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JAMA The Journal of the American Medical Association 05/2012; 307(18):1921-2. · 30.03 Impact Factor
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Julio D Duarte, Issam Zineh,
Ben Burkley,
Yan Gong,
Taimour Y Langaee,
Stephen T Turner,
Arlene B Chapman,
Eric Boerwinkle,
John G Gums,
Rhonda M Cooper-Dehoff,
Amber L Beitelshees,
Kent R Bailey,
Roger B Fillingim,
Bruce C Kone,
Julie A Johnson
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ABSTRACT: Nearly one-third of the United States adult population suffers from hypertension. Hydrochlorothiazide (HCTZ), one of the most commonly used medications to treat hypertension, has variable efficacy. The renal epithelial sodium channel (ENaC) provides a mechanism for fine-tuning sodium excretion, and is a major regulator of blood pressure homeostasis. DOT1L, MLLT3, SIRT1, and SGK1 encode genes in a pathway that controls methylation of the histone H3 globular domain at lysine 79 (H3K79), thereby modulating expression of the ENaCα subunit. This study aimed to determine the role of variation in these regulatory genes on blood pressure response to HCTZ, and secondarily, untreated blood pressure.
We investigated associations between genetic variations in this candidate pathway and HCTZ blood pressure response in two separate hypertensive cohorts (clinicaltrials.gov NCT00246519 and NCT00005520). In a secondary, exploratory analysis, we measured associations between these same genetic variations and untreated blood pressure. Associations were measured by linear regression, with only associations with P ≤ 0.01 in one cohort and replication by P ≤ 0.05 in the other cohort considered significant.
In one cohort, a polymorphism in DOT1L (rs2269879) was strongly associated with greater systolic (P = 0.0002) and diastolic (P = 0.0016) blood pressure response to hydrochlorothiazide in Caucasians. However, this association was not replicated in the other cohort. When untreated blood pressure levels were analyzed, we found directionally similar associations between a polymorphism in MLLT3 (rs12350051) and greater untreated systolic (P < 0.01 in both cohorts) and diastolic (P < 0.05 in both cohorts) blood pressure levels in both cohorts. However, when further replication was attempted in a third hypertensive cohort and in smaller, normotensive samples, significant associations were not observed.
Our data suggest polymorphisms in DOT1L, MLLT3, SIRT1, and SGK1 are not likely associated with blood pressure response to HCTZ. However, a possibility exists that rs2269879 in DOT1L could be associated with HCTZ response in Caucasians. Additionally, exploratory analyses suggest rs12350051 in MLLT3 may be associated with untreated blood pressure in African-Americans. Replication efforts are needed to verify roles for these polymorphisms in human blood pressure regulation.
Journal of Translational Medicine 03/2012; 10:56. · 3.41 Impact Factor
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ABSTRACT: The PPAR-alpha agonists (fibrates) are commonly used in the treatment of dyslipidemia. It has been hypothesized that the cardio-protective effects of fibrates are partially due to immunomodulatory effects. However, there is a paucity of data regarding the effect of fibrates on neutrophilic chemokines such as epithelial neutrophil activating protein (ENA-78) and interleukin (IL)-8. We investigated the influence of fenofibrate on IL-1β-stimulated production of ENA-78 and IL-8 from human endothelial cells (HUVECs).
HUVECs were cultured in the presence or absence of IL-1β and fenofibrate ranging from 1-50 uM. ENA-78 and IL-8 were measured and normalized to total protein content in cell culture supernates by multiplex immunofluorescence detection. Experimental samples were measured in triplicate. Significance was set at P < 0.05 by ANOVA with correction for multiple comparisons.
Endothelial production of both ENA-78 and IL-8 was induced by the proinflammatory cytokine IL-1β. ENA-78 concentrations increased by more than 160-fold over constitutively produced ENA-78 upon IL-1β stimulation (mean ± SEM: 10,129 ± 1591 pg/mg vs. 61 ± 9.5 mg/mg; P < 0.0001). IL-8 concentrations increased by slightly over 5-fold (6145 ± 860 pg/mg vs. 1160 ± 201 pg/mg; P = 0.0003). ENA-78 protein and mRNA were significantly reduced by fenofibrate while no drug effects were observed on IL-8 production.
Fenofibrate blunts IL-1β-mediated ENA-78 production with no effect on IL-8. This represents a novel mechanism by which fenofibrate exerts anti-inflammatory effects and should be further explored.
Cardiovascular Drugs and Therapy 01/2012; 26(2):95-9. · 3.13 Impact Factor
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ABSTRACT: Use of pharmacogenetics to inform treatment decisions remains a priority for clinicians, patients and public health agencies. We previously developed a framework for systematically assessing whether pharmacogenetic test information would likely bring value to clinical decision-making and enjoy practical uptake. We applied this tool to allopurinol to determine potential usefulness of HLA genetic information in assessing risk for allopurinol-induced severe cutaneous adverse reactions. We quantified allopurinol use data and the magnitude of adverse event signals using US FDA databases, reviewed reported cases of allopurinol-associated severe cutaneous adverse reactions to assess whether clinical subtypes of patients could be identified, performed pooled analyses of associations between HLA variation and allopurinol-induced severe cutaneous adverse reactions and described considerations in clinical implementation of allopurinol pharmacogenetics.
Pharmacogenomics 12/2011; 12(12):1741-9. · 3.97 Impact Factor
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ABSTRACT: Pharmacogenomics is the study of how genetic variations influence responses to drugs, diagnostics, or biologic agents. The field of pharmacogenomics has significant potential to enhance drug development and aid in making regulatory decisions. The United States Food and Drug Administration (FDA) has supported pharmacogenomics for nearly a decade by providing regulatory advice and reviewing applications, with the intent of discovering and applying genetic determinants of treatment effects. The FDA will continue to develop policies and processes centered on genomics and individualized therapeutics to guide rational drug development. It will also continue to inform the public of clinically relevant pharmacogenomic issues through various mechanisms of communication, such as drug labeling. In this review, we provide a perspective on several pharmacogenomic activities at the FDA. In addition, we attempt to clarify what we believe are several misperceptions regarding the FDA's pharmacogenomic initiatives. We hope this perspective provides a window into some ways in which the FDA is enabling individualized therapeutics through its mission-critical activities.
Pharmacotherapy 08/2011; 31(8):729-35. · 2.90 Impact Factor
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ABSTRACT: Liver X receptor-α (LXRA) is a nuclear receptor that regulates genes important in cholesterol homeostasis and inflammation. Several single nucleotide polymorphisms (SNPs) in the LXRA gene (NR1H3) have been earlier associated with metabolic phenotypes (dyslipidemia and elevated body mass index). Metabolic dysregulation is a major contributor to coronary disease; therefore, we assessed LXRA in International Verapamil Sustained Release SR Trandolapril Study Genetic Substudy (INVEST-GENES), a genetic-substudy of a large clinical trial in patients with hypertension and coronary artery disease.
Seven tag SNPs in the LXRA gene region (NR1H3) were selected for study: rs11039149, rs12221497, rs2279238, rs7120118, rs326213, rs11039159, and rs10501321. One thousand fifty-nine patients were genotyped from the INVEST-GENES case-control set (verapamil-sustained release-based or atenolol-based treatment strategies) that comprised of 297 cases frequency matched (approximately 2.5:1) with that of event-free controls by sex and race. The primary outcome was defined as first occurrence of all-cause death, nonfatal myocardial infarction, or nonfatal stroke. Adjusted odds ratios (ORs) were calculated using logistic regression.
Three of the seven SNPs were associated with significant effects on the primary outcome in nonBlacks. The variant G allele of rs11039149 and the variant A allele of rs12221497 were associated with reduced risk of experiencing the primary outcome [OR: 0.62, confidence interval (CI): 0.45-0.85, P=0.003 and OR: 0.60, CI: 0.39-0.91, P=0.016, respectively]. The rs2279238 genotype was associated with a significant increase in risk for the primary outcome (OR: 1.42, CI: 1.03-1.95, P=0.03). Furthermore, there was a significant genotype-treatment strategy interaction for carriers of the variant T allele of rs2279238 (OR for verapamil-sustained release strategy compared with atenolol strategy: 2.86, CI: 1.50-5.46, P=0.0015). Diplotype analyses showed that the SNPs are rarely coinherited and support the directionally opposite effects of the SNPs on the primary outcome.
LXRA genotypes were associated with variable risk for cardiovascular outcomes and pharmacogenetic effect in INVEST-GENES. These novel findings suggest that LXRA is a genetic/pharmacogenetic target that should be further explored.
Pharmacogenetics and Genomics 06/2011; 21(6):333-40. · 3.48 Impact Factor
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Maximilian T Lobmeyer,
Liewei Wang, Issam Zineh,
Stephen T Turner,
John G Gums,
Arlene B Chapman,
Rhonda M Cooper-DeHoff,
Amber L Beitelshees,
Kent R Bailey,
Eric Boerwinkle,
Carl J Pepine,
Julie A Johnson
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ABSTRACT: The G-protein-coupled receptor kinases (GRKs) GRK2 and GRK5 are important regulators of β-adrenergic signaling. This study characterized single-nucleotide polymorphisms (SNPs) in the GRK2 gene (ADRBK1) and determined if these and a GRK5 Gln41Leu polymorphism affect the blood pressure (BP) response to atenolol or hydrochlorothiazide or adverse cardiovascular outcomes in hypertensives.
ADRBK1 regions were sequenced for 48 individuals. Putative functional SNPs were tested for mRNA expression differences in 96 lymphoblastoid cell line samples and 12 leukocyte samples from hypertensives. BP response to atenolol and hydrochlorothiazide by ADRBK1 SNPs and GRK5 Gln41Leu was tested in 418 patients from the Pharmacogenomic Evaluation of Antihypertensive Responses Study using linear regression. The influence of ADRBK1 SNPs and GRK5 Gln41Leu on death, myocardial infarction or stroke in treated hypertensives was evaluated in a case-control cohort (1 : 3) of the International Verapamil SR/Trandolapril Study GENEtic Substudy using logistic regression models.
A novel ADRBK1 promoter SNP was not associated with differential GRK2 expression. GRK5 Leu41 decreased the risk for adverse cardiovascular outcomes independent of treatment strategy (adjusted odds ratio 0.535, 95% confidence interval: 0.313-0.951, P=0.0222), but was not associated with BP response to antihypertensive medication. An ADRBK1 SNP (rs1894111 G>A) showed a signal for association with systolic and diastolic BP response to hydrochlorothiazide in Whites [diastolic BP: -11.29±3.74 (G/A) versus -4.26±4.79 mmHg (G/G), P=0.0034 and systolic BP: -18.37±14.90 (G/A), -8.11±7.55 mmHg (G/G), P=0.0191].
The GRK5 Leu41 allele protects from adverse cardiovascular outcomes in treated hypertensives.
Pharmacogenetics and Genomics 01/2011; 21(1):42-9. · 3.48 Impact Factor
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Linda C Surh,
Michael A Pacanowski,
Susanne B Haga,
Stuart Hobbs,
Lawrence J Lesko,
Scott Gottlieb,
Marisa Papaluca-Amati,
Scott D Patterson,
Arlene R Hughes,
Myong-Jin Kim,
Sandra L Close,
Michael Mosteller, Issam Zineh,
Bryan Dechairo,
Nadine A Cohen
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ABSTRACT: The 2010 US FDA-Drug Industry Association (DIA) Pharmacogenomics (PGx) Workshop follows a series that began in 2002 bringing together multidisciplinary experts spanning regulatory authorities, medical research, healthcare and industry. This report summarizes the 'Building PGx into Labels' sessions from the workshop, which discussed the critical elements in developing PGx outcomes leading to product labels that inform efficacy and/or safety. Examples were drawn from US prescribing information, which integrated PGx knowledge into medical decisions (e.g., panitumumab, warfarin and clopidogrel). Attendees indicated the need for broader dialog and for guidelines on evidentiary considerations for PGx to be included into product labels. Also discussed was the understanding of appropriate PGx placement on labels; how to encourage adoption by medical communities of label recommendations on PGx tests; and, given the global nature of drug development, worldwide considerations including European Summary of Product Characteristics.
Pharmacogenomics 12/2010; 11(12):1637-47. · 3.97 Impact Factor
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Andrew N Freedman,
Leah B Sansbury,
William D Figg,
Arnold L Potosky,
Sheila R Weiss Smith,
Muin J Khoury,
Stefanie A Nelson,
Richard M Weinshilboum,
Mark J Ratain,
Howard L McLeod, [......], Issam Zineh,
Gurvaneet Randhawa,
Christine B Ambrosone,
Mary V Relling,
Nat Rothman,
Heng Xie,
Margaret R Spitz,
Rachel Ballard-Barbash,
James H Doroshow,
Lori M Minasian
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ABSTRACT: Recent advances in genomic research have demonstrated a substantial role for genomic factors in predicting response to cancer therapies. Researchers in the fields of cancer pharmacogenomics and pharmacoepidemiology seek to understand why individuals respond differently to drug therapy, in terms of both adverse effects and treatment efficacy. To identify research priorities as well as the resources and infrastructure needed to advance these fields, the National Cancer Institute (NCI) sponsored a workshop titled "Cancer Pharmacogenomics: Setting a Research Agenda to Accelerate Translation" on July 21, 2009, in Bethesda, MD. In this commentary, we summarize and discuss five science-based recommendations and four infrastructure-based recommendations that were identified as a result of discussions held during this workshop. Key recommendations include 1) supporting the routine collection of germline and tumor biospecimens in NCI-sponsored clinical trials and in some observational and population-based studies; 2) incorporating pharmacogenomic markers into clinical trials; 3) addressing the ethical, legal, social, and biospecimen- and data-sharing implications of pharmacogenomic and pharmacoepidemiologic research; and 4) establishing partnerships across NCI, with other federal agencies, and with industry. Together, these recommendations will facilitate the discovery and validation of clinical, sociodemographic, lifestyle, and genomic markers related to cancer treatment response and adverse events, and they will improve both the speed and efficiency by which new pharmacogenomic and pharmacoepidemiologic information is translated into clinical practice.
CancerSpectrum Knowledge Environment 10/2010; 102(22):1698-705. · 14.07 Impact Factor
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ABSTRACT: Proprotein convertase subtilisin kexin type 9 (PCSK9) is a key regulator of serum LDL-cholesterol (LDL-C) levels. PCSK9 is secreted by the liver into the plasma and binds the hepatic LDL receptor (LDLR), causing its subsequent degradation. We first demonstrated that a moderate dose of atorvastatin (40 mg) increases PCSK9 serum levels, suggesting why increasing statin doses may have diminished efficacy with regard to further LDL-C lowering. Since that initial observation, at least two other groups have reported statin-induced PCSK9 increases. To date, no analysis of the effect of high-dose atorvastatin (80 mg) on PCSK9 over time has been conducted. Therefore, we studied the time course of atorvastatin (80 mg) in human subjects. We measured PCSK9 and lipid levels during a 2-week lead-in baseline period and every 4 weeks thereafter for 16 weeks. We observed that atorvastatin (80 mg) caused a rapid 47% increase in serum PCSK9 at 4 weeks that was sustained throughout 16 weeks of dosing. Importantly, while PCSK9 levels were highly correlated with total cholesterol (TC), LDL-C, and triglyceride (TG) levels at baseline, atorvastatin (80 mg) completely abolished all of these correlations. Together, these results further suggest an explanation for why increasing doses of statins fail to achieve proportional LDL-C lowering.
The Journal of Lipid Research 09/2010; 51(9):2714-21. · 5.56 Impact Factor
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Federico M Goodsaid,
Shashi Amur,
Jiri Aubrecht,
Michael E Burczynski,
Kevin Carl,
Jennifer Catalano,
Rosane Charlab,
Sandra Close,
Catherine Cornu-Artis,
Laurent Essioux, [......],
John Roth,
Ina Schuppe-Koistinen,
Leming Shi,
Olivia Spleiss,
Weida Tong,
Sharada L Truter,
Jacky Vonderscher,
Agnes Westelinck,
Li Zhang, Issam Zineh
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ABSTRACT: Heterogeneity in the underlying mechanisms of disease processes and inter-patient variability in drug responses are major challenges in drug development. To address these challenges, biomarker strategies based on a range of platforms, such as microarray gene-expression technologies, are increasingly being applied to elucidate these sources of variability and thereby potentially increase drug development success rates. With the aim of enhancing understanding of the regulatory significance of such biomarker data by regulators and sponsors, the US Food and Drug Administration initiated a programme in 2004 to allow sponsors to submit exploratory genomic data voluntarily, without immediate regulatory impact. In this article, a selection of case studies from the first 5 years of this programme - which is now known as the voluntary exploratory data submission programme, and also involves collaboration with the European Medicines Agency - are discussed, and general lessons are highlighted.
dressNature Reviews Drug Discovery 06/2010; 9(6):435-45. · 29.01 Impact Factor
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ABSTRACT: Over the past 10 years, the US FDA has become a strong pharmacogenomics advocate as part of its mission to both protect and advance public health by enabling innovations that make medicines safer to use and more effective. The agency has evolved its advocacy cautiously on a foundation of science-based information from novel programs, such as the Voluntary Genomics Data Submission initiative, and on careful regulatory assessment of the extraordinary advances in clinical pharmacogenomics that have supported the update of drug labels with genetic information. This commentary goes into detail on the evolution of these achievements. However, many challenges remain for pharmacogenomics, and they will continue to evolve, and all stakeholders must work together. As the decade draws to a close, we have presented four major areas that need to be addressed collectively to assure that pharmacogenomics continues to mature over the next 10 years into a science that is essential to the practice of medicine.
Pharmacogenomics 04/2010; 11(4):507-12. · 3.97 Impact Factor
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ABSTRACT: To determine the effects of the thiazolidinedione rosiglitazone on the adipocyte-derived cytokines adiponectin (an antiinflammatory and insulin-sensitizing cytokine; low levels have been associated with metabolic syndrome) and resistin (an inflammation mediator; high levels have been associated with metabolic syndrome) in nondiabetic patients with metabolic syndrome, and to characterize the effects of rosiglitazone on other components of the metabolic syndrome phenotype in this population.
Prospective, randomized, double-blind, placebo-controlled study.
Outpatient general clinical research center.
Thirty-two nondiabetic men and women with a clinical diagnosis of metabolic syndrome (as defined in the American Heart Association-National Heart, Lung, and Blood Institute scientific statement).
Patients were randomly assigned to receive either oral rosiglitazone 4 mg/day or matching placebo for 12 weeks.
The primary end point was change in serum adiponectin concentrations from baseline to week 12. Secondary end points were changes in serum resistin concentrations, insulin resistance, fasting glucose level, fasting insulin level, body weight, lipid levels, systolic and diastolic blood pressure, and waist circumference from baseline to week 12. Also, changes from baseline in adiponectin and resistin concentrations and insulin resistance were assessed over time at weeks 2, 4, 8, and 12. Rosiglitazone was associated with a significant increase in serum adiponectin concentration after 12 weeks compared with placebo (45.8% vs 2.6%, p=0.002). The increase in adiponectin concentration occurred quickly, with a significant difference observed after 2 weeks of therapy. Compared with placebo, rosiglitazone was not associated with significant 12-week changes in serum resistin concentrations, insulin resistance, fasting glucose level, fasting insulin level, body weight, lipid levels, systolic or diastolic blood pressure, or waist circumference.
Rosiglitazone had beneficial effects on adiponectin concentrations without significantly affecting other components of the metabolic syndrome phenotype. Additional studies that further elucidate the time course of thiazolidinedione pharmacodynamic effects, along with their effects on cardiovascular end points, are warranted in nondiabetic patients with metabolic syndrome.
Pharmacotherapy 03/2010; 30(3):236-47. · 2.90 Impact Factor
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Amber L Beitelshees,
Brian N Finck,
Teresa C Leone,
Sharon Cresci,
Jun Wu,
Michael A Province,
Elisa Fabbrini,
Erik Kirk, Issam Zineh,
Samuel Klein,
John A Spertus,
Daniel P Kelly
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ABSTRACT: UCP2 -866G>A (rs659366) has been implicated in cardiometabolic disease and represents a novel candidate gene for beta-blocker response, particularly among patients with diabetes. We assessed the function of -866G>A and its role as a modifier of beta-blocker treatment outcomes by diabetes status in an acute coronary syndrome (ACS) cohort.
ACS patients with genetic samples and 12 months of follow-up for cardiac rehospitalizations or death (n=468) were assessed. The influence of -866G>A on beta-blocker treatment outcomes was evaluated in those with diabetes and without. To assess functional correlates of -866G>A, we compared uncoupling protein 2 (UCP2) expression in the skeletal muscle of obese participants by genotype and compared the activity of UCP2 luciferase promoters with -866G and -866A alleles.
An interaction between -866G>A and beta-blocker treatment was found in individuals with diabetes (P=0.002) but not those without (P=0.79). Among G/G individuals with diabetes, discharge beta-blocker use was associated with an 80% reduction in cardiac rehospitalization (adjusted hazard ratio: 0.20; 95% confidence interval: 0.04-1.02). In contrast, among A-carrier patients with diabetes, there was an 11-fold increase in cardiac rehospitalizations with discharge beta-blocker therapy (adjusted hazard ratio: 11.75; 95% confidence interval: 1.28-108.2). Promoter activity assays showed that -866G had greater cyclic AMP response element binding protein-responsiveness compared with -866A, and compared with -866A carriers G/G individuals exhibited increased UCP2 expression in the skeletal muscle.
We identified a significant interaction between -866G>A and beta-blocker response among ACS patients with diabetes. Furthermore, -866G conferred greater gene transcriptional activity than -866A in cell lines and in obese patients. These findings may help us gain insight into the mechanisms underlying the beneficial and detrimental effects of beta-blockers in those with diabetes.
Pharmacogenetics and Genomics 02/2010; 20(4):231-8. · 3.48 Impact Factor
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Rhonda M Cooper-DeHoff,
Sheron Wen,
Amber L Beitelshees, Issam Zineh,
John G Gums,
Stephen T Turner,
Yan Gong,
Karen Hall,
Vishal Parekh,
Arlene B Chapman,
Eric Boerwinkle,
Julie A Johnson
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ABSTRACT: We assessed adverse metabolic effects of atenolol and hydrochlorothiazide among hypertensive patients with and without abdominal obesity using data from a randomized, open-label study of hypertensive patients without evidence of cardiovascular disease or diabetes mellitus. Intervention included randomization to 25 mg of hydrochlorothiazide or 100 mg of atenolol monotherapy followed by their combination. Fasting glucose, insulin, triglycerides, high-density lipoprotein cholesterol, and uric acid levels were measured at baseline and after monotherapy and combination therapy. Outcomes included new occurrence of and predictors for new cases of glucose > or =100 mg/dL (impaired fasting glucose), triglyceride > or =150 mg/dL, high-density lipoprotein < or =40 mg/dL for men or < or =50 mg/dL for women, or new-onset diabetes mellitus according to the presence or absence of abdominal obesity. Abdominal obesity was present in 167 (58%) of 395 patients. Regardless of strategy, in those with abdominal obesity, 20% had impaired fasting glucose at baseline compared with 40% at the end of study (P<0.0001). Proportion with triglycerides > or =150 mg/dL increased from 33% at baseline to 46% at the end of study (P<0.01). New-onset diabetes mellitus occurred in 13 patients (6%) with and in 4 patients (2%) without abdominal obesity. Baseline levels of glucose, triglyceride, and high-density lipoprotein predicted adverse outcomes, and predictors for new-onset diabetes mellitus after monotherapy in those with abdominal obesity included hydrochlorothiazide strategy (odds ratio: 46.91 [95% CI: 2.55 to 862.40]), female sex (odds ratio: 31.37 [95% CI: 2.10 to 468.99]), and uric acid (odds ratio: 3.19 [95% CI: 1.35 to 7.52]). Development of adverse metabolic effect, including new-onset diabetes mellitus associated with short-term exposure to hydrochlorothiazide and atenolol was more common in those with abdominal obesity.
Hypertension 11/2009; 55(1):61-8. · 6.21 Impact Factor
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Christopher B Arant,
Timothy R Wessel,
Paul M Ridker,
Marian B Olson,
Steven E Reis,
B Delia Johnson,
Barry L Sharaf,
Daniel F Pauly,
Eileen Handberg, Issam Zineh,
George Sopko,
Sheryl F Kelsey,
C Noel Bairey Merz,
Carl J Pepine
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ABSTRACT: Inflammatory marker and hemoglobin levels (eg biomarkers) considered separately, predict adverse events in selected populations.
A multiple biomarker approach predicts adverse events in women referred for evaluation of ischemia.
We investigated associations between biomarkers (high sensitivity C-reactive protein, interleukin-6, serum amyloid-A, and hemoglobin levels) with adverse outcomes in women referred for coronary angiography for suspected ischemia in the National Heart, Lung, and Blood Institute (NHLBI)-sponsored Women's Ischemia Syndrome Evaluation (WISE).
Among 595 women (mean age 58 years, ejection fraction [EF] 65%, majority without coronary stenosis >or= 50%) followed for 3.6 +/- 1.8 years (mean +/- SD), those without abnormal markers had fewer events (11.6%) compared to those with 1 (18.4%), 2 (20.9%), or 3 (37%) abnormal markers (p < 0.001 for trend). Women without abnormal markers had fewer deaths (1.6%) than women with 1 (6.1%), 2 (9.1%), or 3 (17%) abnormal markers (p < 0.001 for trend). Adding low hemoglobin was associated with higher adverse event and all-cause mortality rates. In multivariate analysis, as the number of abnormal biomarkers increased risk increased. Women with 3 or 4 abnormal biomarkers were approximately 10-20 times more likely to die (p < 0.05). Biomarkers added to the predictive information provided by the Framingham Risk Score.
Among women undergoing coronary angiography for suspected ischemia, a multibiomarker approach predicted adverse events. Biomarkers added prognostic information beyond that obtained from traditional risk factors.
Clinical Cardiology 06/2009; 32(5):244-50. · 2.15 Impact Factor
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Martha Gulati,
Rhonda M Cooper-DeHoff,
Candace McClure,
B Delia Johnson,
Leslee J Shaw,
Eileen M Handberg, Issam Zineh,
Sheryl F Kelsey,
Morton F Arnsdorf,
Henry R Black,
Carl J Pepine,
C Noel Bairey Merz
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ABSTRACT: Women with clinical findings suggestive of ischemia but without findings of obstructive coronary artery disease (CAD) on angiography represent a frequent clinical problem; predicting prognosis is challenging.
The Women's Ischemia Syndrome Evaluation (WISE) study examined symptomatic women referred for clinically indicated coronary angiography and followed up for a mean 5.2 years. The St James Women Take Heart (WTH) Project enrolled asymptomatic, community-based women with no history of heart disease who were followed up for 10 years. We compared cardiovascular events (ie, myocardial infarction, stroke, and hospitalization for heart failure) and death in 540 WISE women with suspected ischemia but no angiographic evidence of obstructive CAD with those from a cohort of 1000 age- and race-matched WTH women.
Compared with the WISE women, asymptomatic WTH women had a lower prevalence of obesity, family history of CAD, hypertension, and diabetes mellitus (P < .001). Five-year annualized event rates for cardiovascular events were 16.0% in WISE women with nonobstructive CAD (stenosis in any coronary artery of 1%-49%), 7.9% in WISE women with normal coronary arteries (stenosis of 0% in all coronary arteries), and 2.4% in asymptomatic WTH women (P < or = .002), after adjusting for baseline CAD risk factors. The cardiovascular events were most frequent in women with 4 or more cardiac risk factors, with the 5-year annualized cardiovascular event rate being 25.3% in women with nonobstructive CAD, 13.9% in WISE women with normal coronary arteries, and 6.5% in asymptomatic women (P = .003).
Women with symptoms and signs suggestive of ischemia but without obstructive CAD are at elevated risk for cardiovascular events compared with asymptomatic community-based women.
Archives of internal medicine 05/2009; 169(9):843-50. · 11.46 Impact Factor
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ABSTRACT: Polymorphisms in the endothelial nitric oxide synthase (NOS3) gene increase susceptibility to hypertension and cardiovascular disease. We examined genetic and pharmacogenetic associations between NOS3 polymorphisms, blood pressure (BP) control, and cardiovascular events in elderly, hypertensive coronary artery disease (CAD) patients.
Patients with CAD were randomly assigned to either verapamil SR- or atenolol-based antihypertensive treatment and followed for cardiovascular events. Cases (all-cause death, nonfatal myocardial infarction (MI), or nonfatal stroke) and an age-, sex-, race/ethnicity-matched control population were genotyped for the -786T>C and Glu298>Asp polymorphisms in NOS3. On-treatment BP and BP control were compared across genotype groups. Logistic regression was performed to estimate odds ratios (ORs) for the -786T>C and Glu298>Asp polymorphisms in the combined population and in randomized treatment groups.
Genotype data were available for 256 cases and 769 controls. Among controls, mean on-treatment BP differed according to -786T>C genotype (T/T 137/78 mm Hg, T/C 133/76 mm Hg, C/C 133/75 mm Hg; P = 0.0007 for systolic, P = 0.09 for diastolic) which corresponded to differing rates of BP control (T/T 63%, T/C 72%, C/C 88%; P = 0.002). Neither polymorphisms was associated with case status, with or without regard to assigned treatment.
The -786T>C, but not the Glu298>Asp variant of NOS3, may correlate with BP but do not appear to be associated with incident cardiovascular events in patients with established cardiovascular disease. The antihypertensive treatment approach did not appear to alter the genetic contribution to either BP control or cardiovascular events.
American Journal of Hypertension 04/2009; 22(7):748-53. · 3.18 Impact Factor
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ABSTRACT: High triglycerides (TG) and low high-density lipoprotein cholesterol (HDL-C) are important cardiovascular risk factors in women. The prognostic utility of the TG/HDL-C ratio, a marker for insulin resistance and small dense low-density lipoprotein particles, is unknown among high-risk women.
We studied 544 women without prior myocardial infarction or coronary revascularization, referred for clinically indicated coronary angiography and enrolled in the Women's Ischemia Syndrome Evaluation (WISE). Fasting lipid profiles and detailed demographic and clinical data were obtained at baseline. Multivariate Cox-proportional hazards models for all-cause mortality and cardiovascular events (death, myocardial infarction, heart failure, stroke) over a median follow-up of 6 years were constructed using log TG/HDL-C ratio as a predictor variable and accounting for traditional cardiovascular risk factors.
Mean age was 57 +/- 11 years; 84% were white, 55% hypertensive, 20% diabetic, 50% current or prior smokers. Triglyceride/HDL-C ranged from 0.3 to 18.4 (median 2.2, first quartile 0.35 to <1.4, fourth quartile 3.66-18.4). Deaths (n = 33) and cardiovascular events (n = 83) increased across TG/HDL-C quartiles (both P < .05 for trend). Triglyceride/HDL-C was a strong independent predictor of mortality in models adjusted for age, race, smoking, hypertension, diabetes, and angiographic coronary disease severity (hazard ratio 1.95, 95% CI 1.05-3.64, P = .04). For cardiovascular events, the multivariate hazard ratio was 1.54 (95% CI 1.05-2.22, P = .03) when adjusted for demographic and clinical variables, but became nonsignificant when angiographic results were included.
Among women with suspected ischemia, the TG/HDL-C ratio is a powerful independent predictor of all-cause mortality and cardiovascular events.
American heart journal 03/2009; 157(3):548-55. · 4.65 Impact Factor
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Julie A Johnson,
Eric Boerwinkle, Issam Zineh,
Arlene B Chapman,
Kent Bailey,
Rhonda M Cooper-DeHoff,
John Gums,
R Whit Curry,
Yan Gong,
Amber L Beitelshees,
Gary Schwartz,
Stephen T Turner
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ABSTRACT: Selection of antihypertensive therapy is often empiric, and use of genetic information to guide drug therapy selection holds future promise.
The objective of this trial is to identify the genetic determinants of the antihypertensive and adverse metabolic responses to a thiazide diuretic (hydrochlorothiazide), a beta-blocker (atenolol), and their combination. This will be accomplished through candidate gene and genome-wide association approaches. Individuals with uncomplicated hypertension (N = 800), with ages 17 and 65 years, are being enrolled. Current antihypertensive therapy is discontinued, and hypertension is confirmed, along with collection of other baseline data. Subjects are then randomized to either hydrochlorothiazide or atenolol, with 1 dose titration step, followed by assessment of response to therapy after at least 6 weeks on the target dose. Those with blood pressure >120/70 mm Hg have the second drug added, with similar dose titration and response assessment procedures. Data collected include home, office, and 24-hour ambulatory blood pressure. Biological samples collected in the fasting state include plasma, serum, DNA (buffy coat), and urine. Epstein-Barr virus transformed lymphocyte cell lines are also being created.
Pharmacogenetic-guided therapy holds clinical potential for hypertension, but the literature in the field is limited. This trial will add substantially to our understanding of the genetic determinants of antihypertensive and adverse metabolic responses to 2 commonly used antihypertensive drug classes.
American heart journal 03/2009; 157(3):442-9. · 4.65 Impact Factor
