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ABSTRACT: Pharmacogenetics primarily uses genetic variation to identify subgroups of patients who may respond differently to a certain medication. Since its first description, the field of pharmacogenetics has expanded to study a broad range of cardiovascular drugs and has become a mainstream research discipline. Three principle classes of pharmacogenetic markers have emerged: 1) pharmacokinetic; 2) pharmacodynamic; and 3) underlying disease mechanism. In the realm of cardiovascular pharmacogenetics, significant advances have identified markers in each class for a variety of therapeutics, some with a potential for improving patient outcomes. While ongoing clinical trials will determine if routine use of pharmacogenetic testing may be beneficial, the data today support pharmacogenetic testing for certain variants on an individualized, case-by-case basis. Our primary goal is to review the association data for the major pharmacogenetic variants associated with commonly used cardiovascular medications: antiplatelet agents, warfarin, statins, beta-blockers, diuretics, and antiarrhythmic drugs. In addition, we highlight which variants and in which contexts pharmacogenetic testing can be implemented by practicing clinicians. The pace of genetic discovery has outstripped the generation of the evidence justifying its clinical adoption. Until the evidentiary gaps are filled, however, clinicians may choose to target therapeutics to individual patients whose genetic background indicates that they stand to benefit the most from pharmacogenetic testing.
Journal of the American College of Cardiology 07/2012; 60(1):9-20. · 14.16 Impact Factor
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ABSTRACT: Statins (inhibitors of the enzyme 3-hydroxy-3-methylglutaryl-coenzyme A reductase) are widely prescribed medications for the
prevention of incident and recurrent cardiovascular disease events and death. They are powerful assets in the current arsenal
of cardiovascular medications, with high efficacy and minimal toxicity. However, heterogeneity exists with respect to the
response to statin medications, and there has been considerable investigation into the genetic determinants of the statin
response. In this review, we separate the response to statins into 1) measures of efficacy (low-density lipoprotein cholesterol
lowering and protection from cardiovascular events) and 2) effects of toxicity (musculoskeletal adverse effects and nonadherence
to statin therapy). The current data suggest that prospective genotyping for certain variants may be of use in tailoring statin
therapy to reduce cardiovascular events and to avoid statin-induced adverse effects.
Current Cardiovascular Risk Reports 04/2012; 3(6):434-440.
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ABSTRACT: To develop an integrated metric of non-COX-1-dependent platelet function (NCDPF) to measure the temporal response to aspirin in healthy volunteers and diabetics. NCDPF on aspirin demonstrates wide variability, despite suppression of COX-1. Although a variety of NCDPF assays are available, no standard exists and their reproducibility is not established. We administered 325 mg/day aspirin to two cohorts of volunteers (HV1, n = 52, and HV2, n = 96) and diabetics (DM, n = 74) and measured NCDPF using epinephrine, collagen, and ADP aggregometry and PFA100 (collagen/epi) before (Pre), after one dose (Post), and after several weeks (Final). COX-1 activity was assessed with arachidonic acid aggregometry (AAA). The primary outcome of the study, the platelet function score (PFS), was derived from a principal components analysis of NCDPF measures. The PFS strongly correlated with each measure of NCDPF in each cohort. After 2 or 4 weeks of daily aspirin the Final PFS strongly correlated (r > 0.7, P < 0.0001) and was higher (P < 0.01) than the Post PFS. The magnitude and direction of the change in PFS (Final–Post) in an individual subject was moderately inversely proportional to the Post PFS in HV1 (r = -0.45), HV2 (r = -0.54), DM (r = -0.68), P < 0.0001 for all. AAA remained suppressed during aspirin therapy. The PFS summarizes multiple measures of NCDPF. Despite suppression of COX-1 activity, NCDPF during aspirin therapy is predictably dynamic: those with heightened NCDPF continue to decline whereas those with low/normal NCDPF return to pre-aspirin levels over time.
Journal of Thrombosis and Thrombolysis 02/2012; 33(3):246-57. · 1.48 Impact Factor
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ABSTRACT: Considerable variability exists in how individual patients respond to oral antiplatelet therapy, specifically to aspirin and to P2Y(12)-receptor inhibitors such as clopidogrel. This variability translates to differences in clinical outcomes and might in part be as a result of common variation within genes that are involved in the absorption, metabolic activation, and biological activity of these medications. The field of pharmacogenetics has yielded several genetic loci that predict variation in patient response to antiplatelet therapies. The most robust data indicate an association between loss-of-function alleles of the CYP2C19 gene and adverse outcomes among high-risk patients treated with clopidogrel. However, several fundamental questions surrounding the information gained from genotyping and the efficacy of modifying therapy on the basis of testing remain unanswered. Routine genetic testing for platelet responsiveness cannot, therefore, be recommended for clinical decision-making. Ongoing and future clinical trials might provide evidence to support a change in practice towards pharmacogenetic-based selection of antiplatelet therapy.
Nature Reviews Cardiology 08/2011; 8(10):560-71. · 8.83 Impact Factor
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ABSTRACT: In 2003 Duke University (Durham, NC, USA) launched the Institute for Genome Sciences & Policy (IGSP) as an interdisciplinary network of centers comprised of scientists, engineers and physicians, as well as experts in law, business, economics public policy and ethics. Within this environment, the IGSP and its Center for Genomic Medicine form the hub for pharmacogenomic research discovery initiatives through collaborations with other scientific and clinical units at the Duke University Medical Center. The Center for Genomic Medicine specifically focuses on developing strategies for translating and implementing pharmacogenomic discoveries into the clinical arena; therefore, by harnessing the resources of the IGSP as well as other complementary centers on campus, Duke University is poised to accelerate the development of novel pharmacgenomic paradigms for the prevention and treatment of disease. These new treatment paradigms can, potentially, ensure that the right dose of the right drug is prescribed to the right individual - an often stated goal of personalized medicine and pharmacogenomics.
Pharmacogenomics 08/2011; 12(8):1095-8. · 3.97 Impact Factor
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ABSTRACT: We hypothesized that single-nucleotide polymorphisms (SNPs) associated with heightened in vitro platelet function during aspirin exposure (which we define as "laboratory aspirin resistance") would be associated with greater risk for death, myocardial infarction (MI) or stroke among patients with coronary artery disease regularly using aspirin.
Duke Databank for Cardiovascular Disease patients with (n = 3,449, CATHeterization GENetics cohort) or without (n = 11,754, nongenetic cohort) banked DNA with ≥1 coronary stenosis >75% were followed up at 6 months, then annually for death, MI, or stroke occurring during periods of reported aspirin use. We evaluated associations of candidate SNPs from GNB3, PEAR1, ITGB3, VAV3, ITGA2, GPVI, PTGS1, F2R, THBS1, A2AR, and GP1BA with events during follow-up using Cox proportional hazards modeling adjusted for clinical characteristics associated with outcomes in the nongenetic cohort.
Over a median of 3.5 years, 2,762 (24%) nongenetic cohort patients and 648 (19%) CATHeterization GENetics cohort patients had the composite outcome during reported aspirin use. No candidate SNPs were significantly associated with death, MI, or stroke in either univariable or multivariable analyses. A prospective analysis demonstrated 80% to 88% power to detect a hazard ratio of ≥1.3 for minor allele carriers.
Patients with angiographically significant coronary artery disease regularly using aspirin and carrying SNPs associated with laboratory aspirin resistance were not at higher risk for death, MI, or stroke. Using these SNPs to guide more aggressive antiplatelet therapy is not justified by these results. Direct extrapolation from in vitro findings to the clinical setting should be avoided.
American heart journal 07/2011; 162(1):166-72.e1. · 4.65 Impact Factor
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Journal of the American College of Cardiology 06/2010; 55(25):2813-5. · 14.16 Impact Factor
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ABSTRACT: Catheter-directed atrial fibrillation (AF) ablation is contraindicated among patients with left atrial appendage (LAA) thrombus. The prevalence of LAA thrombus among fully anticoagulated patients undergoing AF ablation is unknown.
We retrospectively evaluated the prevalence of LAA thrombus among 192 consecutive patients undergoing AF ablation between July 2006 and January 2009. Seven of 192 patients (3.6%) had evidence of thrombus on transesophageal echocardiogram (TEE) despite being fully anticoagulated on warfarin (international normalized ratio [INR] 2-3) for 4 consecutive weeks prior to echocardiogram. Univariate analysis demonstrated that structural heart disease, large left atrial dimension, and number of AF ablations were associated with thrombus. Three patients with thrombus had paroxysmal AF with normal LV function.
Despite full anticoagulation, 3.6% of patients undergoing AF ablation had LAA thrombus. We recommend that all patients, regardless of LV function or left atrial size, should undergo preprocedural TEE to exclude the presence of LAA thrombus.
Journal of Cardiovascular Electrophysiology 02/2010; 21(8):849-52. · 3.06 Impact Factor
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ABSTRACT: We sought to identify single nucleotide polymorphisms associated with mild statin-induced side effects.
Statin-induced side effects can interfere with therapy. Single nucleotide polymorphisms in cytochrome P450 enzymes impair statin metabolism; the reduced function SLCO1B1*5 allele impairs statin clearance and is associated with simvastatin-induced myopathy with creatine kinase (CK) elevation.
The STRENGTH (Statin Response Examined by Genetic Haplotype Markers) study was a pharmacogenetics study of statin efficacy and safety. Subjects (n = 509) were randomized to atorvastatin 10 mg, simvastatin 20 mg, or pravastatin 10 mg followed by 80 mg, 80 mg, and 40 mg, respectively. We defined a composite adverse event (CAE) as discontinuation for any side effect, myalgia, or CK >3x upper limit of normal during follow-up. We sequenced CYP2D6, CYP2C8, CYP2C9, CYP3A4, and SLCO1B1 and tested 7 reduced function alleles for association with the CAE.
The CAE occurred in 99 subjects (54 discontinuations, 49 myalgias, and 9 CK elevations). Sex was associated with CAE (percent female in CAE vs. no CAE groups, 66% vs. 50%, p < 0.01). SLCO1B1*5 was associated with CAE (percent with > or = 1 allele in CAE vs. no CAE groups, 37% vs. 25%, p = 0.03) and those with CAE with no significant CK elevation (p < or = 0.03). Furthermore, there was evidence for a gene-dose effect (percent with CAE in those with 0, 1, or 2 alleles: 19%, 27%, and 50%, trend p = 0.01). Finally, the CAE risk appeared to be greatest in those carriers assigned to simvastatin.
SLCO1B1*5 genotype and female sex were associated mild statin-induced side effects. These findings expand the results of a recent genome-wide association study of statin myopathy with CK >3x normal to milder, statin-induced, muscle side effects.
Journal of the American College of Cardiology 10/2009; 54(17):1609-16. · 14.16 Impact Factor
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ABSTRACT: Prior to clinical use, pharmacogenetic tests should be systematically evaluated for their clinical validity and utility. Here, we evaluated whether the publicly available, online Pharmacogenomics Knowledge Base (PharmGKB) could facilitate such assessments by efficiently identifying relevant peer-reviewed manuscripts. The search targets were 55 manuscripts regarding clinical validity and utility included in systematic reviews of warfarin, antidepressant, and irinotecan pharmacogenetics. When direct inclusion in PharmGKB was the search criterion, recall was 33% and precision was 16%. However, recall increased to 78% when citation within a PharmGKB-identified manuscript was added as a search criterion. These recalled manuscripts accounted for 87% of the study subjects, and domain experts determined that the omission of the remaining manuscripts was unlikely to have changed the conclusions of the reviews. Thus, we conclude that PharmGKB can facilitate the systematic assessment of pharmacogenetic assays through the efficient identification of relevant peer-reviewed manuscripts.
AMIA ... Annual Symposium proceedings / AMIA Symposium. AMIA Symposium 01/2009; 2009:307-11.
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ABSTRACT: There is interindividual variation in low-density lipoprotein cholesterol (LDLc) lowering by statins and limited study into the genetic associations of the dose dependant LDLc lowering by statins.
Five hundred nine patients with hyperlipidemia were randomly assigned atorvastatin 10 mg, simvastatin 20 mg, or pravastatin 10 mg (low-dose phase) followed by 80 mg, 80 mg, and 40 mg (high-dose phase), respectively. Thirty-one genes in statin, cholesterol, and lipoprotein metabolism were sequenced and 489 single nucleotide polymorphisms with minor allele frequencies >2% were tested for associations with percentage LDLc lowering at low doses using multivariable adjusted general linear regression. Significant associations from the analysis at low dose were then repeated at high-dose statins. At low doses, only 1 single nucleotide polymorphism met our experiment-wide significance level, ABCA1 rs12003906. Twenty-six subjects carried the minor allele of rs12003906, which was associated with an attenuated LDLc reduction (LDLc reduction in carriers versus noncarriers -24.1+/-2.6% versus -32.2+/-1.5%; P=0.0001). In addition, we replicated the association with the APOE epsilon3 allele and a reduced LDLc reduction. At high doses, carriers of the minor allele of ABCA1 rs12003906 and the APOE epsilon3 allele improved their LDLc reduction but continued to have a diminished LDLc reduction compared with noncarriers (-30.5+/-4.0% versus -42.0+/-2.4%; P=0.005) and (-38.5+/-1.9% versus -45.3+/-2.8%; P=0.009), respectively.
An intronic single nucleotide polymorphism in ABCA1 and the APOE epsilon3 allele are associated with reduced LDLc lowering by statins and identify individuals who may be resistant to maximal LDLc lowering by statins.
Circulation Cardiovascular Genetics 12/2008; 1(2):100-6. · 6.11 Impact Factor
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Eric A Millican,
Petra A Lenzini,
Paul E Milligan,
Leonard Grosso,
Charles Eby,
Elena Deych,
Gloria Grice,
John C Clohisy,
Robert L Barrack,
R Stephen J Burnett, Deepak Voora,
Susan Gatchel,
Amy Tiemeier,
Brian F Gage
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ABSTRACT: High variability in drug response and a narrow therapeutic index complicate warfarin therapy initiation. No existing algorithm provides recommendations on refining the initial warfarin dose based on genetic variables, clinical data, and international normalized ratio (INR) values. Our goal was to develop such an algorithm. We studied 92 patients undergoing primary or revision total hip or knee replacement. From each patient we collected a blood sample, clinical variables, current medications, and preoperative and postoperative laboratory values. We genotyped for polymorphisms in the cytochrome P450 (CYP) 2C9 and vitamin K epoxide reductase (VKORC1) genes. Using stepwise regression, we developed a model for refining the warfarin dose after the third warfarin dose. The algorithm explained four fifths of the variability in therapeutic dose (R(2)(adj) of 79%). Significant (P > .05) predictors were INR value after 3 doses (47% reduction per 0.25-unit rise), first warfarin dose (+7% per 1 mg), CYP2C9*3 and CYP2C9*2 genotype (-38% and -17% per allele), estimated blood loss (interacting with INR(3)), smoking status (+20% in current smokers), and VKORC1 (-11% per copy of haplotype A). If validated, this model should provide a safer, more effective process for initiating warfarin therapy.
Blood 10/2007; 110(5):1511-5. · 9.90 Impact Factor
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Pharmacogenomics 02/2006; 7(1):1-3. · 3.97 Impact Factor
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ABSTRACT: Vitamin K antagonists (coumarins) are widely-used oral anticoagulants for the prevention of venous thromboembolism and strokes. Wide inter-individual variation in dose response and frequent bleeds characterize the initiation of coumarin therapy. Over the past 10 years both genetic and nongenetic determinants of coumarin dose response have been identified. A comprehensive pharmacogenetics approach to warfarin therapy has the potential to improve the safety and efficiency of warfarin initiation.
Pharmacogenomics 08/2005; 6(5):503-13. · 3.97 Impact Factor
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Deepak Voora,
Charles Eby,
Mark W Linder,
Paul E Milligan,
Bonny L Bukaveckas,
Howard L McLeod,
William Maloney,
John Clohisy,
R Steven Burnett,
Leonard Grosso,
Susan K Gatchel,
Brian F Gage
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ABSTRACT: Cytochrome P-450 2C9 (CYP2C9) polymorphisms (CYP2C9*2 and CYP2C9*3) reduce the clearance of warfarin, increase the risk of bleeding, and prolong the time to stable dosing. Whether prospective use of a retrospectively developed algorithm that incorporates CYP2C9 genotype and nongenetic factors can ameliorate the propensity to bleeding and delay in achieving a stable warfarin dose is unknown. We initiated warfarin therapy in 48 orthopedic patients tailored to the following variables: CYP2C9 genotype, age, weight, height, gender, race, and use of simvastatin or amiodarone. By using pharmacogenetics-based dosing, patients with a CYP2C9 variant achieved a stable, therapeutic warfarin dose without excessive delay. However compared to those without a CYP2C9 variant, patients with a variant continued to be at increased risk (hazard ratio 3.6, 95% confidence interval 1.4-9.5, p = 0.01) for an adverse outcome (principally INR > 4), despite pharmacogenetics-based dosing. There was a linear relationship (R(2) = 0.42, p < 0.001) between the pharmacogenetics-predicted warfarin doses and the warfarin maintenance doses, prospectively validating the dosing algorithm. Prospective, perioperative pharmacogenetics-based dosing of warfarin is feasible; however, further evaluation in a randomized, controlled study is recommended.
Thrombosis and Haemostasis 04/2005; 93(4):700-5. · 5.04 Impact Factor
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ABSTRACT: The Human Genome Project heralds new opportunities for pharmacogenetics, the use of genetics to individualize the application of pharmaceuticals in the practice of medicine (1-3). Single nucleotide polymorphisms (SNPs) and other genetic variants in genes responsible for absorption, metabolism and excretion have been associated with alterations in drug disposition or effect. Warfarin is a potential target for pharmacogenetics-based dosing because of its wide use, variability in individual response, high prevalence of genetic variants and severity of adverse drug reactions (4). The genotype assays for genetic variants relevant to warfarin are widely used and are being developed for commercial use (5), making the promise of a pharmacogenetics-based approach a near reality.
Drugs of today (Barcelona, Spain: 1998) 04/2004; 40(3):247-57. · 1.28 Impact Factor
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ABSTRACT: Mesenteric vein thrombosis (MVT) is a distinct clinical cause of intestinal ischemia representing 5-15% of all ischemic events. MVT has acute, subacute, and chronic presentations and an underlying cause can be found in nearly 75% of cases. Exogenous hormones are used worldwide by millions of women for contraception and postmenopausal replacement therapy. Current preparations include oral, transdermal, and intravaginal delivery systems. The risk of venous and arterial thrombosis with oral preparations is well established, however the risk with parenteral preparations has not been fully established. The mechanisms underlying these increased risks have not been fully elucidated. We report a case of mesenteric vein thrombosis associated with intravaginal hormonal contraception. A review of the current literature reveals no prior reports of this complication of intravaginal or transdermal hormonal therapy. When taking a medical history, it is imperative for physicians to be aware of all medications, including those not taken orally.
Journal of Thrombosis and Thrombolysis 05/2003; 15(2):105-8. · 1.48 Impact Factor
