Genetic Factors in Drug Metabolism

Donna J. Belle, PhD, RPh, and HaRleen SInGH, PharmD, Oregon State University College of Pharmacy, Portland Campus at Oregon Health & Science University, Portland, Oregon

Patients vary widely in their response to drugs. Having an understanding of the pharmacokinetic and pharmacodynamic properties of various medications is important when assessing ethnic differences in drug response. Genetic factors can account for 20 to 95 percent of patient variability. Genetic polymorphisms for many drug-metabolizing enzymes and drug targets (e.g., receptors) have been identified. Although currently limited to a few pathways, pharmacogenetic testing may enable physicians to understand why patients react differently to various drugs and to make better decisions about therapy. Ultimately, this understanding may shift the medical paradigm to highly individualized therapeutic regimens. (Am Fam Physician. 2008;77(11):1553-1560. Copyright 2008 American Academy of Family Physicians.)

lthough patient response to drugs varies widely and the reasons for this are diverse and complex, experts estimate that genetic factors account for 20 to 95 percent of patient variability in response to individual drugs.1 Genetic influences on drug metabolism interact with other intrinsic (i.e., physiologic) and extrinsic (i.e., cultural, behavioral, and environmental) characteristics of a person to determine the outcome from treatment with any pharmacologic agent (Table 1).2 although still in its infancy, the field of pharmacogenetics and pharmacogenomics already provides useful clinical information to enhance patient care and offers a growing potential to individualize drug therapy and improve clinical outcomes. This article reviews the leading areas in which genetic variations currently affect treatment and indicates a need for physicians to monitor this topic as genomic-based treatment guidelines become available. Definitions The study of genetic variations in drug response is called pharmacogenetics when studying an individual gene, or pharmacogenomics when studying all genes. a persons genotype is his or her genetic makeup. The term can pertain to all genes or to a specific

gene. The phenotype is a persons outward physical appearance or function resulting from the interaction between the genotype and the environment. Genetic polymorphisms are naturally occurring variants in gene structure that occur in more than 1 percent of the population. Polymorphisms may influence a drugs action by changing its pharmacokinetics or its pharmacodynamics. Pharmacokinetics Pharmacokinetics is the study of the rate and extent of drug absorption, distribution, metabolism, and excretion. These processes determine the fate of a drug in the body. a combination of metabolism and excretion constitutes drug elimination from the body. The main routes of drug elimination are metabolism (often in the liver) and renal excretion. Genetic polymorphisms have been identified for many drug-metabolizing enzymes, including the cytochrome P450 (CYP450) enzymes. This gives rise to distinct population phenotypes of persons who have metabolism capabilities ranging from extremely poor to extremely fast. The large range of incidence of common CYP polymorphisms in selected population groups is illustrated in Table 2.3-9 Some potential clinical consequences of these polymorphisms are listed in Table 3.

June 1, 2008 of Volume 77, Number 11 site. All other rights reserved. Contact copyrights@aafp.org for copyright questions and/or permissionPhysician 1553 www.aafp.org/afp American Family requests. use one individual user of the Web

Downloaded from the American Family Physician Web site at www.aafp.org/afp. Copyright 2008 American Academy of Family Physicians. For the private, noncommercial

GeneticsinDrugMetabolism

SORT:KEYRECOMMENDATIONSFORPRACTICE Clinical recommendation Physicians should consider the potential for genetic factors (intrinsic and extrinsic) to influence drug response. When a clear genotype-response relationship has been identified and commercial testing is available, pharmacogenetic testing is preferable to the use of ethnic or race categories to individualize therapy. Evidence rating C C References 2 10-12, 54, 55

A = consistent, good-quality patient-oriented evidence; B = inconsistent or limited-quality patient-oriented evidence; C = consensus, disease-oriented evidence, usual practice, expert opinion, or case series. For information about the SORT evidence rating system, see http://www.aafp.orp/afpsort.xml.

CytochromeP4502C9(CYP2C9) The CYP2C9 enzyme is involved in the metabolism of many common drugs such as glipizide (Glucotrol), tolbutamide (orinase; brand not available in United States), losartan (Cozaar), phenytoin (Dilantin), and warfarin (Coumadin). The phenotypes CYP2C9*2 and CYP2C9*3 are the two most common variations and are associated

with reduced enzymatic activity. CYP2C9 is the principal enzyme responsible for the metabolism of S-warfarin. Persons who are CYP2C9 poor metabolizers have reduced S-warfarin clearance. Clinical studies have shown that these persons require lower dosages of warfarin and are at an increased risk of excessive anticoagulation.10,11 CytochromeP4502C19(CYP2C19) The CYP2C19 enzyme metabolizes many drugs, including proton pump inhibitors, citalopram (Celexa), diazepam (Valium), and imipramine (Tofranil). More than 16 variations of CYP2C19, associated with deficient, reduced, normal, or increased activity, have been identified. Genotyping for CYP2C19*2 and CYP2C19*3 identifies most CYP2C19 poor metabolizers. The CYP2C19*17 variant is associated with ultrarapid metabolizers and seems relatively common in Swedes (18 percent), ethiopians (18 percent), and Chinese (4 percent).12 The proton pump inhibitor omeprazole (Prilosec) is primarily metabolized by CYP2C19 to its inactive metabolite, 5-hydroxyomeprazole. Persons who are CYP2C19 poor metabolizers can have fivefold higher blood concentrations of omeprazole and experience superior acid suppression and higher cure rates than the rest of the population. Conversely, blood concentrations of omeprazole are predicted to be 40 percent lower in ultrarapid metabolizers than in the rest of the population, thus putting persons with the CYP2C19 ultrarapid metabolizers phenotype at risk of therapeutic failure.12
Volume 77, Number 11

Table1.FactorsInfluencingDrugResponse
Intrinsic Genetic Absorption, distribution, metabolism, excretion Body weight Genetic conditions Genetic polymorphism of drugmetabolizing enzymes Height Race Receptor sensitivity Sex Extrinsic Alcohol Climate Culture Educational status Language Socioeconomic factors Definition/diagnostics Diet Diseases/conditions Drug adherence Medical practices Pollution Smoking Stress Sunlight Therapeutic approach

Physiologic Absorption, distribution, metabolism, excretion Age Alcohol Body weight Cardiovascular function Diet Diseases/conditions Height Kidney function Liver function Receptor sensitivity Smoking Stress

Adapted from the U.S. Food and Drug Administration, U.S. Dept. of Health and Human Services. International Conference on Harmonisation: guidance on ethnic factors in the acceptability of foreign clinical data; availability. Federal Register 1998;63(111):31790-31796. http://www.fda.gov/cder/guidance/2293fnl.pdf. Accessed October 17, 2007.

1554 American Family Physician

www.aafp.org/afp

June 1, 2008

GeneticsinDrugMetabolism

CytochromeP4502D6(CYP2D6) The enzyme CYP2D6 is involved in the metabolism of an estimated 25 percent of all drugs. More than 75 allelic variants have been identified, with enzyme activities ranging from deficient to ultrarapid. The most common variants associated with poor metabolizer phenotype are CYP2D6*3, CYP2D6*4, CYP2D6*5, and CYP2D6*6 in whites and CYP2D6*17 in blacks. Codeine is metabolized by CYP2D6 to its active metabolite, morphine. Clinical studies have shown that CYP2D6 poor metabolizers have poor analgesic response as a result of the reduced conversion of codeine to morphine. Conversely, CYP2D6 ultrarapid metabolizers quickly convert codeine to morphine and have enhanced analgesic response.13 The activity of drug-metabolizing enzymes may be induced or inhibited by many other intrinsic and extrinsic factors, including comorbid conditions, use of other medications, smoking, alcohol intake, and dietary factors. Pharmacodynamics Pharmacodynamics is the study of the pharmacologic effect resulting from the interaction between the drug and the biologic

system. The relationship between drug concentration and the observed pharmacologic response depends on the drugs mechanism of action. The pharmacologic response to a drug may be mediated through a direct effect, such as binding with a specific
Table2.IncidenceofCytochromeP450Metabolizer PhenotypesAmongEthnicGroups
Metabolizer phenotype Poor Intermediate Ultrarapid Poor Intermediate Ultrarapid Poor Intermediate Ultrarapid Population frequency (%) Asians 0.43 3.54 18 to 233,5 307 1.0 to 4.83,5,8 518 0.9 to 218 Blacks 0.0 4 134 1.2 to 5.35,6 297,8 1.9 to 7.35,6,8 309 4.98 Whites 1.0 4 334 2.0 to 5.03,5 187 7.0 to 103,8 1.0 to 2.08 1.0 to 5.08

Enzyme CYP2C9

CYP2C19

CYP2D6

noTE: Poor

metabolizers have markedly reduced or absent enzyme activity; intermediate metabolizers have reduced enzyme activity; and ultrarapid metabolizers have high enzyme activity. CYP = cytochrome P450. Information from references 3 through 9.

Table3.ClinicalConsequenceofMetabolizerPhenotypesonDrugResponse
Metabolizer phenotype Poor to intermediate Effect on drug metabolism Slow

Drug type Prodrug, needs metabolism to work (e.g., codeine metabolized to morphine)

Potential consequence Poor drug efficacy, patient at risk of therapeutic failure Accumulation of prodrug, patient at increased risk of drug-induced side effects Good drug efficacy, rapid effect Good drug efficacy Accumulation of active drug, patient at increased risk of drug-induced side effects Patient requires lower dosage Poor drug efficacy, patient at risk of therapeutic failure Patient requires higher dosage

Ultrarapid Active drug metabolized to inactive drug (e.g., omeprazole [Prilosec] metabolized to 5-hydroxyomeprazole) Poor to intermediate

Fast Slow

Ultrarapid

Fast

Poor metabolizers have markedly reduced or absent enzyme activity; intermediate metabolizers have reduced enzyme activity; and ultrarapid metabolizers have high enzyme activity.
noTE:

June 1, 2008

Volume 77, Number 11

www.aafp.org/afp

American Family Physician 1555

GeneticsinDrugMetabolism

receptor, or an indirect effect, such as phosphatase activity, increased intracelluinhibiting an enzyme in a protein synthesis lar sodium concentrations, elevated fasting pathway. insulin levels) may explain the potentially different pathophysiology of hypertension Pharmacogenomics in blacks and whites.16 This has led to the inCommonConditions discovery of candidate genes for hypertenCARDIOVASCULARCONDITIONS sion (Table 410,16-25). Polymorphism in these Hypertension is a major risk factor for cardio- genes may be responsible for the high prevavascular morbidity and mortality.14 Despite lence and increased severity of hypertension the availability of several pharmacologic in black persons.16,26-28 The enhanced effects treatment options for hypertension, only of diuretics in blacks are likely related to 34 percent of north americans are achieving many of the extrinsic and intrinsic factors target blood pressure goals, and preventing listed above.16,26 cardiovascular complications is still a notable Typically, black patients require a high challenge.15 extrinsic (e.g., increased sodium dosage of angiotensin-converting enzyme intake, decreased calcium and potassium (aCe) inhibitors or combined therapy with intake, psychosocial stressors) and intrinsic low-dose diuretics to reduce blood presfactors (e.g., low plasma renin activity, higher sure effectively.29 although the risk of aCeprevalence of expanded plasma volume, related angioedema is generally low, there reduced sodium-potassium adenosinetri- is some evidence that it is more common

Table4.GeneticPolymorphismsinDrugReceptorGenesAssociatedwithDrugResponse
Gene ACE Drug class (drug) ACE inhibitors, ARBs, statins (fluvastatin [Lescol]), and fibrates (gemfibrozil [Lopid]) Diuretics (hydrochlorothiazide) ACE inhibitors and ARBs (irbesartan [Avapro]) Statins (simvastatin [Zocor]) Statins (pravastatin [Pravachol]) Beta blockers (metoprolol [Lopressor]) Beta2-adrenergic agonists (albuterol [Proventil]) Statins (pravastatin) Fibrates (gemfibrozil) Leukotriene receptor antagonists (zafirlukast [Accolate]) Leukotriene receptor antagonists Statins (i.e., pravastatin) Warfarin (Coumadin) Response Greater blood pressure reduction 17 Greater LDL cholesterol reduction, increase in HDL cholesterol with statins and fibrates Better blood pressure control with diuretics and fewer cardiovascular events16,18 Greater reduction in blood pressure and left ventricle mass with ACE inhibitors and ARBs19 Greater mortality reduction with simvastatin20 Reduction in coronary atherosclerosis21 Greater reduction in blood pressure May affect survival in heart failure Positive response to bronchodilator therapy 22 Greater effects of pravastatin on slowing coronary atherosclerosis23 Greater reductions in triglycerides Improvement in FEV124 May affect disease predisposition of asthma Pravastatin reduced the incidence of coronary artery restenosis and repeat angioplasty 25 Less variability in dose response10

Alpha-adducin Angiotensinogen Apolipoprotein E Beta-fibrinogen 1-adrenergic receptors 2-adrenergic receptors Cholesteryl ester transfer protein Leukotriene C4 synthase 5-lipoxygenase Stromelysin-1 Vitamin K epoxide reductase complex subunit 1

ACE = angiotensin-converting enzyme; ARB = angiotensin receptor blocker; FEV1 = forced expiratory volume in one second; HDL = high-density lipoprotein; LDL = low-density lipoprotein. Information from references 10, and 16 through 25.

1556 American Family Physician

www.aafp.org/afp

Volume 77, Number 11

June 1, 2008

GeneticsinDrugMetabolism

in blacks.30 Despite the differences between black persons and other ethnic groups, aCe inhibitors have proven highly effective in reducing morbidity and mortality in patients with hypertension who present with other comorbidities such as heart failure, diabetic nephropathy, and myocardial infarction.14 advances in drug therapy have helped reduce mortality in many patients with heart failure, but it is unclear whether all population groups have benefited. Beta blockers and aCe inhibitors are the standard of care in patients with heart failure.31 Therapeutic outcomes have been highly variable, possibly secondary to genetic variability in -adrenergic receptors, the renin-angiotensin-aldosterone system, the endothelin system, and endothelial nitrogen monoxide synthase.32 one of the most important genetic polymorphisms studied in heart failure is an insertion/deletion (I/D) polymorphism of the aCe gene. Persons who are D carriers have higher aCe activity and are at increased risk of developing cardiovascular disease.33,34 Similarly, the response to beta blockers is highly variable in patients with heart failure.35,36 Recently, the african american Heart Failure Trial (a-HeFT) demonstrated that adding isosorbide dinitrate (Isochron) and hydralazine (apresoline; brand not available in United States) to standard therapy for heart failure increases survival in black patients with advanced heart failure.37 It has been proposed that nitric oxide deficiency can result in the progression of heart failure.38 Patients exhibiting genetic polymorphism may have less nitric oxide and, thus, may benefit from nitric oxideenhancing therapy. Because this study included only black patients, it lacked evidence of differences in response between white and black americans. The gene or genes responsible for nitric oxide deficiency have not been identified in black persons. However, several biologic systems are involved in the pathogenesis of heart failure, and each is highly polymorphic. Currently, no prospective studies are investigating the simultaneous impact of multiple genetic variants on cardiovascular outcomes. Several genes are associated with coronary heart disease (CHD). The involvement
June 1, 2008

of multiple genes with potential polymorphisms makes predicting persons at risk of developing CHD highly imprecise. examples of genes affecting CHD include the cholesteryl ester transfer protein, stromelysin-1, beta-fibrinogen, and apolipoprotein e genes. Descriptions of genetic polymorphisms associated with CHD and their response to statin therapy are summarized in Table 4.10,16-25
ASTHMA

approximately 8 to 10 percent of the U.S. population is affected by asthma. In terms of morbidity and cost, asthma is considered a major health risk.39 Research has focused on identifying the potential role of genetics in the pathophysiology and management of asthma.40-43 Common drugs used to control asthma are beta2 agonists (both short- and long-acting), inhaled corticosteroids, and leukotriene antagonists. Response to asthma medications is highly variable, with only 60 to 80 percent of patients deriving therapeutic benefit.40 Inhaled beta2 agonists, such as albuterol (Proventil), are used to control acute attacks of asthma and are prescribed to be used as needed. Several studies have shown that some patients benefit from use of short- acting beta2 agonists whereas others do not.22,44 This variation in response is partly explained by the alteration in the amino acid sequence of the protein or altered transcription of the beta2 receptors. Patients with the beta2 receptor arginine genotype experience poor asthma control with frequent symptoms and a decrease in scores on forced expiratory volume in one second compared with patients who have the glycine genotype.22,45 Studies show that 17 percent of whites and 20 percent of blacks carry the arginine genotype.46 leukotriene (lT) modifiers (e.g., zileuton [Zyflo], montelukast [Singulair], zafirlukast [accolate]) block the 5-lipoxygenase (5-lo) and lTC4 synthase pathways, preventing leukotriene-mediated bronchoconstriction.47,48 only a minority of patients benefit from treatment with lT receptor agonists. Polymorphism in 5-lo and lTC4 synthase pathways has been identified (Table 410,16-25). approximately 5 percent of patients with
www.aafp.org/afp American Family Physician 1557

Volume 77, Number 11

GeneticsinDrugMetabolism

asthma have the 5-lo polymorphism. Patients who had the 5-lo polymorphism showed a greater improvement in their lung function with zafirlukast therapy compared with patients who had the normal 5-lo genotype. Similarly, polymorphisms in the lTC4 synthase gene may predispose a person to asthma. Patients with the variant lTC4 synthase genotype have higher levels of cysteinyl leukotrienes, which have been linked with severe asthma. The use of lT modifiers in this population may be beneficial.24,49 Variation in the genes involved in the biologic action of inhaled corticosteroids may explain the variability to response and adverse effects to inhaled corticosteroids. Polymorphisms in corticotropin-releasing hormone receptor-1 and T-box expressed in T cells have been associated with improved response in patients with asthma.50,51 although these findings are promising in predicting therapeutic response to asthma medication, their usefulness in clinical practice is still under investigation.

ness.10 Understanding environmental and genetic factors will allow the physician to more accurately dose warfarin and improve anticoagulation control. LimitationsoftheCurrentLiterature onPharmacogenomics Most pharmacodynamic studies have been relatively small and the populations studied are not always well characterized. ethnic categories (e.g., asians, blacks, whites) include persons from widely diverse geographic and sociocultural backgrounds with varying genetic composition, and the results might not apply to all members of each ethnic population. Typically, pharmacokinetic variability is no greater than pharmacodynamic variability; however, in most studies, only selected pharmacokinetic parameters were examined. Use of genotyping is more accurate than race or ethnic categories to identify variations in drug response.52 Unlike other influences on drug response, genetic factors remain constant throughout life. The use of pharmacogenetic information to support drug selection and dosing is emerging. Commercial testing is available for drug- metabolizing enzymes and some pharmacodynamic targets such as VKORC1, stromelysin-1, and apolipoprotein e.53,54 Prospective genetic testing would be beneficial for drugs for which a clear genotype-response relationship has been demonstrated, such as warfarin (CYP2C9, VKORC1) and proton pump inhibitors (CYP2C19). The U.S. Food and Drug administration has suggested relabeling warfarin to include genetic information to guide initial dosing.55

Warfarin Warfarin dosing can be challenging because of its narrow therapeutic index and the serious risk of bleeding with overdosage. Typically, warfarin dosing is individualized based on sex, age, vitamin K intake, drug interactions, and disease states. Dosing adjustments are made Prospectivegenetictesting according to the desired Intercouldbebeneficialfordrugs national normalized Ratio. forwhichacleargenotypeenvironmental and genetic responserelationshiphas factors can influence warfabeendemonstrated. rin response. Several studies have focused on CYP2C9 polymorphisms to explain patient variability The authors thank Ganesh Cherala, PhD, for reviewing with warfarin therapy. only about 10 per- the manuscript, and Nathan Thomas for his technical cent of dosage variation in warfarin can be expertise in the preparation of the manuscript. explained by CYP2C9 polymorphisms. This is one in a series of Clinical Pharmacology articles Warfarin exerts its anticoagulant effects coordinated by Allen F. Shaughnessy, PharmD, Tufts Uniby inhibiting hepatic vitamin K epoxide versity Family Medicine Residency at Cambridge Health reductase, an enzyme involved in the syn- Alliance, Malden, Mass. thesis of various clotting factors. Polymorphisms in the vitamin K epoxide reductase TheAuthors complex subunit 1 (VKORC1) gene have DONNA J. BELLE, PhD, RPh, was an assistant research been identified and are believed to contrib- professor of pharmacokinetics in the College of Pharute to the variability in warfarin responsive- macy, Oregon State University, Portland, at the time she 1558 American Family Physician
www.aafp.org/afp Volume 77, Number 11

June 1, 2008

GeneticsinDrugMetabolism

coauthored this article. Dr. Belle received her doctorate degree from the School of Pharmacy at West Virginia University, Morgantown, and completed a postdoctoral research fellowship in the Department of Drug Disposition at Eli Lilly and Company, Indianapolis, Ind. HARLEEN SINGH, PharmD, is an assistant professor of pharmacy in the Department of Pharmacy Practice, College of Pharmacy, Oregon State University. Dr. Singh received her doctor of pharmacy degree from Ohio State University College of Pharmacy, Columbus, where she also completed a residency in adult medicine. Address correspondence to Harleen Singh, PharmD, Oregon State University College of Pharmacy, 3303 SW Bond Ave., CH12C, Portland, OR 97239 (e-mail: singhh@ ohsu.edu). Reprints are not available from the authors. Author disclosure: Nothing to disclose. REFERENCES
1. Kalow W, Tang BK, Endrenyi L. Hypothesis: comparisons of inter- and intra-individual variations can substitute for twin studies in drug research. Pharmacogenetics. 1998;8(4):283-289. 2. U.S. Food and Drug Administration, U.S. Dept. of Health and Human Services. International Conference on Harmonisation: guidance on ethnic factors in the acceptability of foreign clinical data; availability. Federal Register 1998;63(111):31790-31796. http://www.fda. gov/cder/guidance/2293fnl.pdf. Accessed october 17, 2007. 3. Mizutani T. PM frequencies of major CYPs in Asians and Caucasians. Drug Metab Rev. 2003;35(2-3):99-106. 4. Kirchheiner J, Brockmller J. Clinical consequences of cytochrome P450 2C9 polymorphisms. Clin Pharmacol Ther. 2005;77(1):1-16. 5. ozawa S, Soyama A, Saeki M, et al. Ethnic differences in genetic polymorphisms of CYP2D6, CYP2C19, CYP3As and MDR1/ABCB1. Drug Metab Pharmacokinet. 2004; 19(2):83-95. 6. Dandara C, Masimirembwa CM, Magimba A, et al. Genetic polymorphism of CYP2D6 and CYP2C19 in eastand southern African populations including psychiatric patients. Eur J Clin Pharmacol. 2001;57(1):11-17. 7. Luo HR, Poland RE, Lin KM, Wan YJ. Genetic polymorphism of cytochrome P450 2C19 in Mexican Americans: a cross-ethnic comparative study. Clin Pharmacol Ther. 2006;80(1):33-40. 8. Bernard S, neville KA, nguyen AT, Flockhart DA. Interethnic differences in genetic polymorphisms of CYP2D6 in the U.S. population: clinical implications. Oncologist. 2006;11(2):126-135. 9. Gaedigk A, Bradford LD, Marcucci KA, Leeder JS. Unique CYP2D6 activity distribution and genotype-phenotype discordance in black Americans. Clin Pharmacol Ther. 2002;72(1):76-89. 10. Aquilante CL, Langaee TY, Lopez LM, et al. Influence of coagulation factor, vitamin K epoxide reductase complex subunit 1, and cytochrome P450 2C9 gene polymorphisms on warfarin dose requirements. Clin Pharmacol Ther. 2006;79(4):291-302. 11. Higashi MK, Veenstra DL, Kondo LM, et al. Association between CYP2C9 genetic variants and anticoagula-

tion-related outcomes during warfarin therapy. JAMA. 2002;287(13):1690-1698. 12. Sim SC, Risinger C, Dahl ML, et al. A common novel CYP2C19 gene variant causes ultrarapid drug metabolism relevant for the drug response to proton pump inhibitors and antidepressants. Clin Pharmacol Ther. 2006;79(1):103-113. 13. de Leon J, Dinsmore L, Wedlund P. Adverse drug reactions to oxycodone and hydrocodone in CYP2D6 ultrarapid metabolizers. J Clin Psychopharmacol. 2003; 23(4):420-421. 14. Chobanian AV, Bakris GL, Black HR, et al.; for the national Heart, Lung, and Blood Institute Joint national Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure; national High Blood Pressure Education Program Coordinating Committee. The Seventh Report of the Joint national Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure: the JnC 7 report [published correction appears in JAMA. 2003;290(2):197]. JAMA. 2003;289(19):2560-2572. 15. Johnson JA, Turner ST. Hypertension pharmacogenomics: current status and future directions. Curr Opin Mol Ther. 2005;7(3):218-225. 16. Richardson AD, Piepho RW. Effect of race on hypertension and antihypertensive therapy. Int J Clin Pharmacol Ther. 2000;38(2):75-79. 17. Hingorani AD, Jia H, Stevens PA, Hopper R, Dickerson JE, Brown MJ. Renin-angiotensin system gene polymorphisms influence blood pressure and the response to angiotensin converting enzyme inhibition. J Hypertens. 1995;13(12 pt 2):1602-1609. 18. Psaty BM, Smith nL, Heckbert SR, et al. Diuretic therapy, the alpha-adducin gene variant, and the risk of myocardial infarction or stroke in persons with treated hypertension. JAMA. 2002;287(13):1680-1689. 19. Kurland L, Melhus H, Karlsson J, et al. Aldosterone synthase (CYP11B2) 344 C/T polymorphism is related to antihypertensive response: result from the Swedish Irbesartan Left Ventricular Hypertrophy Investigation versus Atenolol (SILVHIA) trial. Am J Hypertens. 2002;15(5):389-393. 20. Gerdes LU, Gerdes C, Kervinen K, et al. The apolipoprotein epsilon4 allele determines prognosis and the effect on prognosis of simvastatin in survivors of myocardial infarction: a substudy of the Scandinavian simvastatin survival study. Circulation. 2000;101(12):1366-1371. 21. de Maat MP, Kastelein JJ, Jukema JW, et al. 455G/A polymorphism of the beta-fibrinogen gene is associated with the progression of coronary atherosclerosis in symptomatic men: proposed role for an acute-phase reaction pattern of fibrinogen. REGRESS group. Arterioscler Thromb Vasc Biol. 1998;18(2):265-271. 22. Israel E, Drazen JM, Liggett SB, et al.; for the national Heart, Lung, and Blood Institutes Asthma Clinical Research network. Effect of polymorphism of the beta(2)-adrenergic receptor on response to regular use of albuterol in asthma. Int Arch Allergy Immunol. 2001;124(1-3):183-186. 23. Brousseau ME, oConnor JJ Jr, ordovas JM, et al. Cholesteryl ester transfer protein TaqI B2B2 genotype is associated with higher HDL cholesterol levels and lower risk of coronary heart disease end points in men with HDL deficiency: Veterans Affairs HDL Cholesterol Intervention Trial. Arterioscler Thromb Vasc Biol. 2002;22(7):1148-1154.

June 1, 2008

Volume 77, Number 11

www.aafp.org/afp

American Family Physician 1559

GeneticsinDrugMetabolism

24. Cowburn AS, Sladek K, Soja J, et al. overexpression of leukotriene C4 synthase in bronchial biopsies from patients with aspirin-intolerant asthma. J Clin Invest. 1998;101(4):834-846. 25. de Maat MP, Jukema JW, Ye S, et al. Effect of the stromelysin-1 promoter on efficacy of pravastatin in coronary atherosclerosis and restenosis. Am J Cardiol. 1999;83(6):852-856. 26. Gibbs CR, Beevers DG, Lip GY. The management of hypertensive disease in black patients. QJM. 1999;92(4):187-192. 27. Koopmans RP, Insel PA, Michel MC. Pharmacogenetics of hypertension treatment: a structured review. Pharmacogenetics. 2003;13(12):705-713. 28. Trotta R, Donati MB, Iacoviello L. Trends in pharmacogenomics of drugs acting on hypertension. Pharmacol Res. 2004;49(4):351-356. 29. Amudha K, Wong LP, Choy AM, Lang CC. Ethnicity and drug therapy for hypertension. Curr Pharm Des. 2003;9(21):1691-1701. 30. Douglas JG, Bakris GL, Epstein M, et al., for the Hypertension in African Americans Working Group of the International Society on Hypertension in Blacks. Management of high blood pressure in African Americans: consensus statement of the Hypertension in African Americans Working Group of the International Society on Hypertension in Blacks. Arch Intern Med. 2003; 163(5):525-541. 31. Hebert PR, Foody JM, Hennekens CH. The renin-angiotensin system: the role of inhibitors, blockers, and genetic polymorphisms in the treatment and prevention of heart failure. Curr Vasc Pharmacol. 2003;1(1):33-39. 32. Cascorbi I, Paul M, Kroemer HK. Pharmacogenomics of heart failurefocus on drug disposition and action. Cardiovasc Res. 2004;64(1):32-39. 33. Kohno M, Yokokawa K, Minami M, et al. Association between angiotensin-converting enzyme gene polymorphisms and regression of left ventricular hypertrophy in patients treated with angiotensin-converting enzyme inhibitors. Am J Med. 1999;106(5):544-549. 34. Mcnamara DM, Holubkov R, Postava L, et al. Pharmacogenetic interactions between angiotensin-converting enzyme inhibitor therapy and the angiotensin-converting enzyme deletion polymorphism in patients with congestive heart failure. J Am Coll Cardiol. 2004;44(10): 2019-2026. 35. Forleo C, Resta n, Sorrentino S, et al. Association of beta-adrenergic receptor polymorphisms and progression to heart failure in patients with idiopathic dilated cardiomyopathy. Am J Med. 2004;117(7):451-458. 36. Terra SG, Pauly DF, Lee CR, et al. beta-Adrenergic receptor polymorphisms and responses during titration of metoprolol controlled release/extended release in heart failure. Clin Pharmacol Ther. 2005;77(3):127-137. 37. Taylor AL, Ziesche S, Yancy C, et al.; for the AfricanAmerican Heart Failure Trial Investigators. Combination of isosorbide dinitrate and hydralazine in blacks with heart failure [published correction appears in N Engl J Med. 2005;352(12):1276]. N Engl J Med. 2004; 351(20):2049-2057. 38. Mnzel T, Harrison DG. Increased superoxide in heart failure: a biochemical baroreflex gone awry. Circulation. 1999;100(3):216-218.

39. Busse W, Banks-Schlegel S, noel P, ortega H, Taggart V, Elias J, for the nHLBI Working Group. Future research directions in asthma: an nHLBI Working Group report. Am J Respir Crit Care Med. 2004;170(6):683-690. 40. Pignatti PF. Trends in pharmacogenomics of drugs used in the treatment of asthma. Pharmacol Res. 2004; 49(4):343-349. 41. Wallace AM, Sandford AJ. Therapeutic response to asthma medications: genotype predictors. Treat Respir Med. 2004;3(3):161-171. 42. Tantisira KG, Weiss ST. The pharmacogenetics of asthma: an update. Curr Opin Mol Ther. 2005;7(3):209-217. 43. Sayers I, Hall IP. Pharmacogenetic approaches in the treatment of asthma. Curr Allergy Asthma Rep. 2005; 5(2):101-108. 44. Liggett SB, Shah SD, Cryer PE. Characterization of betaadrenergic receptors of human skeletal muscle obtained by needle biopsy. Am J Physiol. 1988;254(6 pt 1): E795-E798. 45. Tan S, Hall IP, Dewar J, Dow E, Lipworth B. Association between beta 2-adrenoceptor polymorphism and susceptibility to bronchodilator desensitisation in moderately severe stable asthmatics. Lancet. 1997; 350(9083):995-999. 46. Wechsler ME, Israel E. How pharmacogenomics will play a role in the management of asthma. Am J Respir Crit Care Med. 2005;172(1):12-18. 47. Drazen JM, Israel E, oByrne PM. Treatment of asthma with drugs modifying the leukotriene pathway [published corrections appear in N Engl J Med. 1999;340(8):663 and N Engl J Med. 1999;341(21):1632]. N Engl J Med. 1999;340(3):197-206. 48. Sampson AP. Leukotriene genetics and the efficacy of leukotriene-receptor antagonists. RT J Respir Care Practitioners. 2004;17:30-32. 49. Asano K, Shiomi T, Hasegawa n, et al. Leukotriene C4 synthase gene A(444)C polymorphism and clinical response to a CYS-LT(1) antagonist, pranlukast, in Japanese patients with moderate asthma. Pharmacogenetics. 2002;12(7):565-570. 50. Tantisira KG, Hwang ES, Raby BA, et al. TBX21: a functional variant predicts improvement in asthma with the use of inhaled corticosteroids. Proc Natl Acad Sci U S A. 2004;101(52):18099-18104. 51. Tantisira KG, Lake S, Silverman ES, et al. Corticosteroid pharmacogenetics: association of sequence variants in CRHR1 with improved lung function in asthmatics treated with inhaled corticosteroids. Hum Mol Genet. 2004;13(13):1353-1359. 52. Wilson JF, Weale ME, Smith AC, et al. Population genetic structure of variable drug response. Nat Genet. 2001; 29(3):265-269. 53. Pharmacogentics: personalizing medicine today! http:// w w w.healthanddna.com / professional / pharmaco genetics.html. Accessed october 17, 2007. 54. Molecular Diagnostics Laboratories. http://www.mdllabs.com/testing/. Accessed February 14, 2008. 55. U.S. Food and Drug Administration Pharmaceutical Science Advisory Committee. november 14-15, 2005. http://www.fda.gov/ohrms/dockets/ac/cder05.html# PharmScience. Accessed october 17, 2007.

1560 American Family Physician

www.aafp.org/afp

Volume 77, Number 11

June 1, 2008

Reproduced with permission of the copyright owner. Further reproduction prohibited without permission.