Showing papers by "Eric J. Topol published in 2010"

Corrigendum: Microdroplet-based PCR enrichment for large-scale targeted sequencing

Abstract: Nat. Biotechnol. 27, 1025–1031 (2009); published online 1 November 2009; corrected after print 11 November 2009 In the version of this article initially published, the email address for K.A.F. should have been kafrazer@ucsd.edu. The error has been corrected in the HTML and PDF versions of the article.

Bleeding Complications With Dual Antiplatelet Therapy Among Patients With Stable Vascular Disease or Risk Factors for Vascular Disease Results From the Clopidogrel for High Atherothrombotic Risk and Ischemic Stabilization, Management, and Avoidance (CHARISMA) Trial

Abstract: Background— Uncertainty exists about the frequency, correlates, and clinical significance of bleeding with dual antiplatelet therapy (DAPT), particularly over an extended period in a stable population. We sought to determine the frequency and time course of bleeding with DAPT in patients with established vascular disease or risk factors only; identify correlates of bleeding; and determine whether bleeding is associated with mortality. Methods and Results— We analyzed 15 603 patients enrolled in the Clopidogrel for High Atherothrombotic Risk and Ischemic Stabilization, Management, and Avoidance (CHARISMA) trial, a double-blind, placebo-controlled, randomized trial comparing long-term clopidogrel 75 mg/d versus placebo; all patients received aspirin (75 to 162 mg) daily. Patients had either established stable vascular disease or multiple risk factors for vascular disease without established disease. Median follow-up was 28 months. Bleeding was assessed with the use of the Global Utilization of Streptokinase...

Multicenter validation of the diagnostic accuracy of a blood-based gene expression test for assessing obstructive coronary artery disease in nondiabetic patients.

Abstract: Better noninvasive methods to distinguish patients with chest pain who have clinically important coronary artery disease (CAD) from those who do not would be useful. This study found a modest impro...

Longitudinal Genome-Wide Association of Cardiovascular Disease Risk Factors in the Bogalusa Heart Study

Abstract: Cardiovascular disease (CVD) is the leading cause of death worldwide. Recent genome-wide association (GWA) studies have pinpointed many loci associated with CVD risk factors in adults. It is unclear, however, if these loci predict trait levels at all ages, if they are associated with how a trait develops over time, or if they could be used to screen individuals who are presymptomatic to provide the opportunity for preventive measures before disease onset. We completed a genome-wide association study on participants in the longitudinal Bogalusa Heart Study (BHS) and have characterized the association between genetic factors and the development of CVD risk factors from childhood to adulthood. We report 7 genome-wide significant associations involving CVD risk factors, two of which have been previously reported. Top regions were tested for replication in the Young Finns Study (YF) and two associations strongly replicated: rs247616 in CETP with HDL levels (combined P=9.7610 224 ), and rs445925 at APOE with LDL levels (combined P=8.7610 219 ). We show that SNPs previously identified in adult cross-sectional studies tend to show age-independent effects in the BHS with effect sizes consistent with previous reports. Previously identified variants were associated with adult trait levels above and beyond those seen in childhood; however, variants with time-dependent effects were also promising predictors. This is the first GWA study to evaluate the role of common genetic variants in the development of CVD risk factors in children as they advance through adulthood and highlights the utility of using longitudinal studies to identify genetic predictors of adult traits in children.

Tirofiban as adjunctive therapy for acute coronary syndromes and percutaneous coronary intervention: a meta-analysis of randomized trials

Abstract: Aims To perform a thorough and updated systematic review of randomized clinical trials comparing tirofiban vs. placebo or vs. abciximab. Methods and results We searched for randomized trials comparing tirofiban vs. placebo or any active control. Odds ratios (OR) were computed from individual studies and pooled with random-effect methods. Thirty-one studies were identified involving 20 006 patients (12 874 comparing tirofiban vs. heparin plus placebo or bivalirudin alone, and 7132 vs. abciximab). When compared with placebo, tirofiban was associated at 30 days with a significant reduction in mortality [OR = 0.68 (0.54–0.86); P = 0.001] and death or myocardial infarction (MI) [OR = 0.69 (0.58–0.81); P < 0.001]. The treatment benefit persisted at follow-up but came at an increased risk of minor bleedings [OR = 1.42 (1.13, 1.79), P = 0.002] or thrombocytopenia. When compared with abciximab, mortality at 30 days did not differ [OR = 0.90 (0.53, 1.54); P = 0.70], but in the overall group tirofiban trended to increase the composite of death or MI [OR = 1.18 (0.96, 1.45); P = 0.11]. No such trend persisted at medium-term follow-up or when appraising studies testing tirofiban at 25 µg/kg bolus regimen. Conclusion Tirofiban administration reduces mortality, the composite of death or MI and increases minor bleedings when compared with placebo. An early ischaemic hazard disfavouring tirofiban was noted when compared with abciximab in studies based on 10 but not 25 µg/kg tirofiban bolus regimen.

Accurate detection and genotyping of SNPs utilizing population sequencing data

Abstract: Next-generation sequencing technologies have made it possible to sequence targeted regions of the human genome in hundreds of individuals. Deep sequencing represents a powerful approach for the discovery of the complete spectrum of DNA sequence variants in functionally important genomic intervals. Current methods for single nucleotide polymorphism (SNP) detection are designed to detect SNPs from single individual sequence data sets. Here, we describe a novel method SNIP-Seq (single nucleotide polymorphism identification from population sequence data) that leverages sequence data from a population of individuals to detect SNPs and assign genotypes to individuals. To evaluate our method, we utilized sequence data from a 200-kilobase (kb) region on chromosome 9p21 of the human genome. This region was sequenced in 48 individuals (five sequenced in duplicate) using the Illumina GA platform. Using this data set, we demonstrate that our method is highly accurate for detecting variants and can filter out false SNPs that are attributable to sequencing errors. The concordance of sequencing-based genotype assignments between duplicate samples was 98.8%. The 200-kb region was independently sequenced to a high depth of coverage using two sequence pools containing the 48 individuals. Many of the novel SNPs identified by SNIP-Seq from the individual sequencing were validated by the pooled sequencing data and were subsequently confirmed by Sanger sequencing. We estimate that SNIP-Seq achieves a low false-positive rate of approximately 2%, improving upon the higher false-positive rate for existing methods that do not utilize population sequence data. Collectively, these results suggest that analysis of population sequencing data is a powerful approach for the accurate detection of SNPs and the assignment of genotypes to individual samples.

Transforming Medicine via Digital Innovation

Abstract: The lack of plasticity of the medical profession and health care system in the face of new technology and information is about to be challenged on two major fronts in digital medicine: wireless technologies and genomics. These two areas have been characterized by unprecedented innovation and discovery at a breakneck pace. Whereas the 2000s saw the introduction of digital life-style devices, the 2010s will probably be known as the era of digital medical devices. These devices have exceptional promise for changing the future of medicine because of their ability to produce exquisitely detailed individual biological and physiological data.

Enoxaparin in Primary and Facilitated Percutaneous Coronary Intervention: A Formal Prospective Nonrandomized Substudy of the FINESSE Trial (Facilitated INtervention with Enhanced Reperfusion Speed to Stop Events)

Abstract: Objectives The aim of this study was to assess the risk-benefit of enoxaparin (Sanofi-Aventis, Paris, France) in primary percutaneous coronary intervention (PCI). Background Randomized studies have demonstrated the superiority of enoxaparin over unfractionated heparin (UFH) in acute ST-segment elevation myocardial infarction (STEMI) treated with fibrinolytics. Methods In the FINESSE (Facilitated INtervention with Enhanced Reperfusion Speed to Stop Events) trial—a double-blind, placebo-controlled study—2,452 patients with STEMI were randomized to primary PCI or facilitated PCI with abciximab alone or with half-dose reteplase. In this prospective FINESSE substudy, centers pre-specified use of either enoxaparin (0.5 mg/kg intravenous [IV], 0.3 mg/kg subcutaneous [SC]) or UFH (40 U/kg IV, 3,000 U maximum) with PCI. A logistic-regression model and a propensity multivariate model, both adjusted for baseline variables, were used to evaluate primary safety and secondary efficacy end points for enoxaparin versus UFH. Results Enoxaparin was administered to 759 patients and UFH to 1,693 patients. Nonintracranial Thrombolysis In Myocardial Infarction (TIMI) major/minor bleeding was not significantly different, but lower nonintracranial TIMI major bleeding was found with enoxaparin (2.6% vs. UFH 4.4%, logistic-regression adjusted odds ratio [OR]: 0.55; 95% confidence interval [CI]: 0.31 to 0.99, p = 0.045), whereas intracranial hemorrhage was similar (0.27% vs. 0.24%, adjusted OR: 1.03; 95% CI: 0.11 to 9.68, p = 0.980). Lower death, myocardial infarction, urgent revascularization, or refractory ischemia through 30 days was also associated with enoxaparin (5.3%) versus UFH (8.0%, adjusted OR: 0.47, 95% CI: 0.31 to 0.72, p = 0.0005) as was all-cause mortality through 90 days (3.8% vs. 5.6%, respectively, adjusted OR: 0.59, 95% CI: 0.35 to 0.99, p = 0.046). End points evaluating the net clinical benefit also significantly favored enoxaparin over UFH. Conclusions Enoxaparin seems to be associated with a lower risk of cardiovascular outcomes compared with UFH in patients with STEMI undergoing primary PCI. Confirmation of these findings in a randomized study is warranted. (A Study of Abciximab and Reteplase When Administered Prior to Catheterization After a Myocardial Infarction [Finesse]; NCT00046228)

Pilot study of the antiplatelet effect of increased clopidogrel maintenance dosing and its relationship to CYP2C19 genotype in patients with high on-treatment reactivity

Abstract: Objectives The objective of this study was to evaluate the antiplatelet effect of clopidogrel 150 mg/day in patients with high on-treatment reactivity (OTR) and to further assess this effect according to CYP2C19 genotype. Background High OTR is associated with ischemic events in clopidogrel-treated patients after percutaneous coronary intervention. Alternative dosing regimens might enhance platelet inhibition. Methods Patients with high OTR receiving a standard clopidogrel regimen were identified with the VerifyNow P2Y12 assay and administered clopidogrel 150 mg daily for 7 days, after which OTR was reassessed. Comprehensive CYP2C19 genotyping was performed with the BeadXpress platform (Illumina, San Diego, California) for the *2, *3, *4, *5, *6, *7, *8, and *17 variants. Results A total of 41 subjects were enrolled, 20 of whom were carriers of a CYP2C19 loss-of-function (LoF) allele. High-dose clopidogrel significantly reduced OTR from 285 ± 47 P2Y12 reaction units (PRU) to 220 ± 91 PRU (p Conclusions In patients with high OTR, clopidogrel 150 mg/day results in a significant reduction in platelet reactivity. Carriage of an LoF CYP2C19 polymorphism does not seem to have a major influence on dose effect. The observed lack of effect in patients with 2 copies of a CYP2C19 LoF allele must be confirmed by larger studies.

Population sequencing of two endocannabinoid metabolic genes identifies rare and common regulatory variants associated with extreme obesity and metabolite level

Abstract: Background Targeted re-sequencing of candidate genes in individuals at the extremes of a quantitative phenotype distribution is a method of choice to gain information on the contribution of rare variants to disease susceptibility The endocannabinoid system mediates signaling in the brain and peripheral tissues involved in the regulation of energy balance, is highly active in obese patients, and represents a strong candidate pathway to examine for genetic association with body mass index (BMI)

Effect of Clopidogrel on the Rate and Functional Severity of Stroke Among High Vascular Risk Patients A Prespecified Substudy of the Clopidogrel for High Atherothrombotic Risk and Ischemic Stabilization, Management and Avoidance (CHARISMA) Trial

Abstract: Background and Purpose— Disabling stroke is costly and considered by some patients a fate worse than death. We aimed to determine whether clopidogrel reduces the rate and functional severity of stroke among high vascular risk patients, including patients with previous transient ischemic attack or ischemic stroke, who were enrolled in the Clopidogrel for High Atherothrombotic Risk and Ischemic Stabilization, Management and Avoidance (CHARISMA) trial. Methods— We randomly assigned 15 603 high vascular risk patients to receive clopidogrel (75 mg daily) or placebo in addition to background acetylsalicylic acid and followed them for a median of 28 months. The main outcome of this prespecified substudy was the functional severity of stroke outcome events as measured by the modified Rankin Scale (mRS) score at 3 months after the stroke outcome. Results— During follow-up, 436 (2.8%) patients had a definite adjudicated stroke and a follow-up assessment of the mRS at 3 months poststroke, of whom 202 had been random...

Genotype-based risk and pharmacogenetic sampling in clinical trials.

Abstract: A number of recent genome-wide association (GWA) studies have identified unequivocal statistical associations between inherited genetic variations, mostly single-nucleotide polymorphisms (SNPs), and common complex diseases such as diabetes, cardiovascular disease, and obesity. Genotyping individuals for these variations has the potential to help redefine how pharmacologic agents undergo clinical development. By identifying carriers of known genomic variants that contribute to susceptibility, a high-risk population can be defined, as well as individuals with potential for a better response to a drug. We evaluated the potential utility that selecting individuals for a trial on the basis of genotypes identified in contemporary GWA studies would have had on recently described clinical trials. We pursued this by constraining both the risks of a disease outcome associated with particular genotypes and overall drug responses to those actually observed in genetic association and clinical trial studies, respectively. We pursued these evaluations in the context of clinical trials investigating drugs for macular degeneration, obesity, heart disease, type II diabetes, prostate cancer, and Alzheimer's disease. We show that the increase in incidence of outcomes in trials restricted to individuals with specific genotypic profiles can result in substantial reductions in requisite sample sizes for such trials. In addition, we also derive realistic bounds for samples sizes for clinical trials investigating pharmacogenetic effects that leverage genetic variations identified in recent association studies.

Longitudinal Genome-Wide Association of Cardiovascular Disease Risk Factors in the Bogalusa Heart Study

Abstract: Cardiovascular disease (CVD) is the leading cause of death worldwide. Recent genome-wide association (GWA) studies have pinpointed many loci associated with CVD risk factors in adults. It is unclear, however, if these loci predict trait levels at all ages, if they are associated with how a trait develops over time, or if they could be used to screen individuals who are pre-symptomatic to provide the opportunity for preventive measures before disease onset. We completed a genome-wide association study on participants in the longitudinal Bogalusa Heart Study (BHS) and have characterized the association between genetic factors and the development of CVD risk factors from childhood to adulthood. We report 7 genome-wide significant associations involving CVD risk factors, two of which have been previously reported. Top regions were tested for replication in the Young Finns Study (YF) and two associations strongly replicated: rs247616 in CETP with HDL levels (combined P = 9.7×10−24), and rs445925 at APOE with LDL levels (combined P = 8.7×10−19). We show that SNPs previously identified in adult cross-sectional studies tend to show age-independent effects in the BHS with effect sizes consistent with previous reports. Previously identified variants were associated with adult trait levels above and beyond those seen in childhood; however, variants with time-dependent effects were also promising predictors. This is the first GWA study to evaluate the role of common genetic variants in the development of CVD risk factors in children as they advance through adulthood and highlights the utility of using longitudinal studies to identify genetic predictors of adult traits in children.

Pharmacy Benefit Managers, Pharmacies, and Pharmacogenomic Testing: Prescription for Progress?

Abstract: Few would argue that the ability to match individual patients with the safest and most effective drugs and doses would be a major advance for clinical medicine. But while clinicians have been reluctant to routinely use pharmacogenomic analyses to guide their prescribing practices, pharmacy benefit managers and drugstores are proceeding with major pharmacogenetic initiatives.

Predictive value of high sensitivity C-reactive protein in the diagnosis and outcomes of acute aortic syndromes

Abstract: Objective The purpose of this study was to determine whether high-sensitivity C-reactive protein (hsCRP) levels differ among patients with acute aortic syndromes (AAS) and if hsCRP could predict their long-term outcomes. Design Retrospective observational study. Setting Cleveland Clinic Hospital, Cleveland, Ohio. Patients 115 consecutive patients with AAS admitted to the cardiac intensive care unit. Interventions HsCRP and other laboratory data were measured within 24 h of admission. Demographic, imaging and laboratory data were obtained at the time of presentation. For the long-term survival analysis, the social security death index was used to determine all-cause mortality. Main outcome measures HsCRP levels among AAS patients. Results Hospital mortality was 4.3% for AAS patients. HsCRP levels differed significantly among AAS; the median hsCRP was higher in the aortic dissection group (49 mg/l) than in those with penetrating aortic ulcer (28 mg/l), symptomatic aortic aneurysm (14 mg/l), and intramural haematoma (10 mg/l); (p=0.02). In multivariable analysis, aortic dissection patients had higher hsCRP levels than intramural haematoma (p=0.03) and symptomatic aortic aneurysm (p=0.04) patients, after adjusting for age and gender. Multivariable Cox regression analyses showed that elevated hsCRP levels at presentation were associated with a higher long-term mortality (p=0.007). Conclusions Among patients with AAS, those with aortic dissection have the highest hsCRP levels at presentation. Elevated hsCRP independently predicted a higher long-term mortality in AAS patients.

Response to Letter Regarding Article, “Smoking, Clopidogrel, and Mortality in Patients With Established Cardiovascular Disease”

Abstract: As noted by Dr Aboyans and colleagues, no interaction was noted in the effect of clopidogrel versus placebo on the composite outcome of nonfatal myocardial infarction, nonfatal stroke, or cardiovascular death in the Clopidogrel for High Atherothrombotic Risk and Ischemic Stabilization, Management, and Avoidance (CHARISMA) trial.1 However, in our recently published study,2 we demonstrated a significant interaction of the effect of clopidogrel versus placebo on all-cause mortality and cardiovascular mortality. Dr Aboyans et al suggest that the definition of current smoking may have differed between the 2 studies and that this may account for the difference in results. However, both the randomized trial and our recently published article used smoking ≥1 cigarette a day as the definition of current smoking. When the original randomized trial refers to smoking >15 cigarettes a day, that is referring to the definition of an atherothrombotic risk factor as a study inclusion criterion. As discussed in our recently published article, because smoking status was also used as an entry criterion for inclusion in the study for patients without established cardiovascular disease, patients without established cardiovascular disease were excluded from the smoking analysis. Nevertheless, our findings remained consistent whether we modified the definition of current smoking to ≥1, >5, >10, or >15 cigarettes a day.

Genomics of Myocardial Infarction

Abstract: Publisher Summary Coronary artery disease (CAD) and myocardial infarction (MI) are leading causes of death in the world. Although a number of risk factors contribute to the development of cardiovascular disease, a family history of CAD remains one of the most powerful independent predictors of risk. This suggests a significant genetic component to the disease. Several linkage studies suggest that the genes responsible for plaque rupture and thrombosis may differ from the genes responsible for atherosclerotic disease progression, which may account for the discrepancy. The catastrophic consequences of CAD are related to acute MI due to the rupture of vulnerable plaques and subsequent occlusive thrombosis. The molecular events that lead to plaque rupture and acute MI are influenced by a host of intricately related genetic factors involved in a variety of cellular processes such as inflammatory cascade, extracellular matrix regulation, apoptosis, and lipid metabolism. Advances in molecular biology provide an array of tools to elucidate the genetic factors underlying these diverse mechanisms. The recent discovery of a strong association of a region of chromosome 9p21 with MI has been replicated in four separate genome-wide association studies spanning multinational cohorts including thousands of cases and controls.