Serious adverse drug reactions (SADRs) are a significant cause of death. Genetic factors may underlie some of the susceptibility to SADRs.
We review three SADRs: drug-induced liver injury, statin-induced myotoxicity and drug-induced long QT and torsades de pointes with an emphasis on genetic risk factors.
Characteristics of SADRs that increase the likelihood of informative genetic/genomic analysis include: evidence for a familial or genetic component, accepted criteria for unambiguous diagnosis, low background incidence and availability of sufficient numbers of cases and appropriately matched controls. Furthermore, information about the molecular mechanisms of drug action and elimination can add to candidate gene and pathway selection and investigation.
Clearly defined phenotypes along with standardization of these phenotypes must be in place to ascertain cases and controls and to facilitate replication studies.
Networks of scientists and healthcare providers in academia, industry, healthcare systems and regulatory agencies are needed to drive this effort. Effective and standardized procedures for enlisting physician and patient participation in research protocols, collection and transfer of information, DNA, plasma and other specimens must be developed. Confidentiality and ethical issues must be considered in the design and implementation of studies.
Study design and the methods for data gathering, storing and analysis must be continually addressed.
Replication of findings in diverse population subgroups is important for validating conclusions of these types of studies. For rare SADRs, national and international consortia and networks involving regulatory authorities, health care systems, academic medical centres and industry are crucial for increasing the numbers of cases.
Genome-wide association studies may be used to discover new mechanisms responsible for SADRs.
Serious adverse drug reactions (SADRs) are a major cause of morbidity and mortality worldwide. Some SADRs may be predictable, based upon a drug's pharmacodynamic and pharmacokinetic properties. Many, however, appear to be idiosyncratic. Genetic factors may underlie susceptibility to SADRs and the identification of predisposing genotypes may improve patient management through the prospective selection of appropriate candidates. Here we discuss three specific SADRs with an emphasis on genetic risk factors. These SADRs, selected based on wide-sweeping clinical interest, are drug-induced liver injury, statin-induced myotoxicity and drug-induced long QT and torsades de pointes. Key challenges for the discovery of predictive risk alleles for these SADRs are also considered.
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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.
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.
Severino, G. & Del Zompo, M. Adverse drug reactions: role of pharmacogenomics. Pharmacol. Res. 49, 363–373 (2004).
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).
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.
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).
Weatherall, D. J. Single gene disorders or complex traits: lessons from the thalassaemias and other monogenic diseases. BMJ 321, 1117–1120 (2000).
Beutler, E. Glucose-6-phosphate dehydrogenase deficiency. N. Engl. J. Med. 324, 169–174 (1991).
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).
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).
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).
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).
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.
Hetherington, S. et al. Genetic variations in HLA-B region and hypersensitivity reactions to abacavir. Lancet 359, 1121–1122 (2002).
Chung, W. H. et al. Medical genetics: a marker for Stevens-Johnson syndrome. Nature 428, 486 (2004).
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.
Meier, Y. et al. Incidence of drug-induced liver injury in medical inpatients. Eur. J. Clin. Pharmacol. 61, 135–143 (2005).
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).
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).
Maddrey, W. C. Drug-induced hepatotoxicity: 2005. J. Clin. Gastroenterol. 39, S83–S89 (2005).
Watkins, P. B. & Whitcomb, R. W. Hepatic dysfunction associated with troglitazone. N. Engl. J. Med. 338, 916–917 (1998).
Zimmerman, H. J. Hepatotoxicity the Adverse Effects of Drugs and Other Chemicals on the Liver (Lippincott Williams & Wilkins, Baltimore, 1999).
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.
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.
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).
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).
Yee, H. S. & Fong, N. T. Atorvastatin in the treatment of primary hypercholesterolemia and mixed dyslipidemias. Ann. Pharmacother. 32, 1030–1043 (1998).
Thompson, P. D., Clarkson, P. & Karas, R. H. Statin-associated myopathy. JAMA 289, 1681–1690 (2003).
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.
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).
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).
Pasternak, R. C. et al. ACC/AHA/NHLBI clinical advisory on the use and safety of statins. Circulation 106, 1024–1028 (2002).
Chan, J., Hui, R. L. & Levin, E. Differential association between statin exposure and elevated levels of creatine kinase. Ann. Pharmacother. 39, 1611–1616 (2005).
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.
Draeger, A. et al. Statin therapy induces ultrastructural damage in skeletal muscle in patients without myalgia. J. Pathol. 210, 94–102 (2006).
Graham, D. J. et al. Incidence of hospitalized rhabdomyolysis in patients treated with lipid-lowering drugs. JAMA 292, 2585–2590 (2004).
Davidson, M. H. Rosuvastatin safety: lessons from the FDA review and post-approval surveillance. Expert Opin. Drug Saf. 3, 547–557 (2004).
Ferdinand, K. C. Rosuvastatin: a risk-benefit assessment for intensive lipid lowering. Expert Opin. Pharmacother. 6, 1897–1910 (2005).
Lennernas, H. Clinical pharmacokinetics of atorvastatin. Clin. Pharmacokinet 42, 1141–1160 (2003).
Gibson, D. M. et al. Effect of age and gender on pharmacokinetics of atorvastatin in humans. J. Clin. Pharmacol. 36, 242–246 (1996).
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).
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).
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).
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).
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).
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).
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).
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).
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).
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).
Mauro, V. F. Clinical pharmacokinetics and practical applications of simvastatin. Clin. Pharmacokinet 24, 195–202 (1993).
Prueksaritanont, T. et al. Effects of fibrates on metabolism of statins in human hepatocytes. Drug Metab. Dispos. 30, 1280–1287 (2002).
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).
Prueksaritanont, T. et al. Mechanistic studies on metabolic interactions between gemfibrozil and statins. J. Pharmacol. Exp. Ther. 301, 1042–1051 (2002).
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).
Schneck, D. W. et al. The effect of gemfibrozil on the pharmacokinetics of rosuvastatin. Clin. Pharmacol. Ther. 75, 455–463 (2004).
Nishizato, Y. et al. Polymorphisms of OATP-C (SLC21A6) and OAT3 (SLC22A8) genes: consequences for pravastatin pharmacokinetics. Clin. Pharmacol. Ther. 73, 554–565 (2003).
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).
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).
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.
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).
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).
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).
Vladutiu, G. D. et al. Genetic risk factors associated with lipid-lowering drug-induced myopathies. Muscle Nerve 34, 153–162 (2006).
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).
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).
Soyka, L. F., Wirtz, C. & Spangenberg, R. B. Clinical safety profile of sotalol in patients with arrhythmias. Am.J. Cardiol. 65, 74–81 (1990).
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).
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).
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).
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).
Viskin, S., Justo, D., Halkin, A. & Zeltser, D. Long QT syndrome caused by noncardiac drugs. Prog. Cardiovasc. Dis. 45, 415–427 (2003).
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).
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).
Antzelevitch, C. et al. Heterogeneity within the ventricular wall: electrophysiology and pharmacology of epicardial, endocardial, and M cells. Circ. Res. 69, 1427–1449 (1991).
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).
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).
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).
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).
Roden, D. M. Drug-induced prolongation of the QT Interval. N. Engl. J. Med. 350, 1013–1022 (2004).
Roden, D. M. An underrecognized challenge in evaluating postmarketing drug safety. Circulation 111, 246–248 (2005).
Roden, D. M. & Viswanathan, P. C. Genetics of acquired long QT syndrome. J. Clin. Invest. 115, 2025–2032 (2005).
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.
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).
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).
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).
Romano, C., Gemme, G. & Pongiglione, R. Aritmie cardiache rare in eta' pediatrica. Clin. Pediatr. 45, 656–683 (1963).
Ward, O. C. A new familial cardiac syndrome in children. J. Irish Med. Assoc. 54, 103–106 (1964).
Abbott, G. W. et al. MiRP1 forms IKr potassium channels with HERG and is associated with cardiac arrhythmia. Cell 97, 175–187 (1999).
Curran, M. E. et al. A molecular basis for cardiac arrhythmia: HERG mutations cause long QT syndrome. Cell 80, 795–803 (1995).
Domingo A. et al. Sodium channel β4 subunit mutation causes congenital long QT syndrome. Heart Rhythm 5, S34 (2006).
Mohler, P. J. et al. Ankyrin-B mutation causes type 4 long-QT cardiac arrhythmia and sudden cardiac death. Nature 421, 634–639 (2003).
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).
Splawski, I. et al. Ca(V)1.2 calcium channel dysfunction causes a multisystem disorder including arrhythmia and autism. Cell 119, 19–31 (2004).
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).
Vatta, M. et al. Mutant caveolin-3 induces persistent late sodium current and is associated with long-QT syndrome. Circulation 114, 2104–2112 (2006).
Wang, Q. et al. Positional cloning of a novel potassium channel gene: KVLQT1 mutations cause cardiac arrhythmias. Nature Genet. 12, 17–23 (1996).
Wang, Q. et al. SCN5A mutations associated with an inherited cardiac arrhythmia, long QT syndrome. Cell 80, 805–811 (1995).
Domingo A. Sodium channel á4 subunit mutation causes congenital long QT syndrome. Heart Rhythm 3, S34 (2006).
Roden, D. M. et al. Multiple mechanisms in the long QT syndrome: current knowledge, gaps and future directions. Circulation 94, 1996–2012 (1996).
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).
Belardinelli, L., Antzelevitch, C. & Vos, M. A. Assessing predictors of drug-induced torsade de pointes. Trends Pharmacol. Sci. 24, 619–625 (2003).
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).
Opthof, T., Coronel, R., Janse, M. J. & Rosen, M. R. A wedge is not a heart. Heart Rhythm. 4, 1116–1119 (2007).
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).
Priori, S. G., Napolitano, C. & Schwartz, P. J. Low penetrance in the long-QT syndrome: clinical impact. Circulation 99, 529–533 (1999).
Donger, C. et al. KVLQT1 C-terminal missense mutation causes a forme fruste long-QT syndrome. Circulation 96, 2778–2781 (1997).
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).
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.
Sesti, F. et al. A common polymorphism associated with antibiotic-induced cardiac arrhythmia. Proc. Natl Acad. Sci. 97, 10613–10618 (2000).
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).
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).
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).
Splawski, I. et al. Variant of SCN5A sodium channel implicated in risk of cardiac arrhythmia. Science 297, 1333–1336 (2002).
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.
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.
Woosley, R. L., Chen, Y., Freiman, J. P. & Gillis, R. A. Mechanism of the cardiotoxic actions of terfenadine. JAMA 269, 1532–1536 (1993).
Roden, D. M. Taking the idio out of idiosyncratic - predicting torsades de pointes. Pacing Clin. Electrophysiol. 21, 1029–1034 (1998).
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).
Silva, J. & Rudy, Y. Subunit interaction determines IKs participation in cardiac repolarization and repolarization reserve. Circulation 112, 1384–1391 (2005).
Lesko, L. J. & Woodcock, J. Translation of pharmacogenomics and pharmacogenetics: a regulatory perspective. Nature Rev. Drug Discov. 3, 763–769 (2004).
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).
Campbell, G. Some statistical and regulatory issues in the evaluation of genetic and genomic tests. J. Biopharm Stat. 14, 539–552. (2004).
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).
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.
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).
Acuna, G. et al. Pharmacogenetic analysis of adverse drug effect reveals genetic variant for susceptibility to liver toxicity. Pharmacogenomics J. 2, 327–334 (2002).
Daly, A. K. et al. Genetic susceptibility to diclofenac-induced hepatotoxicity: contribution of UGT2B7, CYP2C8, and ABCC2 genotypes. Gastroenterology 132, 272–281 (2007).
Danoff, T. M. et al. A Gilbert's syndrome UGT1A1 variant confers susceptibility to tranilast-induced hyperbilirubinemia. Pharmacogenomics J. 4, 49–53 (2004).
Huang, Y. S. et al. Cytochrome P450 2E1 genotype and the susceptibility to antituberculosis drug-induced hepatitis. Hepatology 37, 924–930 (2003).
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).
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).
O'Donohue, J. et al. Co-amoxiclav jaundice: clinical and histological features and HLA class II association. Gut 47, 717–720 (2000).
Simon, T. et al. Combined glutathione-S-transferase M1 and T1 genetic polymorphism and tacrine hepatotoxicity. Clin. Pharmacol. Ther. 67, 432–437 (2000).
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).
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).
Fitzgerald, P. T. & Ackerman, M. J. Drug-induced torsades de pointes: the evolving role of pharmacogenetics. Heart Rhythm 2, S30–S37 (2005).
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).
Chevalier, P. et al. Non-invasive testing of acquired long QT syndrome: evidence for multiple arrhythmogenic substrates. Cardiovasc. Res. 50, 386–398 (2001).
We would like to acknowledge support from the National Institutes of Health (NIH) Pharmacogenetics Research Network: GM61390, U01 HL65962, U01 GM061373, HL 69757, U01 GM074492, U01 DK065201 and K24RR02815 and TR2GM008425 as well as the PhRMA Predoctoral Fellowship. Much of the variant data cited in this article have been deposited in www.pharmgkb.org.
David Flockhart is on the advisory board of Labcorp.
Ronal Krauss is a consultant for Merck & Co. Inc, Merck/Schering-Plough, Celeara Diagnostics and a recipient of grants from Merck & Co. Inc. and Merck/Schering-Plough.
Dan Roden is a consultant for Novartis Pharmaceuticals Corp., the International Life Sciences Health and Environmental Sciences Institute, Sapphire Therapeutics Inc., Atlas Venture Advisors Inc., Pfizer, Avanir, Baker Brothers Advisors LLC, Cardiokine Inc., Eli Lilly, Johnson & Johnson and Teva.
- Adverse drug reaction
(ADR). Any noxious, unintended and undesired effect of a drug, which occurs at doses used in humans for prophylaxis, diagnosis or therapy. This excludes therapeutic failures, intentional and accidental poisoning and drug abuse.
The study of processes impacting absorption, distribution, metabolism and excretion of a drug and its metabolites in the body.
The study of the mechanism of action of a drug, including but not limited to processes such as receptor binding and signal transduction.
- Gilbert's syndrome
A common, mild liver disorder caused by reduced activity of glucuronyltransferase, an enzyme required for excreting bilirubin; typically it does not require treatment or pose serious complications.
- Creatine kinase
(CK). An enzyme often measured clinically as a severity marker of muscle damage.
- Phase I metabolism
Phase I reactions may occur by oxidation, reduction, hydrolysis, cyclization and decyclization reactions. The process of oxidation takes place in the presence of mixed function oxidases and mono-oxygenases in the liver.
- Phase II metabolism
Phase II reactions (conjugation reactions) are usually detoxicating and involve the interactions of the polar functional groups of phase I metabolites.
Hypokalaemia is a potentially fatal condition in which the body fails to retain sufficient potassium to maintain health. The condition is also known as potassium deficiency.
The frequency, under given environmental conditions, with which a specific phenotype results from a predetermined genotype; it is usually given as a percentage.
- Subclinical mutation carrier
A carrier of a mutation who does not manifest the pathological effects of the mutation.
The study of how variations in a few genes affect the response to medications.
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Wilke, R., Lin, D., Roden, D. et al. Identifying genetic risk factors for serious adverse drug reactions: current progress and challenges. Nat Rev Drug Discov 6, 904–916 (2007). https://doi.org/10.1038/nrd2423
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