for URM faculty recruitment and retention including institutional leadership, the use of human capital and social relationships and strategic deployment of institutional resources.
Conclusions
Departments of medicine with high proportions of URM faculty employ a number of successful strategies and programs for recruitment and retention. More research is warranted to identify new successful strategies and to determine the impact of specific strategies on establishing and maintaining workforce diversity.
doi:10.1097/ACM.0b013e318280d9f9
PMCID: PMC5044757  PMID: 23348090
4.  Effects of Using Personal Genotype Data on Student Learning and Attitudes in a Pharmacogenomics Course 
Objective. To evaluate the impact of personal genotyping and a novel educational approach on student attitudes, knowledge, and beliefs regarding pharmacogenomics and genomic medicine.
Methods. Two online elective courses (pharmacogenomics and genomic medicine) were offered to student pharmacists at the University of Florida using a flipped-classroom, patient-centered teaching approach. In the pharmacogenomics course, students could be genotyped and apply results to patient cases.
Results. Thirty-four and 19 student pharmacists completed the pharmacogenomics and genomic medicine courses, respectively, and 100% of eligible students (n=34) underwent genotyping. Student knowledge improved after the courses. Seventy-four percent (n=25) of students reported better understanding of pharmacogenomics based on having undergone genotyping.
Conclusions. Completion of a novel pharmacogenomics elective course sequence that incorporated personal genotyping and genomic medicine was associated with increased student pharmacist knowledge and improved clinical confidence with pharmacogenomics.
doi:10.5688/ajpe807122
PMCID: PMC5066925  PMID: 27756930
pharmacogenomics; pharmacogenetics; genomics; genetics; personalized medicine
5.  Pharmacogenomics: Challenges and Opportunities 
Annals of internal medicine  2006;145(10):749-757.
The outcome of drug therapy is often unpredictable, ranging from beneficial effects to lack of efficacy to serious adverse effects. Variations in single genes are 1 well-recognized cause of such unpredictability, defining the field of pharmacogenetics (see Glossary). Such variations may involve genes controlling drug metabolism, drug transport, disease susceptibility, or drug targets. The sequencing of the human genome and the cataloguing of variants across human genomes are the enabling resources for the nascent field of pharmacogenomics (see Glossary), which tests the idea that genomic variability underlies variability in drug responses. However, there are many challenges that must be overcome to apply rapidly accumulating genomic information to understand variable drug responses, including defining candidate genes and pathways; relating disease genes to drug response genes; precisely defining drug response phenotypes; and addressing analytic, ethical, and technological issues involved in generation and management of large drug response data sets. Overcoming these challenges holds the promise of improving new drug development and ultimately individualizing the selection of appropriate drugs and dosages for individual patients.
PMCID: PMC5006954  PMID: 17116919
6.  Population‐specific single‐nucleotide polymorphism confers increased risk of venous thromboembolism in African Americans 
Abstract
Introduction
African Americans have a higher incidence of venous thromboembolism (VTE) than European descent individuals. However, the typical genetic risk factors in populations of European descent are nearly absent in African Americans, and population‐specific genetic factors influencing the higher VTE rate are not well characterized.
Methods
We performed a candidate gene analysis on an exome‐sequenced African American family with recurrent VTE and identified a variant in Protein S (PROS1) V510M (rs138925964). We assessed the population impact of PROS1 V510M using a multicenter African American cohort of 306 cases with VTE compared to 370 controls. Additionally, we compared our case cohort to a background population cohort of 2203 African Americans in the NHLBI GO Exome Sequencing Project (ESP).
Results
In the African American family with recurrent VTE, we found prior laboratories for our cases indicating low free Protein S levels, providing functional support for PROS1 V510M as the causative mutation. Additionally, this variant was significantly enriched in the VTE cases of our multicenter case–control study (Fisher's Exact Test, P = 0.0041, OR = 4.62, 95% CI: 1.51–15.20; allele frequencies – cases: 2.45%, controls: 0.54%). Similarly, PROS1 V510M was also enriched in our VTE case cohort compared to African Americans in the ESP cohort (Fisher's Exact Test, P = 0.010, OR = 2.28, 95% CI: 1.26–4.10).
Conclusions
We found a variant, PROS1 V510M, in an African American family with VTE and clinical laboratory abnormalities in Protein S. Additionally, we found that this variant conferred increased risk of VTE in a case–control study of African Americans. In the ESP cohort, the variant is nearly absent in ESP European descent subjects (n = 3, allele frequency: 0.03%). Additionally, in 1000 Genomes Phase 3 data, the variant only appears in African descent populations. Thus, PROS1 V510M is a population‐specific genetic risk factor for VTE in African Americans.
doi:10.1002/mgg3.226
PMCID: PMC5023936  PMID: 27652279
African American; hypercoagulability; pulmonary embolism; venous thromboembolism
7.  Genome-wide association study of warfarin maintenance dose in a Brazilian sample 
Pharmacogenomics  2015;16(11):1-11.
Aim
Extreme discordant phenotype and genome-wide association (GWA) approaches were combined to explore the role of genetic variants on warfarin dose requirement in Brazilians.
Methods
Patients receiving low (≤20 mg/week; n = 180) or high stable warfarin doses (≥42.5 mg/week; n = 187) were genotyped with Affymetrix Axiom® Biobank arrays. Imputation was carried out using data from the combined 1000 Genomes project.
Results
Genome-wide signals (p ≤5 × 10−8) were identified in the well-known VKORC1 (lead SNP, rs749671; OR: 20.4; p = 1.08 × 10−33) and CYP2C9 (lead SNP, rs9332238, OR: 6.8 and p = 4.4 × 10−13) regions. The rs9332238 polymorphism is in virtually perfect LD with CYP2C9*2 (rs1799853) and CYP2C9*3 (rs1057910). No other genome-wide significant regions were identified in the study.
Conclusion
We confirmed the important role of VKORC1 and CYP2C9 polymorphisms in warfarin dose.
doi:10.2217/PGS.15.73
PMCID: PMC4573240  PMID: 26265036
1000 Genomes Project; Brazilians; CYP2C9; extreme discordant phenotypes; genome-wide association study; VKORC1; warfarin
8.  TET2 and CSMD1genes affect SBP response to hydrochlorothiazide in never-treated essential hypertensives 
Journal of hypertension  2015;33(6):1301-1309.
Background
Thiazide diuretics have been recommended as a first-line antihypertensive treatment, although the choice of ‘the right drug in the individual essential hypertensive patient’ remains still empirical. Essential hypertension is a complex, polygenic disease derived from the interaction of patient’s genetic background with the environment. Pharmacogenomics could be a useful tool to pinpoint gene variants involved in antihypertensive drug response, thus optimizing therapeutic advantages and minimizing side effects.
Methods and results
We looked for variants associated with blood pressure response to hydrochlorothiazide over an 8-week follow-up by means of a genome-wide association analysis in two Italian cohorts of never-treated essential hypertensive patients: 343 samples from Sardinia and 142 from Milan. TET2 and CSMD1 as plausible candidate genes to affect SBP response to hydrochlorothiazide were identified. The specificity of our findings for hydrochlorothiazide was confirmed in an independent cohort of essential hypertensive patients treated with losartan. Our best findings were also tested for replication in four independent hypertensive samples of European Ancestry, such as GENetics of drug RESponsiveness in essential hypertension, Genetic Epidemiology of Responses to Antihypertensives, NORdic DILtiazem intervention, Pharmacogenomics Evaluation of Antihypertensive Responses, and Campania Salute Network-StayOnDiur. We validated a polymorphism in CSMD1 and UGGT2.
Conclusion
This exploratory study reports two plausible loci associated with SBP response to hydrochlorothiazide: TET2, an aldosterone-responsive mediator of αENaC gene transcription; and CSMD1, previously described as associated with hypertension in a case–control study.
doi:10.1097/HJH.0000000000000541
PMCID: PMC4484731  PMID: 25695618
essential hypertension; genome-wide association study; genomics; pharmacogenomics; thiazides diuretics
9.  Association of Branched and Aromatic Amino Acids Levels with Metabolic Syndrome and Impaired Fasting Glucose in Hypertensive Patients 
Abstract
Background: The three branched amino acids (valine, leucine, and isoleucine) and two aromatic amino acids (tyrosine and phenylalanine) have been associated with many adverse metabolic pathways, including diabetes. However, these associations have been identified primarily in otherwise healthy Caucasian populations. We aimed to investigate the association of this five-amino-acid signature with metabolic syndrome and impaired fasting glucose (IFG) in a hypertensive cohort of Caucasian and African Americans.
Methods: We analyzed data from the Pharmacogenomic Evaluation of Antihypertensive Responses (PEAR) studies PEAR and PEAR2 conducted between 2005 and 2014. Subjects were enrolled at the University of Florida (Gainesville, FL), Emory University (Atlanta, GA), and Mayo Clinic (Rochester, MN). A total of 898 patients with essential hypertension were included in this study. Presence of metabolic syndrome and IFG at baseline were determined on the basis of measurements of demographic and biochemical data. Levels of the five amino acids were quantified by liquid chromatography–tandem mass spectroscopy (LC-MS/MS).
Results: With a multiple logistic regression model, we found that all five amino acids were significantly associated with metabolic syndrome in both Caucasian and African Americans. IFG and the five amino acids were associated in the Caucasian Americans. Only valine was significantly associated with IFG in African Americans.
Conclusion: In both Caucasian and African Americans with uncomplicated hypertension, plasma levels of the five-amino-acid signature are associated with metabolic syndrome. Additionally, in Caucasians we have confirmed the five-amino-acid signature was associated with IFG.
doi:10.1089/met.2014.0132
PMCID: PMC4519105  PMID: 25664967
10.  Vascular Smooth Muscle Cells From Hypertensive Patient-Derived Induced Pluripotent Stem Cells to Advance Hypertension Pharmacogenomics 
Stem Cells Translational Medicine  2015;4(12):1380-1390.
Induced pluripotent stem cell (iPSC) technology provides a great interface to bring the cells of hyptertensive patients with their genomic data into the laboratory and to study hypertensive responses. As an initial step, the present study established an iPSC bank from patients with primary hypertension and demonstrated an effective and reproducible method of generating functional vascular smooth muscle cells.
Studies in hypertension (HTN) pharmacogenomics seek to identify genetic sources of variable antihypertensive drug response. Genetic association studies have detected single-nucleotide polymorphisms (SNPs) that link to drug responses; however, to understand mechanisms underlying how genetic traits alter drug responses, a biological interface is needed. Patient-derived induced pluripotent stem cells (iPSCs) provide a potential source for studying otherwise inaccessible tissues that may be important to antihypertensive drug response. The present study established multiple iPSC lines from an HTN pharmacogenomics cohort. We demonstrated that established HTN iPSCs can robustly and reproducibly differentiate into functional vascular smooth muscle cells (VSMCs), a cell type most relevant to vasculature tone control. Moreover, a sensitive traction force microscopy assay demonstrated that iPSC-derived VSMCs show a quantitative contractile response on physiological stimulus of endothelin-1. Furthermore, the inflammatory chemokine tumor necrosis factor α induced a typical VSMC response in iPSC-derived VSMCs. These studies pave the way for a large research initiative to decode biological significance of identified SNPs in hypertension pharmacogenomics.
Significance
Treatment of hypertension remains suboptimal, and a pharmacogenomics approach seeks to identify genetic biomarkers that could be used to guide treatment decisions; however, it is important to understand the biological underpinnings of genetic associations. Mouse models do not accurately recapitulate individual patient responses based on their genetics, and hypertension-relevant cells are difficult to obtain from patients. Induced pluripotent stem cell (iPSC) technology provides a great interface to bring patient cells with their genomic data into the laboratory and to study hypertensive responses. As an initial step, the present study established an iPSC bank from patients with primary hypertension and demonstrated an effective and reproducible method of generating functional vascular smooth muscle cells.
doi:10.5966/sctm.2015-0126
PMCID: PMC4675511  PMID: 26494780
Hypertension; Induced pluripotent stem cells; Personalized medicine; Vascular smooth muscle cells
11.  Pharmacogenomics of antihypertensive drugs: past, present and future 
Pharmacogenomics  2010;11(4):487-491.
Hypertension pharmacogenomics holds the promise of leading to individualized drug treatment approaches for the approximately 1 billion individuals worldwide with hypertension. Prior to 2000, the literature on hypertension pharmacogenomics was quite limited. The last decade has seen a substantial growth in the literature, with several examples of genes that appear to play an important role in antihypertensive response. The last decade has also made apparent the numerous challenges in hypertension pharmacogenomics, and addressing those challenges will be important. Moving forward, it seems clear that collaboration among researchers to allow replication or joint analyses will be essential in advancing the field, as will the use of genome-wide association approaches. The next decade should clearly define the clinical potential for hypertension pharmacogenomics.
doi:10.2217/pgs.10.34
PMCID: PMC4867543  PMID: 20350127
β-blockers; ACE inhibitors; angiotensin receptor blockers; antihypertensive; calcium channel blockers; hypertension; pharmacogenetics; pharmacogenomics; thiazide diuretics
12.  Exposure Profiling of Reactive Compounds in Complex Mixtures 
Toxicology  2012;313(2-3):145-150.
Humans are constantly exposed to mixtures, such as tobacco smoke, exhaust from diesel, gasoline or new bio-fuels, containing several thousand compounds, including many known human carcinogens. Covalent binding of reactive compounds or their metabolites to DNA and formation of stable adducts is believed to be the causal link between exposure and carcinogenesis. DNA and protein adducts are well established biomarkers for the internal dose of reactive compounds or their metabolites and are an integral part of science-based risk assessment. However, technical limitations have prevented comprehensive detection of a broad spectrum of adducts simultaneously. Therefore, most studies have focused on measurement of abundant individual adducts. These studies have produced valuable insight into the metabolism of individual carcinogens, but they are insufficient for risk assessment of exposure to complex mixtures. To overcome this limitation, we present herein proof-of-principle for comprehensive exposure assessment, using N-terminal valine adduct profiles as a biomarker. The reported method is based on our previously established immunoaffinity liquid chromatography-tandem mass spectrometry (LC-MS/MS) method with modification to enrich all N-terminal valine alkylated peptides. The method was evaluated using alkylated peptide standards and globin reacted in vitro with alkylating agents (1,2-epoxy-3-butene, 1,2:3,4-diepoxybutane, propylene oxide, styrene oxide, N-ethyl-N-nitrosourea and methyl methanesulfonate), known to form N-terminal valine adducts. To demonstrate proof-of-principle, the method was successfully applied to globin from mice treated with four model compounds. The results suggest that this novel approach might be suitable for in vivo biomonitoring.
doi:10.1016/j.tox.2012.11.012
PMCID: PMC4868061  PMID: 23219592
N-terminal valine adducts; multiple exposure detection; biomonitoring; mixtures; biomarkers
13.  Future Translational Applications From the Contemporary Genomics Era 
Circulation  2015;131(19):1715-1736.
The field of genetics and genomics has advanced considerably with the achievement of recent milestones encompassing the identification of many loci for cardiovascular disease and variable drug responses. Despite this achievement, a gap exists in the understanding and advancement to meaningful translation that directly affects disease prevention and clinical care. The purpose of this scientific statement is to address the gap between genetic discoveries and their practical application to cardiovascular clinical care. In brief, this scientific statement assesses the current timeline for effective translation of basic discoveries to clinical advances, highlighting past successes. Current discoveries in the area of genetics and genomics are covered next, followed by future expectations, tools, and competencies for achieving the goal of improving clinical care.
doi:10.1161/CIR.0000000000000211
PMCID: PMC4825323  PMID: 25882488
AHA Scientific Statements; adrenergic beta-antagonists; DNA; genetics; genome-wide association study; HapMap Project; Human Genome Project; PCSK9 protein; mouse; polymorphism; single nucleotide
14.  Transethnic meta-analysis suggests genetic variation in the HEME pathway influences potassium response in patients treated with hydrochlorothiazide 
The pharmacogenomics journal  2014;15(2):153-157.
Hypokalemia is a recognized adverse effect of thiazide diuretic treatment. This phenomenon, which may impair insulin secretion, has been suggested to be a reason for the adverse effects on glucose metabolism associated with thiazide diuretic treatment of hypertension. However, the mechanisms underlying thiazide diuretic induced hypokalemia are not well-understood. In an effort to identify, genes or genomic regions associated with potassium response to hydrochlorothiazide, without a priori knowledge of biologic effects; we performed a genome-wide association study and a Multi-Ethnic Meta-Analysis in 718 European- and African-American hypertensive participants from two different pharmacogenetic studies. SNPs rs10845697 (Bayes Factor=5.560) on chromosome 12, near to the HEME binding protein 1 gene, and rs11135740 (Bayes Factor= 5.258) on chromosome 8 near the Mitoferrin-1 gene reached GWAS significance (Bayes Factor > 5). These results, if replicated, suggest a novel mechanism involving effects of genes in the HEME pathway influencing hydrochlorothiazide-induced renal potassium loss.
doi:10.1038/tpj.2014.46
PMCID: PMC4362777  PMID: 25201287
Pharmacogenomics; hydrochlorothiazide; hypokalemia; HEME
15.  The IGNITE network: a model for genomic medicine implementation and research 
Background
Patients, clinicians, researchers and payers are seeking to understand the value of using genomic information (as reflected by genotyping, sequencing, family history or other data) to inform clinical decision-making. However, challenges exist to widespread clinical implementation of genomic medicine, a prerequisite for developing evidence of its real-world utility.
Methods
To address these challenges, the National Institutes of Health-funded IGNITE (Implementing GeNomics In pracTicE; www.ignite-genomics.org) Network, comprised of six projects and a coordinating center, was established in 2013 to support the development, investigation and dissemination of genomic medicine practice models that seamlessly integrate genomic data into the electronic health record and that deploy tools for point of care decision making. IGNITE site projects are aligned in their purpose of testing these models, but individual projects vary in scope and design, including exploring genetic markers for disease risk prediction and prevention, developing tools for using family history data, incorporating pharmacogenomic data into clinical care, refining disease diagnosis using sequence-based mutation discovery, and creating novel educational approaches.
Results
This paper describes the IGNITE Network and member projects, including network structure, collaborative initiatives, clinical decision support strategies, methods for return of genomic test results, and educational initiatives for patients and providers. Clinical and outcomes data from individual sites and network-wide projects are anticipated to begin being published over the next few years.
Conclusions
The IGNITE Network is an innovative series of projects and pilot demonstrations aiming to enhance translation of validated actionable genomic information into clinical settings and develop and use measures of outcome in response to genome-based clinical interventions using a pragmatic framework to provide early data and proofs of concept on the utility of these interventions. Through these efforts and collaboration with other stakeholders, IGNITE is poised to have a significant impact on the acceleration of genomic information into medical practice.
doi:10.1186/s12920-015-0162-5
PMCID: PMC4700677  PMID: 26729011
Precision medicine; Pharmacogenomics; Genomics; Personalized medicine; Clinical decision support; Electronic health record; Implementation
16.  Warfarin Pharmacogenetics 
The cytochrome P450 (CYP) 2C9 and vitamin K epoxide reductase complex 1 (VKORC1) genotypes have been strongly and consistently associated with warfarin dose requirements, and dosing algorithms incorporating genetic and clinical information have been shown to be predictive of stable warfarin dose. However, clinical trials evaluating genotype-guided warfarin dosing produced mixed results, calling into question the utility of this approach. Recent trials used surrogate markers as endpoints rather than clinical endpoints, further complicating translation of the data to clinical practice. The present data do not support genetic testing to guide warfarin dosing, but in the setting where genotype data are available, use of such data in those of European ancestry is reasonable. Outcomes data are expected from an on-going trial, observational studies continue, and more work is needed to define dosing algorithms that incorporate appropriate variants in minority populations; all these will further shape guidelines and recommendations on the clinical utility of genotype-guided warfarin dosing.
doi:10.1016/j.tcm.2014.09.001
PMCID: PMC4278947  PMID: 25282448
18.  Hydrochlorothiazide-induced hyperuricaemia in the Pharmacogenomic Evaluation of Antihypertensive Responses (PEAR) study 
Journal of internal medicine  2014;276(5):486-497.
Objective
Elevations in uric acid (UA) and the associated hyperuricaemia are commonly observed secondary to treatment with thiazide diuretics. We sought to identify novel single-nucleotide polymorphisms (SNPs) associated with hydrochlorothiazide (HCTZ)-induced elevations in UA and hyperuricaemia.
Methods
A genome-wide association study of HCTZ-induced changes in UA was performed in Caucasian and African American participants from the Pharmacogenomic Evaluation of Antihypertensive Response (PEAR) study who were treated with HCTZ monotherapy. Suggestive SNPs were replicated in Caucasians and African Americans from the PEAR study who were treated with HCTZ add-on therapy. Replicated regions were followed up through expression and pathway analysis.
Results
Five unique gene regions were identified in African Americans (LUC7L2, ANKRD17/COX18, FTO, PADI4 and PARD3B) and one region was identified in Caucasians (GRIN3A). Increases in UA of up to 1.8 mg/dL were observed following HCTZ therapy in individuals homozygous for risk alleles, with heterozygotes displaying an intermediate phenotype. Several risk alleles were also associated with an increased risk of HCTZ-induced clinical hyperuricaemia. A composite risk score, constructed in African Americans using the ‘top’ SNP from each gene region, was strongly associated with HCTZ-induced UA elevations (P = 1.79×10−7) and explained 11% of the variability in UA response. Expression studies in RNA from whole blood revealed significant differences in expression of FTO by rs4784333 genotype. Pathway analysis showed putative connections between many of the genes identified through common microRNAs.
Conclusion
Several novel gene regions were associated with HCTZ-induced UA elevations in African Americans (LUC7L2, COX18/ANKRD17, FTO, PADI4 and PARD3B) and one region was associated with these elevations in Caucasians (GRIN3A).
doi:10.1111/joim.12215
PMCID: PMC4130802  PMID: 24612202
genome-wide association study; hydrochlorothiazide; hypertension; pharmacogenetics; polymorphism; uric acid
19.  Predictors for Glucose Change in Hypertensive Participants Following Short-term Treatment with Atenolol or Hydrochlorothiazide 
Pharmacotherapy  2014;34(11):1132-1140.
Study Objective
To develop and validate a predictive model for glucose change and risk for new-onset impaired fasting glucose in hypertensive participants following treatment with atenolol or hydrochlorothiazide (HCTZ).
Design
Randomized multicenter clinical trial.
Patients
A total of 735 white or African-American men and women with uncomplicated hypertension.
Measurements and Main Results
Pharmacogenomic Evaluation of Antihypertensive Responses (PEAR) is a randomized clinical trial to assess the genetic and nongenetic predictors of blood pressure response and adverse metabolic effects following treatment with atenolol or HCTZ. To develop and validate predictive models for glucose change, PEAR participants were randomly divided into a derivation cohort of 367 and a validation cohort of 368. Linear and logistic regression modeling were used to build models of drug-associated glucose change and impaired fasting glucose (IFG), respectively, in the derivation cohorts. These models were then evaluated in the validation cohorts. For glucose change after atenolol or HCTZ treatment, baseline glucose was a significant (p<0.0001) predictor, explaining 13% of the variability in glucose change after atenolol and 12% of the variability in glucose change after HCTZ. Baseline glucose was also the strongest and most consistent predictor (p<0.0001) for development of IFG after atenolol or HCTZ monotherapy. The area under the receiver operating curve was 0.77 for IFG after atenolol and 0.71 after HCTZ treatment, respectively.
Conclusion
Baseline glucose is the primary predictor of atenolol or HCTZ-associated glucose increase and development of IFG after treatment with either drug.
doi:10.1002/phar.1483
PMCID: PMC4227953  PMID: 25202885
β-Blockers; thiazide diuretics; hyperglycemia; atenolol; hydrochlorothiazide; impaired fasting glucose
20.  Emerging Roles for Pharmacists in Clinical Implementation of Pharmacogenomics 
Pharmacotherapy  2014;34(10):1102-1112.
Pharmacists are uniquely qualified to play essential roles in the clinical implementation of pharmacogenomics. However, specific responsibilities and resources needed for these roles have not been defined. We describe roles for pharmacists that emerged in the clinical implementation of genotype-guided clopidogrel therapy in the University of Florida Health Personalized Medicine Program, summarize preliminary program results, and discuss education, training, and resources needed to support such programs. Planning for University of Florida Health Personalized Medicine Program began in summer 2011 under leadership of a pharmacist, with clinical launch in June 2012 of a clopidogrel-CYP2C19 pilot project aimed at tailoring antiplatelet therapies for patients undergoing percutaneous coronary intervention and stent placement. More than 1000 patients were genotyped in the pilot project in year 1. Essential pharmacist roles and responsibilities that developed and/or emerged required expertise in pharmacy informatics (development of clinical decision support in the electronic medical record), medication safety, medication-use policies and processes, development of group and individual educational strategies, literature analysis, drug information, database management, patient care in targeted areas, logistical issues in genetic testing and follow-up, research and ethical issues, and clinical precepting. In the first 2 years of the program (1 year planning and 1 year postimplementation), a total of 14 different pharmacists were directly and indirectly involved, with effort levels ranging from a few hours per month, to 25–30% effort for the director and associate director, to nearly full-time for residents. Clinical pharmacists are well positioned to implement clinical pharmacogenomics programs, with expertise in pharmacokinetics, pharmacogenomics, informatics, and patient care. Education, training, and practice-based resources are needed to support these roles and to facilitate the development of financially sustainable pharmacist-led clinical pharmacogenomics practice models.
doi:10.1002/phar.1481
PMCID: PMC4188772  PMID: 25220280
pharmacist roles; pharmacogenomics; pharmacogenetics; clinical implementation
21.  The influence of the CYP2C19*10 allele on clopidogrel activation and CYP2C19*2 genotyping 
Pharmacogenetics and genomics  2014;24(8):381-386.
The polymorphic hepatic enzyme CYP2C19 catalyzes the metabolism of clinically important drugs such as clopidogrel, proton-pump inhibitors, and others and clinical pharmacogenetic testing for clopidogrel is increasingly common. The CYP2C19*10 SNP is located 1 bp upstream the CYP2C19*2 SNP. Despite the low frequency of the CYP2C19*10 allele, its impact on metabolism of CYP2C19 substrates and CYP2C19*2 genotyping makes it an important SNP to consider for pharmacogenetic testing of CYP2C19. However, the effect of the CYP2C19*10 allele on clopidogrel metabolism has not been explored to date. We measured the enzymatic activity of the CYP2C19.10 protein against clopidogrel. The catalytic activity of CYP2C19.10 in the biotransformation of clopidogrel and 2-oxo-clopidgorel was significantly decreased relative to wild type CYP2C19.1B. We also report that the CYP2C19*10 SNP interferes with the CYP2C19*2 TaqMan® genotyping assay, resulting in miscalling of CYP2C19*10/*2 as CYP2C19*2/*2. Our data provide evidence of CYP2C19.10’s reduced metabolism of clopidogrel and 2-oxo-clopidogrel.
doi:10.1097/FPC.0000000000000068
PMCID: PMC4090277  PMID: 24945780
CYP2C19*10; Clopidogrel; Pharmacokinetic; Pharmacogenetic; genotyping
22.  Impact of CYP2D6 polymorphisms on clinical efficacy & tolerability of metoprolol tartrate 
Metoprolol is a selective β-1 adrenergic receptor blocker that undergoes extensive metabolism by the polymorphic enzyme, CYP2D6. Our objective was to investigate the influence of CYP2D6 polymorphisms on efficacy and tolerability of metoprolol tartrate. 281 study participants with uncomplicated hypertension received 50 mg of metoprolol twice daily followed by response guided titration to 100 mg twice daily. Phenotypes were assigned based on results of CYP2D6 genotyping and copy number variation assays. Clinical response to metoprolol and adverse effect rates were analyzed in relation to CYP2D6 phenotypes by using appropriate statistical tests. Heart rate response differed significantly by CYP2D6 phenotype (p-value <0.0001) with poor metabolizers & intermediate metabolizers showing greater HR reduction. However, blood pressure response and adverse effect rates were not significantly different by CYP2D6 phenotype. Other than a significant difference in heart rate response, CYP2D6 polymorphisms were not a determinant of the variability in response or tolerability to metoprolol.
doi:10.1038/clpt.2014.62
PMCID: PMC4111800  PMID: 24637943
CYP2D6; metoprolol; genotype; phenotype; copy number variation; clinical efficacy; tolerability
23.  CYP2C19 Polymorphisms and Therapeutic Drug Monitoring of Voriconazole: Are We Ready for Clinical Implementation of Pharmacogenomics? 
Pharmacotherapy  2014;34(7):703-718.
Since its approval by the United States Food and Drug Administration in 2002, voriconazole has become a key component in the successful treatment of many invasive fungal infections, including the most common, aspergillosis and candidiasis. Despite voriconazole’s widespread use, optimizing its treatment in an individual can be challenging due to significant interpatient variability in plasma concentrations of the drug. Variability is due to nonlinear pharmacokinetics and the influence of patient characteristics such as age, sex, weight, liver disease, and genetic polymorphisms in the cytochrome P450 2C19 gene (CYP2C19) encoding for the CYP2C19 enzyme, the primary enzyme responsible for metabolism of voriconazole. CYP2C19 polymorphisms account for the largest portion of variability in voriconazole exposure, posing significant difficulty to clinicians in targeting therapeutic concentrations. In this review, we discuss the role of CYP2C19 polymorphisms and their influence on voriconazole’s pharmacokinetics, adverse effects, and clinical efficacy. Given the association between CYP2C19 genotype and voriconazole concentrations, as well as the association between voriconazole concentrations and clinical outcomes, particularly efficacy, it seems reasonable to suggest a potential role for CYP2C19 genotype to guide initial voriconazole dose selection followed by therapeutic drug monitoring to increase the probability of achieving efficacy while avoiding toxicity.
doi:10.1002/phar.1400
PMCID: PMC4082739  PMID: 24510446
voriconazole; pharmacogenomics; pharmacogenetics; CYP2C19 polymorphisms; genotype-guided dosing; pharmacokinetics; antifungal; therapeutic drug monitoring
24.  Alteration in Fasting Glucose after Prolonged Treatment with a Thiazide Diuretic 
Aims
Thiazide diuretics are recommended as first line antihypertensive treatment, but may contribute to new onset diabetes. We aimed to describe change in fasting glucose (FG) during prolonged thiazide treatment in an observational setting.
Methods
We conducted an observational, non-randomized, open label, follow-up study of the Pharmacogenomic Evaluation of Antihypertensive Responses (PEAR) and PEAR-2 studies. We enrolled previous participants from the PEAR or PEAR-2 studies with at least six months of continuous treatment with either hydrochlorothiazide (HCTZ) or chlorthalidone. Linear regression was used to identify associations with changes in FG after prolonged thiazide and thiazide-like diuretic treatment.
Results
A total of 40 participants were included with a mean 29 (range 8–72) months of thiazide treatment. FG increased 6.5 (SD 13.0) mg/dL during short-term thiazide treatment and 3.6 (SD 15.3) mg/dL FG during prolonged thiazide treatment. Increased FG at follow-up was associated with longer thiazide treatment duration (beta=0.34, p=0.008) and lower baseline FG (beta=−0.46, p=0.02). β blocker treatment in combination with prolonged thiazide diuretic treatment was also associated with increased FG and increased two-hour glucose obtained from OGTT.
Conclusions
Our results indicate that prolonged thiazide treatment duration is associated with increased FG and that overall glycemic status worsens when thiazide/thiazide-like diuretics are combined with β blockers.
doi:10.1016/j.diabres.2014.04.004
PMCID: PMC4074403  PMID: 24794890
hypertension; hydrochlorothiazide; chlorthalidone; glucose; diabetes; thiazide diuretics; β blockers
25.  CYP2C19 Metabolizer Status and Clopidogrel Efficacy in the Secondary Prevention of Small Subcortical Strokes (SPS3) Study 
Background
The role of the CYP2C19 genotype on clopidogrel efficacy has been studied widely, with data suggesting reduced clopidogrel efficacy in loss-of-function variant carriers taking clopidogrel after percutaneous coronary intervention; however, data are limited regarding the association between CYP2C19 genetic variants and outcomes in stroke patients. We investigated whether CYP2C19 metabolizer status affects the risk of recurrent stroke or major bleeding in subcortical stroke patients taking dual antiplatelet therapy with aspirin and clopidogrel.
Methods and Results
CYP2C19*2 and CYP2C19*17 were genotyped in 522 patients treated with dual antiplatelet therapy from the Secondary Prevention of Small Subcortical Strokes (SPS3) study. CYP2C19 metabolizer status was inferred from genotype, and associations with the risk of recurrent stroke and major bleeding were assessed in the overall cohort and by race/ethnic group with logistic regression modeling. In the overall cohort, there were no differences in outcomes by CYP2C19 metabolizer status (recurrent stroke, odds ratio 1.81 [95% CI 0.76 to 4.30]; major bleeding, odds ratio 0.67 [95% CI 0.22 to 2.03]). In white participants, those with CYP2C19 intermediate or poor metabolizer status had higher odds of recurrent stroke (odds ratio 5.19 [95% CI 1.08 to 24.90]) than those with extensive or ultrarapid metabolizer status, but there was no evidence of difference in major bleeding.
Conclusions
There were significant differences in recurrent stroke by CYP2C19 genotype-inferred metabolizer status in white subcortical stroke patients receiving dual antiplatelet therapy with aspirin and clopidogrel, consistent with cardiovascular studies on CYP2C19 and clopidogrel; however, the bleeding risk that led to early termination of the antiplatelet arm of the SPS3 trial does not appear to be explained by CYP2C19 genotype. This study was relatively underpowered; therefore, these findings should be interpreted with caution and warrant replication.
Clinical Trial Registration
URL: http://www.clinicaltrials.gov. Unique identifier: NCT00059306.
doi:10.1161/JAHA.114.001652
PMCID: PMC4599525  PMID: 26019129
clopidogrel; CYP2C19; pharmacogenomics; stroke prevention; subcortical stroke

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