Pharmacogenomics: Challenges and Opportunities

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

Molecular cloning and analysis of zebrafish voltage-gated sodium channel beta subunit genes: implications for the evolution of electrical signaling in vertebrates

<p>Abstract</p> <p>Background</p> <p>Action potential generation in excitable cells such as myocytes and neurons critically depends on voltage-gated sodium channels. In mammals, sodium channels exist as macromolecular complexes that include a pore-forming alpha subunit and 1 or more modulatory beta subunits. Although alpha subunit genes have been cloned from diverse metazoans including flies, jellyfish, and humans, beta subunits have not previously been identified in any non-mammalian species. To gain further insight into the evolution of electrical signaling in vertebrates, we investigated beta subunit genes in the teleost <it>Danio rerio </it>(zebrafish).</p> <p>Results</p> <p>We identified and cloned single zebrafish gene homologs for beta1-beta3 (<it>zbeta1-zbeta3</it>) and duplicate genes for beta4 (<it>zbeta4.1, zbeta4.2</it>). Sodium channel beta subunit loci are similarly organized in fish and mammalian genomes. Unlike their mammalian counterparts, <it>zbeta1 </it>and <it>zbeta2 </it>subunit genes display extensive alternative splicing. Zebrafish beta subunit genes and their splice variants are differentially-expressed in excitable tissues, indicating tissue-specific regulation of <it>zbeta1-4 </it>expression and splicing. Co-expression of the genes encoding zbeta1 and the zebrafish sodium channel alpha subunit Na_v1.5 in Chinese Hamster Ovary cells increased sodium current and altered channel gating, demonstrating functional interactions between zebrafish alpha and beta subunits. Analysis of the synteny and phylogeny of mammalian, teleost, amphibian, and avian beta subunit and related genes indicated that all extant vertebrate beta subunits are orthologous, that beta2/beta4 and beta1/beta3 share common ancestry, and that beta subunits are closely related to other proteins sharing the V-type immunoglobulin domain structure. Vertebrate sodium channel beta subunit genes were not identified in the genomes of invertebrate chordates and are unrelated to known subunits of the <it>para </it>sodium channel in <it>Drosophila</it>.</p> <p>Conclusion</p> <p>The identification of conserved orthologs to all 4 voltage-gated sodium channel beta subunit genes in zebrafish and the lack of evidence for beta subunit genes in invertebrate chordates together indicate that this gene family emerged early in vertebrate evolution, prior to the divergence of teleosts and tetrapods. The evolutionary history of sodium channel beta subunits suggests that these genes may have played a key role in the diversification and specialization of electrical signaling in early vertebrates.</p

Exaggerated QT prolongation after cardioversion of atrial fibrillation

AbstractOBJECTIVESThe purpose of this study was to test the hypothesis that the extent of drug-induced QT prolongation by dofetilide is greater in sinus rhythm (SR) after cardioversion compared with during atrial fibrillation (AF).BACKGROUNDAnecdotes suggest that when action potential–prolonging antiarrhythmic drugs are used for AF, excessive QT prolongation and torsades de pointes (TdP) often occur shortly after sinus rhythm is restored.METHODSQT was measured in nine patients with AF who received two identical infusions of dofetilide: 1) before elective direct current cardioversion and 2) within 24 h of restoration of SR.RESULTSDuring AF, dofetilide did not prolong QT (baseline: 368 ± 48 ms vs. drug: 391 ± 60, p = NS) whereas during SR, QT was prolonged from 405 ± 55 to 470 ± 67 ms (p < 0.01). In four patients (group I), the SR dofetilide infusion was terminated early because QT prolonged to >500 ms, and one patient developed asymptomatic nonsustained TdP. The remaining five patients (group II) received the entire dose during SR. Although ΔQT was greater in group I during SR (91 ± 22 vs. 45 ± 25 ms, p < 0.05), plasma dofetilide concentrations during SR were similar in the two groups (2.72 ± 0.96 vs. 2.77 ± 0.25 ng/ml), and in AF (2.76 ± 1.22 ng/ml). ΔQT in SR correlated inversely with baseline SR heart rate (r = −0.69, p < 0.05), and QT dispersion developing during the infusion (r = 0.79, p < 0.01).CONCLUSIONSShortly after restoration of SR, there was increased sensitivity to QT prolongation by this IKr-specific blocker. Slower heart rates after cardioversion and QT dispersion during treatment appear to be important predictors of this response

Electrophysiologic actions of high plasma concentrations of propranolol in human subjects

The authors have previously shown that 40% of patients whose ventricular arrhythmias respond to propranolol require plasma concentrations in excess of those producing substantial beta-receptor blockade (> 150 ng/ml). However, the electrophysiologic actions of propranolol have only been examined in human beings after small intravenous doses achieving concentrations of less than 100 ng/ml. In this study, the electrophysiologic effects of a wider concentration range of propranolol was examined in nine patients. Using a series of loading and maintenance infusions, measurements were made at baseline, at low mean plasma propranolol concentrations (104 ± 17 ng/ml) and at high concentrations (472 ± 68 ng/ml). Significant (p < 0.05) increases in AH interval and sinus cycle length were seen at low concentrations of propranolol, with no further prolongation at the high concentrations; these effects are typical of those produced by beta-blockade. However, progressive shortening of the endocardial monophasic action potential duration and QTc interval were seen over the entire concentration range tested (p < 0.05). At high concentrations, there was significant (p < 0.05) further shortening of both the QTc and monophasic action potential duration beyond that seen at low propranolol concentrations, along with a progressive increase in the ratio of the ventricular effective refractory period to monophasic action potential duration. No significant changes were seen in HV interval, QRS duration or ventricular effective refractory period.In summary, the concentration-response relations for atrioventricular conductivity and sinus node automat-icity were flat above concentrations of 150 ng/ml. On the other hand, the durations of the monophasic action potential and the QTc interval shortened at high concentrations. It is concluded that propranolol, in addition to blocking beta-receptors, produces other beta-receptor independent electrophysiologic effects in human beings

Enabling genomic-phenomic association discovery without sacrificing anonymity

Health information technologies facilitate the collection of massive quantities of patient-level data. A growing body of research demonstrates that such information can support novel, large-scale biomedical investigations at a fraction of the cost of traditional prospective studies. While healthcare organizations are being encouraged to share these data in a de-identified form, there is hesitation over concerns that it will allow corresponding patients to be re-identified. Currently proposed technologies to anonymize clinical data may make unrealistic assumptions with respect to the capabilities of a recipient to ascertain a patients identity. We show that more pragmatic assumptions enable the design of anonymization algorithms that permit the dissemination of detailed clinical profiles with provable guarantees of protection. We demonstrate this strategy with a dataset of over one million medical records and show that 192 genotype-phenotype associations can be discovered with fidelity equivalent to non-anonymized clinical data

Clinical and genetic determinants of warfarin pharmacokinetics and pharmacodynamics during treatment initiation

Variable warfarin response during treatment initiation poses a significant challenge to providing optimal anticoagulation therapy. We investigated the determinants of initial warfarin response in a cohort of 167 patients. During the first nine days of treatment with pharmacogenetics-guided dosing, S-warfarin plasma levels and international normalized ratio were obtained to serve as inputs to a pharmacokinetic-pharmacodynamic (PK-PD) model. Individual PK (S-warfarin clearance) and PD (I max) parameter values were estimated. Regression analysis demonstrated that CYP2C9 genotype, kidney function, and gender were independent determinants of S-warfarin clearance. The values for I max were dependent on VKORC1 and CYP4F2 genotypes, vitamin K status (as measured by plasma concentrations of proteins induced by vitamin K absence, PIVKA-II) and weight. Importantly, indication for warfarin was a major independent determinant of I max during initiation, where PD sensitivity was greater in atrial fibrillation than venous thromboembolism. To demonstrate the utility of the global PK-PD model, we compared the predicted initial anticoagulation responses with previously established warfarin dosing algorithms. These insights and modeling approaches have application to personalized warfarin therapy. © 2011 Gong et al