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Genetic Factors in Donna J. Belle, PhD, RPh, and HARLEEN SINGH, PharmD, Oregon State University College of , Portland Campus at Oregon Health & Science University, Portland, Oregon

Patients vary widely in their response to . Having an under- standing of the pharmacokinetic and pharmacodynamic properties of various 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-metabo- lizing and drug targets (e.g., receptors) have been identi- fied. Although currently limited to a few pathways, pharmacogenetic testing may enable physicians to understand why patients react dif- ferently 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 gene. The phenotype is a person’s outward varies widely and the reasons for physical appearance or function resulting this are diverse and complex, from the interaction between the genotype experts estimate that genetic fac- and the environment. Genetic polymor- A tors account for 20 to 95 percent of patient phisms are naturally occurring variants variability in response to individual drugs.1 in gene structure that occur in more than Genetic influences on 1 percent of the population. Polymorphisms interact with other intrinsic (i.e., physiologic) may influence a drug’s action by changing its and extrinsic (i.e., cultural, behavioral, and or its . environmental) characteristics of a person to determine the outcome from treatment with Pharmacokinetics any pharmacologic agent (Table 1).2 Pharmacokinetics is the study of the rate Although still in its infancy, the field of and extent of drug absorption, distribution, pharmacogenetics and metabolism, and . These processes already provides useful clinical information determine the fate of a drug in the body. to enhance patient care and offers a grow- A combination of metabolism and excretion ing potential to individualize drug therapy constitutes drug elimination from the body. and improve clinical outcomes. This article The main routes of drug elimination are reviews the leading areas in which genetic metabolism (often in the ) and renal variations currently affect treatment and excretion. Genetic polymorphisms have indicates a need for physicians to monitor been identified for many drug-metabolizing this topic as genomic-based treatment guide- enzymes, including the lines become available. (CYP450) enzymes. This gives rise to dis- tinct population phenotypes of persons who Definitions have metabolism capabilities ranging from The study of genetic variations in drug extremely poor to extremely fast. The large response is called pharmacogenetics when range of incidence of common CYP poly- studying an individual gene, or pharmacoge- morphisms in selected population groups is nomics when studying all genes. A person’s illustrated in Table 2.3-9 Some potential clini- genotype is his or her genetic makeup. The cal consequences of these polymorphisms term can pertain to all genes or to a specific are listed in Table 3.

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SORT: KEY RECOMMENDATIONS FOR PRACTICE

Evidence Clinical recommendation rating References

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

A = consistent, good-quality patient-oriented evidence; B = inconsistent or limited-quality patient-oriented evi- dence; 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.

Cytochrome P450 2C9 (CYP2C9) with reduced enzymatic activity. CYP2C9 The CYP2C9 is involved in the is the principal enzyme responsible for the metabolism of many common drugs such metabolism of S-. Persons who are as (Glucotrol), (Ori- CYP2C9 poor metabolizers have reduced nase; brand not available in United States), S-warfarin . Clinical studies have (Cozaar), (Dilantin), shown that these persons require lower dos- and warfarin (Coumadin). The pheno- ages of warfarin and are at an increased risk types CYP2C9*2 and CYP2C9*3 are the two of excessive anticoagulation.10,11 most common variations and are associated Cytochrome P450 2C19 (CYP2C19) The CYP2C19 enzyme metabolizes many Table 1. Factors Influencing Drug Response drugs, including proton pump inhibitors, (Celexa), (Valium), and (Tofranil). More than 16 Intrinsic Extrinsic variations of CYP2C19, associated with Genetic Physiologic deficient, reduced, normal, or increased Absorption, Absorption, distribution, Climate activity, have been identified. Genotyp- distribution, metabolism, excretion Culture ing for CYP2C19*2 and CYP2C19*3 iden- metabolism, Age Educational status excretion tifies most CYP2C19 poor metabolizers. Alcohol Language Body weight The CYP2C19*17 variant is associated with Body weight Socioeconomic Genetic conditions Cardiovascular function factors ultrarapid metabolizers and seems relatively Genetic Diet Definition/diagnostics common in Swedes (18 percent), Ethiopians polymorphism 12 Diseases/conditions Diet (18 percent), and Chinese (4 percent). The of drug- proton pump inhibitor (Prilo- metabolizing Height Diseases/conditions enzymes function Drug adherence sec) is primarily metabolized by CYP2C19 Height Liver function Medical practices to its inactive , 5-hydroxyome- Race sensitivity Pollution prazole. Persons who are CYP2C19 poor Receptor sensitivity Smoking Smoking metabolizers can have fivefold higher blood Sex Stress Stress concentrations of omeprazole and experi- Sunlight ence superior acid suppression and higher Therapeutic approach cure rates than the rest of the popula- tion. Conversely, blood concentrations of Adapted from the U.S. Food and Drug Administration, U.S. Dept. of Health and omeprazole are predicted to be 40 percent Services. International Conference on Harmonisation: guidance on eth- lower in ultrarapid metabolizers than in the nic factors in the acceptability of foreign clinical data; availability. Federal Regis- ter 1998;63(111):31790-31796. http://www.fda.gov/cder/guidance/2293fnl.pdf. rest of the population, thus putting persons Accessed October 17, 2007. with the CYP2C19 ultrarapid metabolizers phenotype at risk of therapeutic failure.12

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Cytochrome P450 2D6 (CYP2D6) system. The relationship between drug The enzyme CYP2D6 is involved in the concentration and the observed pharma- metabolism of an estimated 25 percent cologic response depends on the drug’s of all drugs. More than 75 allelic variants . The pharmacologic have been identified, with enzyme activi- response to a drug may be mediated through ties ranging from deficient to ultrarapid. a direct effect, such as binding with a specific The most common variants associated with poor metabolizer phenotype are CYP2D6*3, CYP2D6*4, CYP2D6*5, and CYP2D6*6 in Table 2. Incidence of Cytochrome P450 Metabolizer Phenotypes Among Ethnic Groups whites and CYP2D6*17 in blacks. is metabolized by CYP2D6 to its active Population frequency (%) metabolite, . Clinical studies have Metabolizer shown that CYP2D6 poor metabolizers have Enzyme phenotype Asians Blacks Whites poor analgesic response as a result of the 3 4 4 reduced conversion of codeine to morphine. CYP2C9 Poor 0.4 0.0 1.0 4 4 4 Conversely, CYP2D6 ultrarapid metaboliz- Intermediate 3.5 13 33 ers quickly convert codeine to morphine Ultrarapid — — — 3,5 5,6 3,5 and have enhanced analgesic response.13 CYP2C19 Poor 18 to 23 1.2 to 5.3 2.0 to 5.0 7 7,8 7 The activity of drug-metabolizing enzymes Intermediate 30 29 18 may be induced or inhibited by many other Ultrarapid — — — 3,5,8 5,6,8 3,8 intrinsic and extrinsic factors, including CYP2D6 Poor 1.0 to 4.8 1.9 to 7.3 7.0 to 10 8 9 8 comorbid conditions, use of other medica- Intermediate 51 30 1.0 to 2.0 8 8 8 tions, smoking, alcohol intake, and dietary Ultrarapid 0.9 to 21 4.9 1.0 to 5.0 factors. note: Poor metabolizers have markedly reduced or absent enzyme activity; intermedi- ate metabolizers have reduced enzyme activity; and ultrarapid metabolizers have high Pharmacodynamics enzyme activity. Pharmacodynamics is the study of the phar- CYP = cytochrome P450. macologic effect resulting from the inter- Information from references 3 through 9. action between the drug and the biologic

Table 3. Clinical Consequence of Metabolizer Phenotypes on Drug Response

Metabolizer Effect on drug Drug type phenotype metabolism Potential consequence

Prodrug, needs metabolism to Poor to Slow Poor drug , patient at risk of therapeutic work (e.g., codeine metabolized intermediate failure to morphine) Accumulation of , patient at increased risk of drug-induced side effects Ultrarapid Fast Good drug efficacy, rapid effect Active drug metabolized to Poor to Slow Good drug efficacy inactive drug (e.g., omeprazole intermediate Accumulation of active drug, patient at increased [Prilosec] metabolized to risk of drug-induced side effects 5-hydroxyomeprazole) Patient requires lower dosage Ultrarapid Fast Poor drug efficacy, patient at risk of therapeutic failure Patient requires higher dosage

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

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receptor, or an indirect effect, such as phosphatase activity, increased intracellu- inhibiting an enzyme in a protein synthesis lar sodium concentrations, elevated fasting pathway. insulin levels) may explain the potentially different pathophysiology of Pharmacogenomics in blacks and whites.16 This has led to the in Common Conditions discovery of candidate genes for hyperten- CARDIOVASCULAR CONDITIONS sion (Table 410,16-25). Polymorphism in these Hypertension is a major risk factor for cardio- genes may be responsible for the high preva- vascular 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 pres- factors (e.g., low plasma renin activity, higher sure effectively.29 Although the risk of ACE- prevalence of expanded plasma volume, related angioedema is generally low, there reduced sodium-potassium adenosinetri- is some evidence that it is more common

Table 4. Genetic Polymorphisms in Drug Receptor Genes Associated with Drug Response

Gene (drug) Response

ACE ACE inhibitors, ARBs, Greater blood pressure reduction 17 ( [Lescol]), and fibrates Greater LDL reduction, increase in HDL ( [Lopid]) cholesterol with statins and fibrates Alpha-adducin Diuretics () Better blood pressure control with diuretics and fewer cardiovascular events16,18 Angiotensinogen ACE inhibitors and ARBs ( Greater reduction in blood pressure and left ventricle [Avapro]) mass with ACE inhibitors and ARBs19 Apolipoprotein E Statins ( [Zocor]) Greater mortality reduction with simvastatin20 Beta-fibrinogen Statins ( [Pravachol]) Reduction in coronary atherosclerosis21

β1-adrenergic receptors Beta blockers ( [Lopressor]) Greater reduction in blood pressure

β2-adrenergic receptors Beta2-adrenergic (albuterol May affect survival in failure [Proventil]) Positive response to bronchodilator therapy 22 Cholesteryl ester transfer Statins (pravastatin) Greater effects of pravastatin on slowing coronary protein Fibrates (gemfibrozil) atherosclerosis23 Greater reductions in triglycerides 24 Leukotriene C4 synthase Leukotriene receptor antagonists Improvement in FEV1 ( [Accolate]) 5-lipoxygenase Leukotriene receptor antagonists May affect disease predisposition of asthma Stromelysin-1 Statins (i.e., pravastatin) Pravastatin reduced the incidence of coronary artery restenosis and repeat angioplasty 25 Vitamin K epoxide reductase Warfarin (Coumadin) Less variability in dose response10 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.

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in blacks.30 Despite the differences between of multiple genes with potential polymor- black persons and other ethnic groups, ACE phisms makes predicting persons at risk of inhibitors have proven highly effective in developing CHD highly imprecise. Examples reducing morbidity and mortality in patients of genes affecting CHD include the choles- with hypertension who present with other teryl ester transfer protein, stromelysin-1, comorbidities such as heart failure, diabetic beta-fibrinogen, and apolipoprotein E genes. nephropathy, and myocardial infarction.14 Descriptions of genetic polymorphisms asso- Advances in drug therapy have helped ciated with CHD and their response to reduce mortality in many patients with heart therapy are summarized in Table 4.10,16-25 failure, but it is unclear whether all popula- tion groups have benefited. Beta blockers and ASTHMA ACE inhibitors are the standard of care in Approximately 8 to 10 percent of the U.S. patients with heart failure.31 Therapeutic out- population is affected by asthma. In terms comes have been highly variable, possibly sec- of morbidity and cost, asthma is considered ondary to genetic variability in β-adrenergic a major health risk.39 Research has focused receptors, the renin-angiotensin-aldosterone on identifying the potential role of genetics system, the endothelin system, and endothe- in the pathophysiology and management of lial nitrogen monoxide synthase.32 one of asthma.40-43 Common drugs used to control the most important genetic polymorphisms asthma are beta2 agonists (both short- and studied in heart failure is an insertion/dele- long-acting), inhaled corticosteroids, and tion (I/D) polymorphism of the aCE gene. leukotriene antagonists. Response to asthma Persons who are D carriers have higher ACE medications is highly variable, with only activity and are at increased risk of develop- 60 to 80 percent of patients deriving thera- ing cardiovascular disease.33,34 Similarly, the peutic benefit.40 response to beta blockers is highly variable in Inhaled beta2 agonists, such as albuterol patients with heart failure.35,36 (Proventil), are used to control acute attacks Recently, the african american Heart of asthma and are prescribed to be used “as Failure Trial (A-HeFT) demonstrated that needed.” Several studies have shown that adding (Isochron) and some patients benefit from use of short- (Apresoline; brand not available acting beta2 agonists whereas others do in United States) to standard therapy for heart not.22,44 This variation in response is partly failure increases survival in black patients explained by the alteration in the amino acid with advanced heart failure.37 It has been pro- sequence of the protein or altered transcrip- posed that nitric oxide deficiency can result tion of the beta2 receptors. Patients with the 38 in the progression of heart failure. Patients beta2 receptor arginine genotype experience exhibiting genetic polymorphism may have poor asthma control with frequent symptoms less nitric oxide and, thus, may benefit from and a decrease in scores on forced expiratory nitric oxide–enhancing therapy. Because this volume in one second compared with patients study included only black patients, it lacked who have the genotype.22,45 Studies evidence of differences in response between show that 17 percent of whites and 20 percent white and black Americans. The gene or genes of blacks carry the arginine genotype.46 responsible for nitric oxide deficiency have Leukotriene (LT) modifiers (e.g., zileu- not been identified in black persons. How- ton [Zyflo], [Singulair], zafir- ever, several biologic systems are involved in lukast [Accolate]) block the 5-lipoxygenase the pathogenesis of heart failure, and each is (5-LO) and LTC4 synthase pathways, prevent- highly polymorphic. Currently, no prospec- ing leukotriene-mediated bronchoconstric- tive studies are investigating the simultane- tion.47,48 only a minority of patients benefit ous impact of multiple genetic variants on from treatment with lT receptor agonists. cardiovascular outcomes. Polymorphism in 5-LO and lTC4 synthase Several genes are associated with coro- pathways has been identified (Table 410,16-25). nary heart disease (CHD). The involvement Approximately 5 percent of patients with

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asthma have the 5-LO polymorphism. ness.10 Understanding environmental and Patients who had the 5-LO polymorphism genetic factors will allow the physician to showed a greater improvement in their more accurately dose warfarin and improve function with zafirlukast therapy compared anticoagulation control. with patients who had the normal 5-LO geno- Limitations of the Current Literature type. Similarly, polymorphisms in the lTC4 synthase gene may predispose a person to on Pharmacogenomics

asthma. Patients with the variant LTC4 syn- Most pharmacodynamic studies have been thase genotype have higher levels of cysteinyl relatively small and the populations stud- leukotrienes, which have been linked with ied are not always well characterized. eth- severe asthma. The use of LT modifiers in this nic categories (e.g., asians, blacks, whites) population may be beneficial.24,49 include persons from widely diverse geo- Variation in the genes involved in the graphic and sociocultural backgrounds with biologic action of inhaled corticosteroids varying genetic composition, and the results may explain the variability to response and might not apply to all members of each eth- adverse effects to inhaled corticosteroids. nic population. Typically, pharmacokinetic Polymorphisms in corticotropin-releasing variability is no greater than pharmacody- hormone receptor-1 and T-box expressed in namic variability; however, in most studies, T cells have been associated with improved only selected pharmacokinetic parameters response in patients with asthma.50,51 were examined. Although these findings are promising in Use of genotyping is more accurate than predicting therapeutic response to asthma race or ethnic categories to identify varia- , their usefulness in clinical prac- tions in drug response.52 Unlike other influ- tice is still under investigation. ences on drug response, genetic factors remain constant throughout life. The use Warfarin of pharmacogenetic information to sup- Warfarin dosing can be challenging because port drug selection and dosing is emerging. of its narrow and the Commercial testing is available for drug- serious risk of bleeding with overdosage. metabolizing enzymes and some pharmaco- Typically, warfarin dosing is individualized dynamic targets such as VKORC1, stromely- based on sex, age, vitamin K intake, drug sin-1, and apolipoprotein E.53,54 Prospective interactions, and disease states. genetic testing would be beneficial for drugs Dosing adjustments are made for which a clear genotype-response relation- Prospective genetic testing according to the desired Inter- ship has been demonstrated, such as warfa- could be beneficial for drugs national normalized Ratio. rin (CYP2C9, VKORC1) and proton pump for which a clear genotype- Environmental and genetic inhibitors (CYP2C19). The U.S. Food and response relationship has factors can influence warfa- Drug Administration has suggested relabel- been demonstrated. rin response. Several studies ing warfarin to include genetic information have focused on CYP2C9 poly- to guide initial dosing.55 morphisms 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 ” articles Warfarin exerts its anticoagulant effects coordinated by Allen F. Shaughnessy, PharmD, Tufts Uni- by inhibiting hepatic vitamin K epoxide versity Family Residency at Cambridge Health reductase, an enzyme involved in the syn- Alliance, Malden, Mass. thesis of various clotting factors. Polymor- phisms in the vitamin K epoxide reductase The Authors 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 Phar- ute to the variability in warfarin responsive- macy, Oregon State University, Portland, at the time she

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coauthored this article. Dr. Belle received her doctorate tion-related outcomes during warfarin therapy. JAMA. degree from the School of Pharmacy at West Virginia 2002;287(13):1690-1698. University, Morgantown, and completed a postdoctoral 12. Sim SC, Risinger C, Dahl ML, et al. A common novel research fellowship in the Department of Drug Disposition CYP2C19 gene variant causes ultrarapid drug metabo- at Eli Lilly and Company, Indianapolis, Ind. lism relevant for the drug response to proton pump inhibitors and . Clin Pharmacol Ther. HARLEEN SINGH, PharmD, is an assistant professor of 2006;79(1):103-113. pharmacy in the Department of Pharmacy Practice, Col- 13. de Leon J, Dinsmore L, Wedlund P. Adverse drug reac- lege of Pharmacy, Oregon State University. Dr. Singh tions to and in CYP2D6 ultra- received her doctor of pharmacy degree from Ohio State rapid metabolizers. J Clin Psychopharmacol. 2003; University College of Pharmacy, Columbus, where she also 23(4):420-421. completed a residency in medicine. 14. Chobanian AV, Bakris GL, Black HR, et al.; for the Address correspondence to Harleen Singh, PharmD, National Heart, Lung, and Blood Institute Joint National Oregon State University College of Pharmacy, 3303 SW Committee on Prevention, Detection, Evaluation, and Bond Ave., CH12C, Portland, OR 97239 (e-mail: singhh@ Treatment of High Blood Pressure; National High Blood ohsu.edu). Reprints are not available from the authors. Pressure Education Program Coordinating Committee. The Seventh Report of the Joint National Committee Author disclosure: Nothing to disclose. on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure: the JNC 7 report [published cor- rection appears in JAMA. 2003;290(2):197]. JAMA. REFERENCES 2003;289(19):2560-2572. 15. Johnson JA, Turner ST. Hypertension pharmacogenom- 1. Kalow W, Tang BK, Endrenyi L. 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1560 American Family Physician www.aafp.org/afp Volume 77, Number 11 ◆ June 1, 2008