Identifying genetic risk factors for serious adverse drug reactions: current progress and challenges (original) (raw)

• Pirmohamed, M. & Park, B. K. Genetic susceptibility to adverse drug reactions. Trends Pharmacol. Sci. 22, 298–305 (2001). Review of adverse drug reaction (ADR) classifications and more common ADRs (in receptors, enzymes, transporters and immune response genes) with associations to genetic susceptibility.
  CAS PubMed Google Scholar
• Lazarou, J., Pomeranz, B. H. & Corey, P. N. Incidence of adverse drug reactions in hospitalized patients: a meta-analysis of prospective studies. JAMA 279, 1200–1205 (1998). Frequently cited meta-analysis of 39 prospective studies from US hospitals that determines the incidence of adverse drug reactions in US hospitals.
  CAS PubMed Google Scholar
• Severino, G. & Del Zompo, M. Adverse drug reactions: role of pharmacogenomics. Pharmacol. Res. 49, 363–373 (2004).
  CAS PubMed Google Scholar
• Pasanen, M. K., Neuvonen, M., Neuvonen, P. J. & Niemi, M. SLCO1B1 polymorphism markedly affects the pharmacokinetics of simvastatin acid. Pharmacogenet. Gen. 16, 873–879 (2006).
  CAS Google Scholar
• Giacomini, K. M. et al. When good drugs go bad. Nature 446, 975–977 (2007). An article highlighting the need for a global research consortium to study mechanisms and risk factors that contribute to severe adverse drug reactions.
  CAS PubMed Google Scholar
• Molokhia, M. & McKeigue, P. EUDRAGENE: European collaboration to establish a case-control DNA collection for studying the genetic basis of adverse drug reactions. Pharmacogenomics 7, 633–638 (2006).
  CAS PubMed Google Scholar
• Weatherall, D. J. Single gene disorders or complex traits: lessons from the thalassaemias and other monogenic diseases. BMJ 321, 1117–1120 (2000).
  CAS PubMed PubMed Central Google Scholar
• Beutler, E. Glucose-6-phosphate dehydrogenase deficiency. N. Engl. J. Med. 324, 169–174 (1991).
  CAS PubMed Google Scholar
• Barta, C. et al. Analysis of mutations in the plasma cholinesterase gene of patients with a history of prolonged neuromuscular block during anesthesia. Mol. Genet. Metab. 74, 484–488 (2001).
  CAS PubMed Google Scholar
• Lennard, L., Lilleyman, J. S., Van Loon, J. & Weinshilboum, R. M. Genetic variation in response to 6-mercaptopurine for childhood acute lymphoblastic leukaemia. Lancet 336, 225–229 (1990).
  CAS PubMed Google Scholar
• Center for Drug Evaluation and Research. Improving publich health through human drugs. FDA (online) 2005.
• Tufts Center for the Study of Drug Development. Drug safety withdrawals in the US not linked to speed of FDA approval. Tufts University (online) 2005.
• Committee on the assessment of the US drug safety. The Future of Drug Safety: Promoting and Protecting the Health of the Public (The National Academies Press, Washington DC, 2006).
• Hennessy, S. & Strom, B. L. PDUFA reauthorization — drug safety's golden moment of opportunity? N. Engl. J. Med. 356, 1703–1704 (2007).
  CAS PubMed Google Scholar
• DiMasi, J. A., Hansen, R. W. & Grabowski, H. G. The price of innovation: new estimates of drug development costs. J. Health Econ. 22, 151–185 (2003).
  PubMed Google Scholar
• Phillips, K. A., Veenstra, D. L., Oren, E., Lee, J. K. & Sadee, W. Potential role of pharmacogenomics in reducing adverse drug reactions: a systematic review. JAMA 286, 2270–2279 (2001). A comprehensive, systematic review of the literature on 27 frequently cited drugs in ADRs and the role of potential role of pharmacogenomics in reducing ADRs.
  CAS PubMed Google Scholar
• Hetherington, S. et al. Genetic variations in HLA-B region and hypersensitivity reactions to abacavir. Lancet 359, 1121–1122 (2002).
  CAS PubMed Google Scholar
• Chung, W. H. et al. Medical genetics: a marker for Stevens-Johnson syndrome. Nature 428, 486 (2004).
  CAS PubMed Google Scholar
• Watkins, P. B. Idiosyncratic liver injury: challenges and approaches. Toxicol. Pathol. 33, 1–5 (2005). A paper that outlines the clinical presentation of drug-induced liver injury with a special focus on severe drug-induced liver injury (DILI). To fully understand DILI, the author highlights the need for pharmacogenetic studies as well as focused and well-controlled phenotype/genotype studies of patients who have survived this type of injury.
  CAS PubMed Google Scholar
• Meier, Y. et al. Incidence of drug-induced liver injury in medical inpatients. Eur. J. Clin. Pharmacol. 61, 135–143 (2005).
  PubMed Google Scholar
• Ostapowicz, G. et al. Results of a prospective study of acute liver failure at 17 tertiary care centers in the United States. Ann. Intern. Med. 137, 947–954 (2002).
  PubMed Google Scholar
• Bissell, D. M., Gores, G. J., Laskin, D. L. & Hoofnagle, J. H. Drug-induced liver injury: mechanisms and test systems. Hepatology 33, 1009–1013 (2001).
  CAS PubMed Google Scholar
• Maddrey, W. C. Drug-induced hepatotoxicity: 2005. J. Clin. Gastroenterol. 39, S83–S89 (2005).
  PubMed Google Scholar
• Watkins, P. B. & Whitcomb, R. W. Hepatic dysfunction associated with troglitazone. N. Engl. J. Med. 338, 916–917 (1998).
  CAS PubMed Google Scholar
• Zimmerman, H. J. Hepatotoxicity the Adverse Effects of Drugs and Other Chemicals on the Liver (Lippincott Williams & Wilkins, Baltimore, 1999).
  Google Scholar
• Kaplowitz, N. Idiosyncratic drug hepatotoxicity. Nature Rev. Drug Discov. 4, 489–499 (2005). Examines the current understanding of the pathophysiology of idiosyncratic drug hepatotoxicity, outlines its clinical signatures and the role of monitoring in prevention.
  CAS Google Scholar
• Hoofnagle, J. H. Drug-induced liver injury network (DILIN). Hepatology. 40, 773 (2004). A description of the drug-induced liver injury network as a network to advance understanding of drug-induced liver disease.
  PubMed Google Scholar
• Lucena, M. I., Camargo, R., Andrade, R. J., Perez-Sanchez, C. J. & Sanchez De La Cuesta, F. Comparison of two clinical scales for causality assessment in hepatotoxicity. Hepatology. 33, 123–130 (2001).
  CAS PubMed Google Scholar
• Randomised trial of cholesterol lowering in 4444 patients with coronary heart disease: the Scandinavian Simvastatin Survival Study (4S). Lancet 344, 1383–1389 (1994).
• Shepherd, J. et al. Prevention of coronary heart disease with pravastatin in men with hypercholesterolemia. West of Scotland coronary prevention study group. N. Engl. J. Med. 333, 1301–1307 (1995).
  CAS PubMed Google Scholar
• Yee, H. S. & Fong, N. T. Atorvastatin in the treatment of primary hypercholesterolemia and mixed dyslipidemias. Ann. Pharmacother. 32, 1030–1043 (1998).
  CAS PubMed Google Scholar
• Thompson, P. D., Clarkson, P. & Karas, R. H. Statin-associated myopathy. JAMA 289, 1681–1690 (2003).
  CAS PubMed Google Scholar
• McKenney, J. M., Davidson, M. H., Jacobson, T. A. & Guyton, J. R. Final conclusions and recommendations of the National Lipid Association Statin Safety Assessment Task Force. Am. J. Cardiol 97, 89–94 (2006). This article summarizes the final conclusions of the national lipid association (NLA) statin safety task force, based on a review and independent research of new drug application information, FDA adverse event reporting system (AERS) data, cohort and clinical trial results, analysis of administrative claims database information and the assessment of its four expert panels, which focused on issues of statin safety with regard to liver, muscle, renal and neurologic systems.
  Google Scholar
• McClure, D. L., Valuck, R. J., Glanz, M., Murphy, J. R. & Hokanson, J. E. Statin and statin-fibrate use was significantly associated with increased myositis risk in a managed care population. J. Clin. Epidemiol. 60, 812–818 (2007).
  PubMed Google Scholar
• Thompson, P. D., Clarkson, P. M. & Rosenson, R. S. An assessment of statin safety by muscle experts. Am. J. Cardiol 97, 69-76 (2006).
• Phillips, P. S. et al. Statin-associated myopathy with normal creatine kinase levels. Ann. Intern. Med. 137, 581–585 (2002).
  PubMed Google Scholar
• Pasternak, R. C. et al. ACC/AHA/NHLBI clinical advisory on the use and safety of statins. Circulation 106, 1024–1028 (2002).
  PubMed Google Scholar
• Chan, J., Hui, R. L. & Levin, E. Differential association between statin exposure and elevated levels of creatine kinase. Ann. Pharmacother. 39, 1611–1616 (2005).
  CAS PubMed Google Scholar
• Wilke, R. A., Moore, J. H. & Burmester, J. K. Relative impact of CYP3A genotype and concomitant medication on the severity of atorvastatin-induced muscle damage. Pharmacogenet. Gen. 15, 415–421 (2005). Association study using a retrospective cohort to determine whether there is an association of genetic variants of CYP3A with atorvastatin-induced muscle-damage.
  CAS Google Scholar
• Draeger, A. et al. Statin therapy induces ultrastructural damage in skeletal muscle in patients without myalgia. J. Pathol. 210, 94–102 (2006).
  CAS PubMed Google Scholar
• Graham, D. J. et al. Incidence of hospitalized rhabdomyolysis in patients treated with lipid-lowering drugs. JAMA 292, 2585–2590 (2004).
  CAS PubMed Google Scholar
• Davidson, M. H. Rosuvastatin safety: lessons from the FDA review and post-approval surveillance. Expert Opin. Drug Saf. 3, 547–557 (2004).
  CAS PubMed Google Scholar
• Ferdinand, K. C. Rosuvastatin: a risk-benefit assessment for intensive lipid lowering. Expert Opin. Pharmacother. 6, 1897–1910 (2005).
  CAS PubMed Google Scholar
• Lennernas, H. Clinical pharmacokinetics of atorvastatin. Clin. Pharmacokinet 42, 1141–1160 (2003).
  PubMed Google Scholar
• Gibson, D. M. et al. Effect of age and gender on pharmacokinetics of atorvastatin in humans. J. Clin. Pharmacol. 36, 242–246 (1996).
  CAS PubMed Google Scholar
• Worz, C. R. & Bottorff, M. The role of cytochrome P450-mediated drug–drug interactions in determining the safety of statins. Expert Opin. Pharmacother. 2, 1119–1127 (2001).
  CAS PubMed Google Scholar
• Neuvonen, P. J., Kantola, T. & Kivisto, K. T. Simvastatin but not pravastatin is very susceptible to interaction with the CYP3A4 inhibitor itraconazole. Clin. Pharmacol. Ther. 63, 332–341 (1998).
  CAS PubMed Google Scholar
• Bullen, W. W., Miller, R. A. & Hayes, R. N. Development and validation of a high-performance liquid chromatography tandem mass spectrometry assay for atorvastatin, ortho-hydroxy atorvastatin, and para-hydroxy atorvastatin in human, dog, and rat plasma. J. Am. Soc. Mass Spectrom. 10, 55–66 (1999).
  CAS PubMed Google Scholar
• Nordin, C., Dahl, M. L., Eriksson, M. & Sjoberg, S. Is the cholesterol-lowering effect of simvastatin influenced by CYP2D6 polymorphism? Lancet 350, 29–30 (1997).
  CAS PubMed Google Scholar
• Mulder, A. B. et al. Association of polymorphism in the cytochrome CYP2D6 and the efficacy and tolerability of simvastatin. Clin. Pharmacol. Ther. 70, 546–551 (2001).
  CAS PubMed Google Scholar
• Geisel, J., Kivisto, K. T., Griese, E. U. & Eichelbaum, M. The efficacy of simvastatin is not influenced by CYP2D6 polymorphism. Clin. Pharmacol. Ther. 72, 595–596 (2002).
  PubMed Google Scholar
• Mulder, A. B., van den Bergh, F. A. & Vermes, I. Response to “The efficacy of simvastatin is not influenced by CYP2D6 polymorphism” by Geisel et al. Clin. Pharmacol. Ther. 73, 475 (2003).
  CAS PubMed Google Scholar
• Prueksaritanont, T., Ma, B. & Yu, N. The human hepatic metabolism of simvastatin hydroxy acid is mediated primarily by CYP3A, and not CYP2D6. Br. J. Clin. Pharmacol. 56, 120–124 (2003).
  CAS PubMed PubMed Central Google Scholar
• Kirchheiner, J. et al. Influence of CYP2C9 polymorphisms on the pharmacokinetics and cholesterol-lowering activity of (–)-3S, 5R-fluvastatin and (+)-3R, 5S-fluvastatin in healthy volunteers. Clin. Pharmacol. Ther. 74, 186–194 (2003).
  CAS PubMed Google Scholar
• Kirchheiner, J., Roots, I., Goldammer, M., Rosenkranz, B. & Brockmoller, J. Effect of genetic polymorphisms in cytochrome p450 (CYP) 2C9 and CYP2C8 on the pharmacokinetics of oral antidiabetic drugs: clinical relevance. Clin. Pharmacokinet 44, 1209–1225 (2005).
  CAS PubMed Google Scholar
• Mauro, V. F. Clinical pharmacokinetics and practical applications of simvastatin. Clin. Pharmacokinet 24, 195–202 (1993).
  CAS PubMed Google Scholar
• Prueksaritanont, T. et al. Effects of fibrates on metabolism of statins in human hepatocytes. Drug Metab. Dispos. 30, 1280–1287 (2002).
  CAS PubMed Google Scholar
• Jemal, M., Ouyang, Z., Chen, B. C. & Teitz, D. Quantitation of the acid and lactone forms of atorvastatin and its biotransformation products in human serum by high-performance liquid chromatography with electrospray tandem mass spectrometry. Rapid Commun. Mass Spectrom. 13, 1003–1015 (1999).
  CAS PubMed Google Scholar
• Prueksaritanont, T. et al. Mechanistic studies on metabolic interactions between gemfibrozil and statins. J. Pharmacol. Exp. Ther. 301, 1042–1051 (2002).
  CAS PubMed Google Scholar
• Shitara, Y., Hirano, M., Sato, H. & Sugiyama, Y. Gemfibrozil and its glucuronide inhibit the organic anion transporting polypeptide 2 (OATP2/OATP1B1:SLC21A6)-mediated hepatic uptake and CYP2C8-mediated metabolism of cerivastatin: analysis of the mechanism of the clinically relevant drug–drug interaction between cerivastatin and gemfibrozil. J. Pharmacol. Exp. Ther. 311, 228–236 (2004).
  CAS PubMed Google Scholar
• Schneck, D. W. et al. The effect of gemfibrozil on the pharmacokinetics of rosuvastatin. Clin. Pharmacol. Ther. 75, 455–463 (2004).
  CAS PubMed Google Scholar
• Nishizato, Y. et al. Polymorphisms of OATP-C (SLC21A6) and OAT3 (SLC22A8) genes: consequences for pravastatin pharmacokinetics. Clin. Pharmacol. Ther. 73, 554–565 (2003).
  CAS PubMed Google Scholar
• Mwinyi, J., Johne, A., Bauer, S., Roots, I. & Gerloff, T. Evidence for inverse effects of OATP-C (SLC21A6) 5 and 1b haplotypes on pravastatin kinetics. Clin. Pharmacol. Ther. 75, 415–421 (2004).
  CAS PubMed Google Scholar
• Niemi, M., Pasanen, M. K. & Neuvonen, P. J. SLCO1B1 polymorphism and sex affect the pharmacokinetics of pravastatin but not fluvastatin. Clin. Pharmacol. Ther. 80, 356–366 (2006).
  CAS PubMed Google Scholar
• Wilke, R. A., Reif, D. M. & Moore, J. H. Combinatorial pharmacogenetics. Nature Rev. Drug Discovery 4, 911–918 (2005). A review proposing the application of multifactor dimensionality reduction to defining gene–gene interactions directed toward the characterization of drug-treatment outcomes, especially targeting polymorphic drug-metabolizing enzymes and their role in adverse drug reactions.
  CAS Google Scholar
• Ishikawa, C. et al. A frameshift variant of CYP2C8 was identified in a patient who suffered from rhabdomyolysis after administration of cerivastatin. J. Hum. Genet. 49, 582–585 (2004).
  PubMed Google Scholar
• Morimoto, K. et al. A novel variant allele of OATP-C (SLCO1B1) found in a Japanese patient with pravastatin-induced myopathy. Drug Metab. Pharmacokinet 19, 453–455 (2004).
  CAS PubMed Google Scholar
• Fiegenbaum, M. et al. The role of common variants of ABCB1, CYP3A4, and CYP3A5 genes in lipid-lowering efficacy and safety of simvastatin treatment. Clin. Pharmacol. Ther. 78, 551–558 (2005).
  CAS PubMed Google Scholar
• Vladutiu, G. D. et al. Genetic risk factors associated with lipid-lowering drug-induced myopathies. Muscle Nerve 34, 153–162 (2006).
  CAS PubMed Google Scholar
• Oh, J., Ban, M. R., Miskie, B. A., Pollex, R. L. & Hegele, R. A. Genetic determinants of statin intolerance. Lipids Health Dis. 6, 7 (2007).
  PubMed PubMed Central Google Scholar
• Roden, D. M., Woosley, R. L. & Primm, R. K. Incidence and clinical features of the quinidine-associated long QT syndrome: implications for patient care. Am.Heart J. 111, 1088–1093 (1986).
  CAS PubMed Google Scholar
• Soyka, L. F., Wirtz, C. & Spangenberg, R. B. Clinical safety profile of sotalol in patients with arrhythmias. Am.J. Cardiol. 65, 74–81 (1990).
  Google Scholar
• Stambler, B. S. et al. Efficacy and safety of repeated intravenous doses of ibutilide for rapid conversion of atrial flutter or fibrillation. Circulation 94, 1613–1621 (1996).
  CAS PubMed Google Scholar
• Torp-Pedersen, C. et al. Dofetilide in patients with congestive heart failure and left ventricular dysfunction. Danish Investigations of Arrhythmia and Mortality on Dofetilide Study Group. N. Engl. J. Med. 341, 857–865 (1999).
  CAS PubMed Google Scholar
• Torp-Pedersen, C., Moller, M., Kober, L. & Camm, A. J. Dofetilide for the treatment of atrial fibrillation in patients with congestive heart failure. Eur. Heart J. 21, 1204–1206 (2000).
  CAS PubMed Google Scholar
• Kay, G. N., Plumb, V. J., Arciniegas, J. G., Henthorn, R. W. & Waldo, A. L. Torsades de pointes: The long-short initiating sequence and other clinical features: Observations in 32 patients. J. Am. Coll. Cardiol. 2, 806–817 (1983).
  CAS PubMed Google Scholar
• Viskin, S., Justo, D., Halkin, A. & Zeltser, D. Long QT syndrome caused by noncardiac drugs. Prog. Cardiovasc. Dis. 45, 415–427 (2003).
  CAS PubMed Google Scholar
• Dangman, K. H. & Hoffman, B. F. In vivo and in vitro antiarrhythmic and arrhythmogenic effects of _N_-acetyl procainamide. J. Pharmacol. Exp. Ther. 217, 851–862 (1981).
  CAS PubMed Google Scholar
• Strauss, H. C., Bigger, J. T. & Hoffman, B. F. Electrophysiological and beta-receptor blocking effects of MJ 1999 on dog and rabbit cardiac tissue. Circ. Res. 26, 661–678 (1970).
  CAS PubMed Google Scholar
• Antzelevitch, C. et al. Heterogeneity within the ventricular wall: electrophysiology and pharmacology of epicardial, endocardial, and M cells. Circ. Res. 69, 1427–1449 (1991).
  CAS PubMed Google Scholar
• Davidenko, J. M., Cohen, L., Goodrow, R. & Antzelevitch, C. Quinidine-induced action potential prolongation, early afterdepolarizations, and triggered activity in canine Purkinje fibers. Circulation 79, 674–686 (1989).
  CAS PubMed Google Scholar
• Roden, D. M. & Hoffman, B. F. Action potential prolongation and induction of abnormal automaticity by low quinidine concentrations in canine Purkinje fibers. Relationship to potassium and cycle length. Circ. Res. 56, 857–867 (1985).
  CAS PubMed Google Scholar
• Choy, A. M. J., Darbar, D., Dell'Orto, S. & Roden, D. M. Increased sensitivity to QT prolonging drug therapy immediately after cardioversion to sinus rhythm. J. Am. Coll. Cardiol. 34, 396–401 (1999).
  CAS PubMed Google Scholar
• Makkar, R. R., Fromm, B. S., Steinman, R. T., Meissner, M. D. & Lehmann, M. H. Female gender as a risk factor for torsades de pointes associated with cardiovascular drugs. JAMA 270, 2590–2597 (1993).
  CAS PubMed Google Scholar
• Roden, D. M. Drug-induced prolongation of the QT Interval. N. Engl. J. Med. 350, 1013–1022 (2004).
  CAS PubMed Google Scholar
• Roden, D. M. An underrecognized challenge in evaluating postmarketing drug safety. Circulation 111, 246–248 (2005).
  PubMed Google Scholar
• Roden, D. M. & Viswanathan, P. C. Genetics of acquired long QT syndrome. J. Clin. Invest. 115, 2025–2032 (2005).
  CAS PubMed PubMed Central Google Scholar
• Fenichel, R. R. et al. Drug-induced torsades de pointes and implications for drug development. J. Cardiovasc. Electrophysiol. 15, 475–495 (2004). One of several reviews on the implications for drug development and regulation of the link between HERG/I Kr channel block and drug-induced torsades de pointes.
  PubMed PubMed Central Google Scholar
• Haverkamp, W. et al. The potential for QT prolongation and proarrhythmia by non-antiarrhythmic drugs: clinical and regulatory implications. Report on a policy conference of the European Society of Cardiology. Eur. Heart J. 21, 1216–1231 (2000).
  CAS PubMed Google Scholar
• Anderson, M. E., Al Khatib, S. M., Roden, D. M. & Califf, R. M. Cardiac repolarization: current knowledge, critical gaps, and new approaches to drug development and patient management. Am. Heart J. 144, 769–781 (2002).
  CAS PubMed Google Scholar
• Jervell, A. & Lange-Nielsen, F. Congenital deaf-mutism, functional heart disease with prolongation of the QT interval and sudden death. Am. Heart J. 54, 59–68 (1957).
  CAS PubMed Google Scholar
• Romano, C., Gemme, G. & Pongiglione, R. Aritmie cardiache rare in eta' pediatrica. Clin. Pediatr. 45, 656–683 (1963).
  CAS Google Scholar
• Ward, O. C. A new familial cardiac syndrome in children. J. Irish Med. Assoc. 54, 103–106 (1964).
  CAS Google Scholar
• Abbott, G. W. et al. MiRP1 forms IKr potassium channels with HERG and is associated with cardiac arrhythmia. Cell 97, 175–187 (1999).
  CAS PubMed Google Scholar
• Curran, M. E. et al. A molecular basis for cardiac arrhythmia: HERG mutations cause long QT syndrome. Cell 80, 795–803 (1995).
  CAS PubMed Google Scholar
• Domingo A. et al. Sodium channel β4 subunit mutation causes congenital long QT syndrome. Heart Rhythm 5, S34 (2006).
  Google Scholar
• Mohler, P. J. et al. Ankyrin-B mutation causes type 4 long-QT cardiac arrhythmia and sudden cardiac death. Nature 421, 634–639 (2003).
  CAS PubMed Google Scholar
• Plaster, N. M. et al. Mutations in Kir2.1 cause the developmental and episodic electrical phenotypes of Andersen's Syndrome. Cell 105, 511–5199 (2001).
  CAS PubMed Google Scholar
• Splawski, I. et al. Ca(V)1.2 calcium channel dysfunction causes a multisystem disorder including arrhythmia and autism. Cell 119, 19–31 (2004).
  CAS PubMed Google Scholar
• Splawski, I., Tristanti-Firouzi, M., Lehmann, M. H., Sanguinetti, M. C. & Keating, M. T. Mutations in the hminK gene cause long QT syndrome and suppress IKs function. Nature Genet. 17, 338–340 (1997).
  CAS PubMed Google Scholar
• Vatta, M. et al. Mutant caveolin-3 induces persistent late sodium current and is associated with long-QT syndrome. Circulation 114, 2104–2112 (2006).
  CAS PubMed Google Scholar
• Wang, Q. et al. Positional cloning of a novel potassium channel gene: KVLQT1 mutations cause cardiac arrhythmias. Nature Genet. 12, 17–23 (1996).
  PubMed Google Scholar
• Wang, Q. et al. SCN5A mutations associated with an inherited cardiac arrhythmia, long QT syndrome. Cell 80, 805–811 (1995).
  CAS PubMed Google Scholar
• Domingo A. Sodium channel á4 subunit mutation causes congenital long QT syndrome. Heart Rhythm 3, S34 (2006).
  Google Scholar
• Roden, D. M. et al. Multiple mechanisms in the long QT syndrome: current knowledge, gaps and future directions. Circulation 94, 1996–2012 (1996).
  CAS PubMed Google Scholar
• Sanguinetti, M. C., Jiang, C., Curran, M. E. & Keating, M. T. A mechanistic link between an inherited and an acquired cardiac arrhythmia: HERG encodes the IKr potassium channel. Cell 81, 299–307 (1995).
  CAS PubMed Google Scholar
• Belardinelli, L., Antzelevitch, C. & Vos, M. A. Assessing predictors of drug-induced torsade de pointes. Trends Pharmacol. Sci. 24, 619–625 (2003).
  CAS PubMed Google Scholar
• Opthof, T. et al. Dispersion of repolarization in canine ventricle and the electrocardiographic T wave: Tp-e interval does not reflect transmural dispersion. Heart Rhythm. 4, 341–348 (2007).
  PubMed Google Scholar
• Opthof, T., Coronel, R., Janse, M. J. & Rosen, M. R. A wedge is not a heart. Heart Rhythm. 4, 1116–1119 (2007).
  Google Scholar
• Szabo, B., Sweidan, R., Rajagopalan, C. B. & Lazzara, R. Role of Na+:Ca2+ exchange current in Cs+-induced early after-depolarizations in Purkinje fibers. J. Cardiovasc. Electrophysiol. 5, 933–944 (1994).
  CAS PubMed Google Scholar
• Priori, S. G., Napolitano, C. & Schwartz, P. J. Low penetrance in the long-QT syndrome: clinical impact. Circulation 99, 529–533 (1999).
  CAS PubMed Google Scholar
• Donger, C. et al. KVLQT1 C-terminal missense mutation causes a forme fruste long-QT syndrome. Circulation 96, 2778–2781 (1997).
  CAS PubMed Google Scholar
• Napolitano, C. et al. Evidence for a cardiac ion channel mutation underlying drug-induced QT prolongation and life-threatening arrhythmias. J. Cardiovasc. Electrophysiol. 11, 691–696 (2000).
  CAS PubMed Google Scholar
• Yang, P. et al. Allelic variants in long QT disease genes in patients with drug-associated torsades de pointes. Circulation 105, 1943–1948 (2002). Examines the role of variants in the congenital long QT syndrome disease genes as modulators of the normal QT or of risk for acquired forms of the disease.
  CAS PubMed Google Scholar
• Sesti, F. et al. A common polymorphism associated with antibiotic-induced cardiac arrhythmia. Proc. Natl Acad. Sci. 97, 10613–10618 (2000).
  CAS PubMed PubMed Central Google Scholar
• Mohler, P. J. et al. Defining the cellular phenotype of “Ankyrin-B Syndrome” variants: Human ANK2 variants associated with clinical phenotypes display a spectrum of activities in cardiomyocytes. Circulation 115, 432–441 (2007).
  PubMed Google Scholar
• Wei, J. et al. KCNE1 polymorphism confers risk of drug-induced long QT syndrome by altering kinetic properties of IKs potassium channels. Circulation 100, 495 (1999).
  Google Scholar
• Plant, L. D. et al. A common cardiac sodium channel variant associated with sudden infant death in African Americans, SCN5A S1103Y. J. Clin. Invest. 116, 430–435 (2006).
  CAS PubMed PubMed Central Google Scholar
• Splawski, I. et al. Variant of SCN5A sodium channel implicated in risk of cardiac arrhythmia. Science 297, 1333–1336 (2002).
  CAS PubMed Google Scholar
• Pfeufer, A. et al. Common variants in myocardial ion channel genes modify the QT interval in the general population: results from the KORA study. Circ. Res. 96, 693–701 (2005). Examines the role of variants in the congenital LQTS disease genes as modulators of the normal QT or of risk for acquired forms of the disease.
  CAS PubMed Google Scholar
• Arking, D. E. et al. A common genetic variant in the NOS1 regulator NOS1AP modulates cardiac repolarization. Nature Genet. 38, 644–651 (2006). A paper that uses genome-wide association to identify a locus in NOS1AP that modulates normal QT.
  CAS PubMed Google Scholar
• Woosley, R. L., Chen, Y., Freiman, J. P. & Gillis, R. A. Mechanism of the cardiotoxic actions of terfenadine. JAMA 269, 1532–1536 (1993).
  CAS PubMed Google Scholar
• Roden, D. M. Taking the idio out of idiosyncratic - predicting torsades de pointes. Pacing Clin. Electrophysiol. 21, 1029–1034 (1998).
  CAS PubMed Google Scholar
• Jost, N. et al. Restricting excessive cardiac action potential and QT prolongation: a vital role for IKs in human ventricular muscle. Circulation 112, 1392–1399 (2005).
  PubMed Google Scholar
• Silva, J. & Rudy, Y. Subunit interaction determines IKs participation in cardiac repolarization and repolarization reserve. Circulation 112, 1384–1391 (2005).
  PubMed PubMed Central Google Scholar
• Lesko, L. J. & Woodcock, J. Translation of pharmacogenomics and pharmacogenetics: a regulatory perspective. Nature Rev. Drug Discov. 3, 763–769 (2004).
  CAS Google Scholar
• Lesko, L. J. et al. Pharmacogenetics and pharmacogenomics in drug development and regulatory decision making: report of the first FDA-PWG-PhRMA-DruSafe Workshop. J. Clin. Pharmacol. 43, 342–358. (2003).
  CAS PubMed Google Scholar
• Campbell, G. Some statistical and regulatory issues in the evaluation of genetic and genomic tests. J. Biopharm Stat. 14, 539–552. (2004).
  PubMed Google Scholar
• Genome-wide association study of 14,000 cases of seven common diseases and 3,000 shared controls. Nature 447, 661–678 (2007).
• Haga, S. B., Thummel, K. E. & Burke, W. Adding pharmacogenetics information to drug labels: lessons learned. Pharmacogenet. Genomics 16, 847–854 (2006).
  CAS PubMed Google Scholar
• Prometheus, Laboratories Inc., Imuran (azathioprine), NDA 16-324/S-030 (online) 2005.
• Questions and answers on new labelling for warfarin (marketed as Coumadin). FDA (online) 2007.
• Pazdur, R. Changes in Camptosar package insert regarding dosing recommendations and risk assessment in patients with UGT1A1 enzyme deficiency. FDA (online) 2005.
  Google Scholar
• Kindmark, A. et al. Genome-wide pharmacogenetic investigation of a hepatic adverse event without clinical signs of immunopathology suggests an underlying immune pathogenesis. Pharmacogenomics J. 15, 15 (2007).
  Google Scholar
• Acuna, G. et al. Pharmacogenetic analysis of adverse drug effect reveals genetic variant for susceptibility to liver toxicity. Pharmacogenomics J. 2, 327–334 (2002).
  CAS PubMed Google Scholar
• Daly, A. K. et al. Genetic susceptibility to diclofenac-induced hepatotoxicity: contribution of UGT2B7, CYP2C8, and ABCC2 genotypes. Gastroenterology 132, 272–281 (2007).
  CAS PubMed Google Scholar
• Danoff, T. M. et al. A Gilbert's syndrome UGT1A1 variant confers susceptibility to tranilast-induced hyperbilirubinemia. Pharmacogenomics J. 4, 49–53 (2004).
  CAS PubMed Google Scholar
• Huang, Y. S. et al. Cytochrome P450 2E1 genotype and the susceptibility to antituberculosis drug-induced hepatitis. Hepatology 37, 924–930 (2003).
  CAS PubMed Google Scholar
• Roy., B. et al. Increased risk of antituberculosis drug-induced hepatotoxicity in individuals with glutathione _S_-transferase M1 'null' mutation. J. Gastroenterol. Hepatol. 16, 1033–1037 (2001).
  CAS Google Scholar
• Sharma, S. K., Balamurugan, A., Saha, P. K., Pandey, R. M. & Mehra, N. K. Evaluation of clinical and immunogenetic risk factors for the development of hepatotoxicity during antituberculosis treatment. Am. J. Respir. Crit. Care Med. 166, 916–919 (2002).
  PubMed Google Scholar
• O'Donohue, J. et al. Co-amoxiclav jaundice: clinical and histological features and HLA class II association. Gut 47, 717–720 (2000).
  CAS PubMed PubMed Central Google Scholar
• Simon, T. et al. Combined glutathione-_S_-transferase M1 and T1 genetic polymorphism and tacrine hepatotoxicity. Clin. Pharmacol. Ther. 67, 432–437 (2000).
  CAS PubMed Google Scholar
• Watanabe, I. et al. A study to survey susceptible genetic factors responsible for troglitazone-associated hepatotoxicity in Japanese patients with type 2 diabetes mellitus. Clin. Pharmacol. Ther. 73, 435–455 (2003).
  CAS PubMed Google Scholar
• Harrison-Woolrych, M., Clark, D. W., Hill, G. R., Rees, M. I. & Skinner, J. R. QT interval prolongation associated with sibutramine treatment. Br. J. Clin. Pharmacol. 61, 464–469 (2006).
  CAS PubMed PubMed Central Google Scholar
• Fitzgerald, P. T. & Ackerman, M. J. Drug-induced torsades de pointes: the evolving role of pharmacogenetics. Heart Rhythm 2, S30–S37 (2005).
  PubMed Google Scholar
• Paulussen, A. D. et al. Genetic variations of KCNQ1, KCNH2, SCN5A, KCNE1, and KCNE2 in drug-induced long QT syndrome patients. J. Mol. Med. 82, 182–188 (2004).
  CAS PubMed Google Scholar
• Chevalier, P. et al. Non-invasive testing of acquired long QT syndrome: evidence for multiple arrhythmogenic substrates. Cardiovasc. Res. 50, 386–398 (2001).
  CAS PubMed Google Scholar