TY - JOUR
AU - Langaee, Taimour, Y.
AB - Abstract Purpose. The basic concepts of pharmacogenetics, pharmacogenetic study approaches, factors to consider when applying pharmacogenetic discoveries to patient care, and potential roles for pharmacists in pharmacogenetics are discussed. Summary. The Food and Drug Administration (FDA) has recognized pharmacogenomics as an opportunity to identify new biomarkers that may expedite the drug development process. Currently, there are over 50 drugs with pharmacogenetic discoveries on their labeling. Sequence variations in drug disposition genes can alter the pharmacokinetics of a drug, while sequence variations in drug target genes can change the pharmacodynamics of the drug. The two most common strategies to test a pharmacogenetic question are the candidate-gene approach and genomewide association study. Given the complex interplay among the many factors that influence a drug dose, determination of an appropriate dose of a particular drug for a given patient will eventually require knowledge about both genetic and nongenetic factors that affect drug disposition and pharmacodynamics. Many factors can influence the application of pharmacogenetic discoveries to patient care. Before these discoveries find widespread application in clinical practice, additional work is needed, including randomized clinical trials to evaluate the clinical utility of a pharmacogenetic test, the development of guidelines for the clinical use of various pharmacogenetic tests, and provider education on pharmacogenetics. Conclusion. Pharmacogenetics has made significant progress in the past decade, and many pharmacogenetic discoveries have now been included on FDA-approved drug labeling. Pharmacogenetic discoveries may further promote safe and effective use of medications by more accurately predicting an individual’s drug response. Food and Drug Administration (U.S.), Labeling, Methodology, Patient care, Pharmacists, Pharmacogenetics, Research The first pharmacogenetic discovery was made more than five decades ago in patients deficient in glucose-6-phosphate dehydrogenase who developed hemolysis after treatment with primaquine.1 The term pharmacogenetics was coined by Vogel in 1959.2 Although pharmacogenetics focuses on the effect of a single gene on drug response and pharmacogenomics deals with the effects of multiple genes on drug response, both terms are used interchangeably in this review to simplify the discussion (see the appendix for a glossary and resources).3,–6 Despite almost 50 years of history, most of the progress in pharmacogenetics has been made in recent years, and the number of publications associated with pharmacogenetics has dramatically increased. The completion of the Human Genome Project7 and the International HapMap Project,8 along with the rapid development of advanced genetic technologies, has greatly affected pharmacogenetic discoveries and may increase the number of publications containing new pharmacogenetic discoveries. Currently, there are over 120 drugs whose labeling includes pharmacogenetic discoveries,9 and that number is likely to increase in the future. These drugs encompass a variety of therapeutic areas including infectious diseases (voriconazole), cardiology and hematology (warfarin), neurology (carbamazepine), psychiatry (atomoxetine), and oncology (azathioprine, irinotecan, trastuzumab, and cetuximab). In a white paper, the Food and Drug Administration (FDA) recognized pharmacogenomics as an opportunity to identify new biomarkers that may expedite the drug development process.10 The agency also published a guidance document to facilitate the use of pharmacogenomic discoveries in drug development and has taken a leading role in evaluating a genomic marker as a new biomarker by forming various consortiums including the government, industry, and academia.11 Thus, many future pharmacogenetic discoveries are expected to be used in both drug development and clinical practice. Compared with the rapid progress being made in the field of pharmacogenetics, knowledge of and experience with pharmacogenetics among pharmacists are rather limited.12,–14 Most practicing pharmacists have not received any formal education and training in pharmacogenetics, and the Accreditation Council for Pharmacy Education has only recently required pharmacogenetics to be included in the curriculum of all accredited doctor of pharmacy programs.14,15 In addition, it is not easy for most practicing pharmacists to keep up with the rapid developments in pharmacogenetics. This article reviews the basic concepts of pharmacogenetics to help pharmacists interpret different approaches to pharmacogenetic studies and pharmacogenetic discoveries recognized by FDA. To make the discussion more practical, examples of genes and drugs that are included in FDA-approved package inserts are presented. Finally, future directions and the potential roles for pharmacists in applying pharmacogenetic discoveries to patient care are also discussed. Basic concepts The human genome consists of approximately 3 billion base pairs, and the sequence of these varies among individuals. These variations include single nucleotide polymorphisms (SNPs), base insertions or deletions, copy-number variations, and variable numbers of tandem repeats.4,–6 Because these variations can change the function of proteins that interact with a drug, the response to a drug may differ among individuals. Understanding how these variations influence drug response could help in tailoring drug therapy based on an individual’s genetic makeup. The study of pharmacogenetics can arbitrarily be divided into drug disposition and drug targets. Sequence variations in drug-disposition genes can alter the pharmacokinetics of a drug, while those in drug-target genes can change the pharmacodynamics of a drug. Because it may be easier to understand the basic concepts with this classification, the following section is divided into drug-disposition pharmacogenetics and drug-target pharmacogenetics. Drug-disposition pharmacogenetics The disposition of a drug includes its absorption, metabolism, distribution, and excretion. If a genetic polymorphism alters the function of a protein that is involved in the disposition of a drug, then concentrations of the parent drug or its active metabolites at the site of drug action may also be affected. For example, if a genetic polymorphism leads to lower activity of a metabolizing enzyme, the plasma concentrations of the parent drug may increase and plasma concentrations of metabolites may decrease. If only the parent drug exhibits pharmacologic activity, the genetic polymorphism will potentiate the drug response, including adverse drug reactions. If only the metabolites have pharmacologic activity, then the genetic polymorphism may reduce the drug response. Examples of genetic variability impairing the function of metabolizing enzymes and altering drug responses include warfarin and the cytochrome P-450 (CYP) isoenzyme 2C9 (CYP2C9 polymorphisms, tamoxifen and CYP2D6 polymorphisms, and thiopurine drugs and thiopurine S-methyltransferase (TPMT) polymorphisms. Warfarin Warfarin, an oral anticoagulant, is a racemic drug. S-warfarin, which is three to five times more potent than R-warfarin, is primarily metabolized by CYP2C9.16 The CYP2C9 gene is highly polymorphic.17 Most polymorphisms are located in noncoding regions, and many of them are in strong linkage disequilibrium with SNPs in the coding regions. Thus, studies of SNPs located in the coding regions would also cover the genetic variations in the noncoding regions. Two polymorphisms in the coding region that are relatively common (6–10% frequency) in Caucasians and rare in African Americans and Asians have been extensively studied for their influence on the variability in stable warfarin dose requirements.18 One is CYP2C9*2 (a cytosine to thymine [C to T] change at nucleotide position 430, abbreviated 430C>T), which encodes an amino acid substitution (arginine to cysteine change at codon 144 [Arg144Cys]) that results in a 30–40% reduction in enzymatic activity for S-warfarin metabolism.19 The other is CYP2C9*3 (1075A>C), which encodes an Ile359Leu change that causes an almost complete loss of S-warfarin metabolism.20 Thus, one would expect that patients carrying either one or both of these two alleles would have higher serum concentrations of S-warfarin at a given dosage and require smaller dosages of warfarin to maintain a therapeutic International Normalized Ratio (INR) compared with patients who do not have a variant allele. A study in Caucasians found that patients carrying either CYP2C9*2 or CYP2C9*3 required significantly lower daily dosages of warfarin to maintain a therapeutic INR compared with patients carrying CYP2C9*1/*1, abbreviated *1/*1 here (p < 0.001).21 The mean ± S.D. daily warfarin sodium dose was 5.63 ± 2.56 mg with *1/*1, 4.88 ± 2.57 mg in patients with *1/*2, 3.32 ± 0.94 mg in patients with *1/*3, 4.07 ± 1.48 mg in patients with *2/*2, 2.34 ± 0.35 mg in patients with*2/*3, and 1.60 ± 0.81 mg in patients with *3/*3.21 Tamoxifen The study of tamoxifen pharmacogenetics demonstrates how serum concentrations of an active metabolite are influenced by genetic variations in the tamoxifen-metabolizing enzyme. Tamoxifen is commonly used for breast cancer treatment. Endoxifen, a metabolite of tamoxifen, is 100 times more potent than the parent drug as a selective estrogen receptor modulator and exhibits about 7 times higher plasma concentrations than the other active metabolites at steady state.22,–24 CYP2D6 is involved in generating endoxifen from tamoxifen, and its genotype and phenotype have been associated with variability in plasma concentrations of endoxifen among individuals.25 The CYP2D6 phenotype—traditionally classified as an ultraextensive metabolizer, an extensive metabolizer, an intermediate metabolizer, or a poor metabolizer—is determined by the urinary metabolic ratio of a probe drug such as sparteine or debrisoquine.26 The CYP2D6 phenotype may also be determined using the CYP2D6 genotype. The CYP2D6 gene, which has over 70 alleles, contains a variety of genetic polymorphisms, such as SNPs, gene deletions, and gene duplications.27 Because CYP2D6 activity differs by CYP2D6 allele (Table 1), the CYP2D6 phenotype may be determined by the number of functional, nonfunctional, and reduced-functional alleles a person carries.28,29 In general, the ultraextensive metabolizer phenotype may be present in people who carry multiple copies of a functional CYP2D6 allele, the extensive metabolizer phenotype may be present in people who carry a functional CYP2D6 allele, the intermediate metabolizer phenotype in individuals who are heterozygous for a reduced-functional allele and a nonfunctional allele, and the poor metabolizer phenotype in those who carry neither a functional nor a reduced-functional allele.30 For example, CYP2D6*1/*1 denotes an extensive metabolizer, CYP2D6*3/*17 an intermediate metabolizer, CYP2D6*3/*3 a poor metabolizer, and CYP2D6*1/*1XN (gene duplication) an ultraextensive metabolizer. Since higher-metabolizing- enzyme activity results in higher blood concentrations of an active metabolite of a drug that is metabolized by the enzyme, extensive or ultraextensive metabolizers would have significantly higher serum concentrations of endoxifen compared with intermediate and poor metabolizers. Jin et al.,31 in fact, showed that serum concentrations of endoxifen in ultraextensive and extensive metabolizers were about two and four times higher than in intermediate and poor metabolizers, respectively. Though not confirmed, one study suggested that breast cancer patients with intermediate- or poor-metabolizer phenotypes had significantly lower relapse-free survival rates compared with extensive or ultraextensive metabolizers.32 Thiopurines The pharmacogenetics of thiopurines provides a classic example of how alleles that produce defective drug-metabolizing enzymes increase the risk of adverse drug events. TPMT metabolizes cytotoxic and immunosuppressant thiopurine drugs such as mercaptopurine and azathioprine, a prodrug of mercaptopurine. TPMT activity is highly variable among individuals, and reduced TPMT activity is associated with a higher frequency of mercaptopurine-associated adverse events, such as neutropenia.33 Genetic polymorphisms of TPMT have been associated with variability in TPMT activity. Of the more than 20 TPMT alleles that have been linked with variable TPMT activity, 3 alleles are common (Table 2) and account for over 95% of TPMT inherited deficiency.34,35,TPMT*2 (238G>C) encodes an amino acid change (Ala80Pro).36 Allele *3A (460G>A and 719A>G) causes two amino acid changes (Ala154Thr and Tyr240Cys), and *3C (719A>G) c h a n g e s o n e a m i n o a c i d (Tyr240Cys).37,38 The resultant proteins are nonfunctional because these alleles produce an enzyme more susceptible than normal to cellular degradation.39,40 Patients who do not carry a wild type TPMT allele (TPMT*1) have extremely low TPMT enzyme activity and almost always develop neutropenia compared with patients with TPMT*1/*1.35,41 Based on these data, FDA has recommended that clinicians consider a reduction in the dosage of a thiopurine in patients carrying a nonfunctional TPMT allele and suggested alternative therapies in patients with homozygous nonfunctional TPMT alleles.42 Drug-target pharmacogenetics In general, drugs exert their pharmacologic effects by modulating activities of enzymes or receptors. Thus, genetic polymorphisms that change the activity of the drug target may also alter the drug response. For example, if a genetic polymorphism reduces the activity of a drug-target enzyme, the amount of drug required to inhibit the enzyme may be less than the amount required to inhibit the enzyme with normal activity. Also, drugs that inhibit or antagonize an enzyme or a receptor will produce a greater response at a given dosage in patients whose genetic polymorphisms confer higher activities of the target protein. Fewer genetic polymorphisms in pharmacodynamic genes have been recognized by FDA when compared with the genetic polymorphisms of the drug-disposition genes. Two good examples that illustrate this concept include (1) vitamin K epoxide reductase complex subunit 1 gene polymorphisms (VKORC1) and warfarin response and (2) β1-adrenergic receptor gene polymorphisms (ADRB1) and β-blocker response. VKORC1 VKORC1 encodes vitamin K epoxide reductase, which is inhibited by warfarin.43,44 This inhibition interferes with carboxylation of vitamin K-dependent coagulation factors II, VII, IX, and X and anticoagulation proteins C and S.16 Two haplotypes (A and B) formed by five noncoding VKORC1 SNPs in strong linkage disequilibrium have been associated with differences in mean ± S.D. daily warfarin sodium dosage (2.7 ± 0.2 mg per day for patients with A/A haplotype, 4.9 ± 0.2 mg per day for patients with A/B, and 6.2 ± 0.3 mg per day for patients with B/B).45 This finding has been replicated in other studies.46,–48 The A haplotype has been shown to be associated with lower levels of VKORC1 mRNA expression compared with B haplotype.45,49 Thus, patients with A haplotype may produce smaller amounts of VKORC1 (the warfarin target protein) than do patients with B haplotype. Importantly, this association is independent of CYP2C9 genotype.45,50 This finding also explains, in part, the well-known clinical observation that Asian patients require smaller warfarin doses to maintain a therapeutic INR than other races since the majority of Asians carry VKORC1 haplotype A (Table 3).45 ADRB1 Ser49Gly and Arg389Gly are two common SNPs in ADRB1. Ser49Ser β1-adrenergic receptors were more resistant to agonist-promoted receptor down regulation, and Arg389Arg receptors had higher basal and agonist-stimulated receptor activities compared with Gly49Gly and Gly389Gly receptors, respectively.51,52 Because of higher receptor activities with Ser49Ser or Arg389Arg β1-adrenergic receptors, it is hypothesized that hypertensive patients carrying Ser49 or Arg389 would have greater reduction in blood pressure with β-blocker therapy. Several studies have found that hypertensive patients with Ser49Arg389/Ser49Arg389 haplotype had the greatest reduction in blood pressure with oral metoprolol (a reduction of 19 mm Hg in systolic pressure and a reduction of 6.0–14.7 mm Hg in diastolic pressure) compared with patients who had other haplotypes (a reduction of 1.0–13 mm Hg in systolic pressure and a reduction of 1.0–8.8 mm Hg in diastolic pressure for Ser49Arg389/ Gly49Arg389, Ser49Arg389/Ser49 Gly389, Gly49Arg389/Ser49Gly389, and Ser49Gly389/Ser49Gly389 haplotypes).53,54 Beta-blocker pharmacogenetics may help to explain the clinical observation that Caucasians are more likely to have a better blood pressure response to a β-blocker than do African Americans, since the frequency of the Arg389 allele in ADRB1 is higher in Caucasians (73%) than in African Americans (58%) and carrying the Arg389 allele predicts a greater blood pressure reduction after β-blocker treatment.55 Common pharmacogenetic study approaches The candidate-gene and genome-wide association study (GWAS) are the two most common strategies to test a pharmacogenetic question. Both approaches can be used for gene–disease and gene–drug response association studies. Candidate-gene studies The candidate-gene approach tests whether a particular allele or a set of alleles is more frequent in patients who have a better (or worse) drug response.56,57 Most often, genes are selected based on their known physiological or pharmacologic effect on disease or drug response. Thus, prior knowledge about the function of a gene is essential for selecting a gene to study. If there is a known genetic polymorphism that affects the function of a protein, that polymorphism is often selected for the study. For example, CYP2C9*2 and CYP2C9*3 were chosen to study the association with warfarin requirements because these polymorphisms had previously been shown to change the function of the CYP2C9 enzyme.17,19,20 If there are many SNPs in a gene of interest, it is often not feasible to genotype all of them. It is a common practice to set the minor allele frequency (MAF) to >5% to select SNPs, because SNPs with a frequency of <5% usually do not provide enough power to the study and may be of little clinical relevance.58 The number of selected SNPs can be further reduced based on the degree of linkage disequilibrium among the SNPs. SNPs in strong linkage disequilibrium form haplotypes, and genotyping at one locus enables researchers to infer genotypes at the other loci in a haplotype. The SNP that is genotyped and used to infer the genotypes at the other loci in a haplotype is called a tag SNP. By genotyping only the tagging SNPs, the number of SNPs for genotyping can be reduced without compromising required coverage of the genetic variations in a gene. The discovery of the association of VKORC1 haplotypes with warfarin dosage requirements shows how the candidate-gene approach is used. Although VKORC1 has several nonsynonymous SNPs, they are clinically insignificant because they are rare (MAF of <5%).44,45,VKORC1 was found to have 28 new SNPs in noncoding regions in Caucasian patients.45 Among them, 10 SNPs with an MAF of >5% were selected to study the association of warfarin dosage requirements. Among the 10 SNPs, 5 with strong linkage disequilibrium formed two haplotypes (designated as A and B) that were associated with variability in warfarin dosage requirements. Because of strong linkage disequilibrium among these 5 SNPs, one locus can be genotyped to infer genotypes at the other four loci and the two haplotypes can be differentiated (Table 4).45 These findings were replicated in multiple independent populations.49,50,59 Given the risk for a false association, such confirmation is important.60 The candidate-gene approach is a useful tool to study a genetic association with drug response if there is a plausible link between the gene and the drug response. Because physiological or pharmacologic effects of the genes (or genetic variations) on disease or drug response may already have been characterized, the results of a study (especially a positive association) using the candidate-gene approach are often easier to understand than GWAS results. This approach is less expensive and requires a smaller sample size than GWAS.61,62 A major disadvantage of the candidate-gene approach is that it requires prior knowledge of the function of the gene regarding the drug response. If information on the function of the gene is limited, the selection of the gene is difficult to justify. GWAS The GWAS surveys the common genetic variations for a role in disease or drug response by genotyping large sets of SNPs across the genome.58,–63 The human genome is estimated to have about 12 million common SNPs. There are many small regions (10–100 kb) in the genome where SNPs are in linkage disequilibrium and form two to four common haplotypes.64 Thus, an SNP in a region can be selected to represent its genetic variation. In other words, a tag SNP can be used as a proxy for the other SNPs in the region. This enables the genetic variations across the genome to be surveyed by genotyping tag SNPs. The number of SNPs used in a GWAS ranges from 100,000 to 1,000,000, with a higher number generally providing better coverage of the variations in the genome.65 Most GWASs have been conducted as a case–control, cohort, or family study.66,–70 The goal is to determine whether a particular allele or a set of alleles is more common in patients with a certain disease or a better (worse) drug response. Since a large number of SNPs are surveyed and compared, the a priori level of significance should be lowered to account for an increasing chance of a false-positive finding by multiple comparisons.71 The strength of an association is usually assessed using an odds ratio (OR) or a relative risk and p value. As with the candidate-gene association study, the findings should be replicated in multiple independent populations.60 Since a GWAS does not hypothesize a possible role of a gene in the drug response, it is a great tool to discover new functions of a gene or to identify a new genetic biomarker that may be used as a surrogate for the drug response. For example, a GWAS that compared the allele frequencies of SNPs among patients with coronary artery disease and control groups revealed that the SNP (rs1333049) at chromosome 9q21.3 was associated with an increased risk of coronary artery disease.68,72 This discovery has been replicated in multiple independent populations.71 The region of chromosome 9 that harbors this SNP contains cyclin-dependent kinase inhibitor 2A (CDKN2A) and cyclin-dependent kinase inhibitor 2B (CDKN2B) genes, which encode cyclin-dependent kinase inhibitor INK4 proteins p16INK4a and p15INK4b, respectively.68 Although both proteins are thought to play an important role in cell-cycle regulation, neither has ever been proposed as having a role in coronary artery disease.74 This discovery may help in exploring new functions for the genes involved in the development of coronary artery disease. Since rare but serious adverse drug reactions are not predictably associated with the known pharmacology of a drug and are not easily predicted with current biomarkers, GWASs can be used to identify new biomarkers that could explain the underlying mechanisms of adverse drug reactions. The development of ximelagatran, an oral direct thrombin inhibitor, was stopped due to its association with elevated liver enzyme levels, which was unpredictable.75 A recent GWAS found that two major histocompatibility complex (MHC) alleles, DRB1*07 and DQA1*02, were associated with elevated liver enzyme levels after ximelagatran treatment, suggesting the involvement of the immune system in the pathogenesis of the drug’s hepatotoxicity.76 If the roles of the MHC alleles in the development of liver toxicity are characterized and the findings are replicated with other hepatotoxic drugs, these two alleles could be used as biomarkers for monitoring drug-induced liver toxicity in clinical practice. The requirement for a large clinical sample size and the high cost of whole-genome SNP panels for GWASs compared with the candidate-gene approach have been the limiting factors in using GWASs.58,61 The coverage of genetic variations also differs among various commercial SNP panels. For example, rare SNPs and copy-number variations may not be included in a certain set of SNPs in a GWAS.58 Despite the abovementioned limitations, the GWAS holds great potential for contributing to the understanding of complex disease development and identifying the factors that affect variable drug responses. Pharmacogenetic test information on drug labels The pharmacogenetic tests mentioned on drug labels can be classified as “test required,” “test recommended,” and “information only” (Table 5).77 Currently, four drugs are required to have pharmacogenetic testing performed before they are prescribed: cetuximab, trastuzumab, maraviroc, and dasatinib. Cetuximab treatment needs a confirmation of epidermal growth factor receptor (EGFR) expression. Trastuzumab therapy requires testing for HER2/ NEU overexpression. Infection with CCR-5-tropic HIV-1 should be confirmed before initiation of therapy with maraviroc (an antiretroviral). Dasatinib is used for the treatment of patients with Philadelphia chromosome-positive acute lymphoblastic leukemia resistant to or intolerant of prior therapy. In December 2007, FDA added a black-box warning on the carbamazepine label, recommending testing for the HLA-B*1502 allele in patients with Asian ancestry before initiating carbamazepine therapy because these patients are at high risk of developing carbamazepine-induced Stevens-Johnson syndrome (SJS) or toxic epidermal necrolysis (TEN).78 Interestingly, while Asians or patients with Asian ancestry have been reported to have a strikingly high frequency (98%; OR = 1357; 95% CI, 193–8838) of carbamazepine-induced SJS or TEN if they carry an HLA-B*1502 allele, other races carrying the allele do not seem to have the increased risk.79,–82 In addition, the frequency of HLA-B*1502 is higher in South Asians, including Taiwanese, Hong Kong Chinese, Thai, and Indians (8–11%), than in North Asians, such as Beijing Chinese, Japanese, and Koreans (1–2%).82,83 Pharmacogenetic testing is recommended for patients treated with warfarin, thiopurines, valproic acid, irinotecan, abacavir, or rasburicase (Table 5). Irinotecan is a prodrug used for the treatment of colorectal cancer, small-cell lung cancer, and other solid tumors. The active metabolite of irinotecan is SN-38, a topoisomerase I inhibitor, and uridine diphosphate glucuronosyltransferase 1A1 (UGT1A1) plays a critical role in inactivating SN-38.84,85 The low activity of the UGT1A1 enzyme may increase the risk for adverse events associated with irinotecan therapy (e.g., neutropenia) by increasing serum concentrations of the active metabolite. The promoter region in UGT1A1 contains a TATAA box, a regulatory sequence that is polymorphic, consisting of five to eight copies of TA repeats [(TA)nTAA]. 86,87 The wild-type regulatory sequence has six repeats of dinucleotide TA (UGT1A1*1), while the common variant sequence contains seven repeats of the dinucleotide (UGT1A1*28).84,86,87 The other two alleles (five and eight TA repeats) are rare. It has been found that the longer the repeat allele, the lower the promoter activity.87 Patients homozygous for the UGT1A1*28 allele may have lower enzyme expression and activity compared with patients with wild-type alleles and may have higher serum concentrations of SN-38 with an associated increased risk of adverse events. In clinical studies, patients homozygous for UGT1A1*28 demonstrated a significantly higher risk of neutropenia compared with those patients carrying UGT1A1*1.88,–90 Based on these findings, FDA recommended reducing the irinotecan dose in patients with UGT1A1*28/*28. For pharmacogenetic testing to be widely used in clinical practice, the test should show analytic and clinical validities and clinical utility.91 Analytic validity refers to “the ability of the test to accurately and reliably measure the genotype of interest.”91 Clinical validity is “the ability of the test to detect or predict” the response to a drug therapy, while clinical utility refers to “the balance of the test’s associated risks and benefits when the test is used in clinical practice.” Clinical utility is usually tested in a randomized trial comparing clinical outcomes between genotype-guided and usual care. In addition, overall treatment-related cost savings with genotype testing, the length of time required to obtain genotyping results, and availability of alternative tests to predict the phenotypes should be assessed. Moreover, the risk:benefit ratio for heterozygous versus homozygous individuals should be evaluated, because, in most cases, the majority of patients are heterozygotes and may not benefit from genotyping as much as variant homozygotes.92,93 Finally, the phenotype variability in a given genotype should also be evaluated, since there may be variability in phenotype associated with a genotype, as has been observed in the TPMT activity in red blood cells with the TPMT genotype.93 Factors influencing the application of pharmacogenetic discoveries to patient care Many factors can influence the application of pharmacogenetic discoveries to patient care. These include mechanisms to introduce a pharmacogenetic test into clinical practice, turnaround time, cost, reimbursability, and interpretation of a test. Test regulation There are two mechanisms by which a pharmacogenetic test can be introduced to clinical practice. In the first mechanism, FDA regulates in vitro diagnostic devices (IVDs) or test kits, which manufacturers produce, package, and sell with all ingredients and instructions needed to perform the test. Table 6 lists pharmacogenetic tests that have been approved by the FDA as IVDs for clinical use.94,95 In the second mechanism, an individual clinical laboratory develops and offers a test.95 These so-called “home-brew” tests account for the vast majority of the more than 1300 genetic tests available for clinical use.96 These tests do not require FDA approval. Instead, the quality of testing in the clinical laboratories is regulated under the Clinical Laboratory Improvement Amendment of 1988 (CLIA). Both the Centers for Medicare and Medicaid Services and the Centers for Disease Control and Prevention are responsible for ensuring the quality of the clinical laboratories.95 Under CLIA, clinical laboratories performing tests that are classified as moderate to highly complex are required to be enrolled in a proficiency test program in order to maintain a high quality of testing. Although genetic testing, including pharmacogenetic testing, is classified as moderately or highly complex, laboratories performing genetic testing are not currently required to be enrolled in a proficiency test program.97 Thus, whenever possible, it is important to have the pharmacogenetic tests performed by a reliable and experienced laboratory. Test availability, cost, and reimbursement Despite technological improvement in pharmacogenetic tests, which can genotype multiple loci in a short time, test availability limits application of pharmacogenetic discoveries to patient care. A recent survey found that only 8% of U.S. laboratories offer pharmacogenetic testing. Table 7 lists some of the clinical laboratories that offer pharmacogenetic tests for clinical use.98,–107 Limited test availability also influences its turnaround time for test results. The turnaround time for the results of a pharmacogenetic test performed in an inhouse laboratory may be within a day because an assay itself usually takes only about two to six hours to perform. If, however, pharmacogenetic testing must be conducted by an outside laboratory, turnaround may take several days.99,–107 The significance of the turnaround time depends on the purpose for testing. If a test is performed for a drug that should be administered immediately, such as warfarin, the turnaround time is crucial for clinical decision-making. In contrast, if the purpose of testing is to obtain genotype information for future use, a fast turnaround time is not as important. The price of testing ranges from $250 to $500.108,–110 The cost of pharmacogenetic testing required by FDA is generally reimbursed by most insurance plans. The cost of testing not required by FDA may be covered by an insurance plan if the test is considered medically necessary. This usually requires high-quality evidence for the clinical utility of the testing.95 Currently, few pharmacogenetic tests have evidence to support their clinical utility because many of them have been recently introduced. Thus, most insurance plans consider a vast majority of pharmacogenetic tests “experimental.” 95 This lack of high-quality study results and limited reimbursability may delay widespread adoption of pharmacogenetic testing to clinical practice. Interestingly, Medicare’s “Coverage with Evidence Development” policy may cover a pharmacogenetic test if a patient has “appropriate” indications for an “experimental” test or if the patient participates in a registry to help develop evidence to support testing.95 Test interpretation Interpretation of a pharmacogenetic test result is particularly important for a test that influences a dosage of a drug in clinical practice. In its draft guidelines, National Academy of Clinical Biochemistry (NACB) recommends that clinical laboratories should not indicate a specific dosage of a drug in the laboratory report.111 The package insert of a drug with pharmacogenetic information on the label does not generally provide a specific dosage of the drug for patients with a particular genotype. However, in the case of atomoxetine, FDA recommends that the starting dosage should be based on the patient’s phenotype. For example, the recommended starting dosage of atomoxetine hydrochloride is 0.5 mg/kg daily in poor metabolizers of CYP2D6 who weigh 70 kg or less.112 Some experts have proposed clinical guidelines for the use of CYP2C19/ CYP2D6 polymorphism testing, which provide dosing recommendations for antidepressants and antipsychotics according to CYP2C19/ CYP2D6 genotype.30 Given the complex interplay among the many factors that influence drug dosage, determination of an appropriate dosage of a particular drug for a given patient will eventually require knowledge about genetic and nongenetic factors that affect drug disposition and pharmacodynamics. One way to determine a drug dosage with genotype information is to use a dosing algorithm that accounts for genetic and nongenetic factors that cause dose variability of the drug. Although algorithms are useful, clinicians should be aware of advantages of and limitations in using an algorithm, which has been well illustrated for warfarin dosing algorithms. The warfarin dosing algorithms are essentially a linear regression model that predicts an individualized warfarin dosage based on genetic and nongenetic variables obtained from an individual patient.113,–115 While all warfarin dosing algorithms require genotype information from at least three loci (CYP2C9*2, CYP2C9*3, and VKORC1-1639G/A [or its equivalent]), the required nongenetic variables (e.g., age, race, interacting drugs, smoking status, target INR) for dosage calculation vary by algorithm.48,113,–115 Despite this, it appears that the predicted warfarin dosages do not statistically differ among the algorithms.116 The R2 value of the algorithms ranges from 0.4 to 0.7, suggesting that 40–70% of the variability in warfarin dosage is explained by the regression models.48,113,–115 When compared with models using only nongenetic variables, the models including both nongenetic and genetic variables had 20–40% higher R2 values, indicating a substantial contribution of genetic variables to warfarin dosage variability. Other factors should also be considered when a dosing algorithm is used. The dosing algorithms cannot predict who will be outliers from the regression line. In addition, most dosing algorithms may not be useful when adjusting the dosage after warfarin is given. Thus, an individual patient’s genotype data should be obtained before warfarin is prescribed. Finally, the algorithms do not predict when a therapeutic INR is reached. Thus, it is still important to closely monitor the INR and to adjust the dosage even when a dosing algorithm is used. Given the many factors that influence dosage variability among individuals and some limitations in the algorithms, a dosing algorithm using pharmacogenetic discoveries should be viewed as a tool to decrease uncertainty about a patient’s dosage in the early phase of the drug treatment; subsequent doses should be adjusted based on the patient’s clinical response. Future directions and roles for pharmacists Despite the great potential for pharmacogenetic discoveries to improve patient care, additional work is required before these discoveries find widespread application in clinical practice. Need for additional research Randomized clinical trials are needed to evaluate the clinical utility of a pharmacogenetic test. Although pharmacogenetic tests may help inform clinical decisions involving drug selection and dosing, it has not been shown whether these tests improve clinical outcomes. Until the clinical benefit and risk of the use of a pharmacogenetic test are defined, routine use of the test is likely to be delayed. The clinical utility data may also help in estimating the costeffectiveness of a test and whether its cost should be reimbursed by insurance plans. Need for guidelines The government and professional organizations need to develop more guidelines for the clinical use of various pharmacogenetic tests. A couple of guidelines address the use of a particular pharmacogenetic test and have been supported by the government or professional organizations. The National Comprehensive Cancer Network Task Force has published guidelines on HER2 testing in breast cancer, which review important characteristics of the current HER2 tests available and how to interpret the test results.117 The Evaluation of Genomic Applications in Practice and Prevention Working Group supported by the Agency for Health Research and Quality has developed guidelines for the use of CYP2C19/ CYP2D6 polymorphism testing.118 It discourages the use of this test in nonpsychotic, depressed patients who are beginning treatment with a selective serotonin-reuptake inhibitor because of “insufficient evidence to support a recommendation for or against use of the test.” A working group of the American College of Medical Genetics reviewed warfarin pharmacogenetics and does not presently endorse routine use of warfarin pharmacogenetic testing, though the group suggests that “CYP2C9 and VKORC1 testing may be useful and warranted in determining the cause of unusual therapeutic responses to warfarin therapy in certain situations.”119 Because many new pharmacogenetic tests may be introduced into clinical practice in the future, it is important to develop guidelines supported by respected professional organizations and the government to guide the use of such tests. Need for education Provider education on pharmacogenetics is needed. Although health care providers’ knowledge of pharmacogenetics has not been well studied, many health care providers do not feel comfortable with offering and interpreting genetic tests in their clinical practice, due in part to a lack of knowledge about genetics.120,121 In addition, a majority of community pharmacists feel their knowledge about pharmacogenetics is “less than adequate,” though many community pharmacists expect advances in human genetics will influence their role and delivery of pharmaceuticals.13 Thus, given the high likelihood that pharmacogenetics may change pharmacy practice in the future, education on pharmacogenetics should be provided to doctor of pharmacy students as well as practicing pharmacists. Need for a clinical practice model A clinical practice model that can apply pharmacogenetic discoveries to patient care is needed. Although readouts of some pharmacogenetic tests such as AmpliChip CYP450 (Roche Diagnostics, Indianapolis, IN) report both genotype and phenotype, a majority of pharmacogenetic tests report only the genotype. Also, clinical laboratories are recommended to report only genotypes.111 Thus, it is important for a health care institution to have a mechanism to relate a patient’s genotype that is reported by a clinical laboratory to a phenotype. This may require a strong collaboration among professionals of various disciplines including pharmacists. Role of pharmacy Pharmacists may play a key role in applying pharmacogenetic discoveries to patient care. Application of pharmacogenetic discoveries requires knowledge and understanding of the disposition and pharmacodynamics of drugs. In addition, a good understanding of clinical factors that can influence pharmacokinetics and pharmacodynamics of drugs is also important in the effective application of pharmacogenetic discoveries to patient care. Because pharmacists are experts in pharmacokinetics and pharmacodynamics, they can take a lead in application of pharmacogenetics in clinical practice. For example, NACB draft guidelines suggest that pharmacists may be engaged in interpreting pharmacogenetic testing results.111 In addition, some experts have suggested that pharmacists need access to patients’ genetic information in order to provide individualized pharmaceutical care before they fill prescriptions.122 Although such involvement would require regulations and systems that secure and maintain patient confidentiality, the application of pharmacogenetics in clinical practice presents an opportunity where pharmacists can expand their roles in the genomic era. Conclusion Pharmacogenetics has made significant progress in the past decade, and many pharmacogenetic discoveries have now been included on FDA-approved drug labeling. Pharmacogenetic discoveries may further promote safe and effective use of medications by more accurately predicting an individual’s drug response. Appendix—Glossary of pharmacogenetic terms3,–6 and useful resources Allele: An alternative form of a gene at a given locus. Coding region: A segment of DNA sequences that is transcribed into mRNA and translated into proteins. Copy-number variation: A deletion or a duplication resulting in a loss or increase of a DNA segment which can lead to copy-number changes at multiple sequence-related loci in the genome. Genetic polymorphism: Minor allele frequency of ≥1% in the population. Genome: The complete DNA sequence of an organism. Genomewide association study: A genetic association study in which the density of genetic markers and the extent of linkage disequilibrium are sufficient to capture a large proportion of the common variation in the human genome in the population under study, and the number of specimens genotyped provides sufficient power to detect variants of modest effect. Genotype: The alleles at a specific locus an individual carries. Haplotype: A group of alleles from two or more loci on a chromosome; inherited as a unit. Linkage disequilibrium: The nonrandom association of alleles of different linked polymorphisms in a population. Minisatellite: An intermediate size (0.1–20 kb) of a short, tandemly repeated DNA sequence. Minor allele: A less common allele at a polymorphic locus. Minor allele frequency: Frequency of the less-common allele. Noncoding region: A segment of DNA sequences that is not transcribed into mRNA and translated into proteins. Nonsynonymous polymorphism: A polymorphism in the coding region that changes amino acid. Pharmacogenetics: A study of genetic causes of individual variations in drug response. In this review, the term “pharmacogenetics” is interchangeable with “pharmacogenomics.” Pharmacogenomics: Genomewide analysis of the genetic determinants of drug efficacy and toxicity. Pharmacogenetics focuses on a single gene while pharmacogenomics studies multiple genes. Phenotype: Observable expression of a particular gene or genes. Promoter: A segment of DNA sequence that controls initiation of transcription of the gene and is usually located upstream of the gene. Short tandem repeat: DNA sequences of three to seven base pairs in length that are repeated in tandem at a locus. Synonymous polymorphism: A polymorphism in the coding region that does not change amino acid. Tag single nucleotide polymorphism: A single nucleotide polymorphism (SNP) that is correlated with much of the known remaining common variations in a region. Thus, a tag SNP can serve as a proxy for the other common variations. Variable-number tandem repeat: A class of genetic polymorphisms resulting from multiple repeated segments of DNA; sometimes referred to as minisatellites. For general information on genes, OMIM (Online Mendelian Inheritance in Man, www.ncbi.nlm.nih.gov/sites/entrez?db=omim) and PharmGKB (The Pharmacogenetics and Pharmacogenomics Knowledge Base, www.pharmgkb.org/#public) are useful web-sites. OMIM, a public database at the National Center for Biotechnology Information (NCBI), provides a variety of gene information, such as gene symbols, chromosomal locations, gene functions, and a summary of published studies on genes. PharmGKB, supported by a National Institutes of Health grant, provides curated pharmacogenetic information, along with drug pathways. Perhaps the most useful feature of PharmGKB for clinicians is its annotated gene information, including those for “Very Important Pharmacogenes” (VIP) (www.pharmgkb.org/search/annotatedGene/index.jsp). The links provided for each VIP annotation summarize clinically relevant pharmacogenetic discoveries in important genes. Individual SNP information, such as genetic location, nucleotide and amino acid changes, and allele frequencies in diverse populations, can be obtained from dbSNP (www.ncbi.nlm.nih.gov/sites/entrez?db=snp). dbSNP, a database at NCBI, has a broad collection of SNPs for a variety of organisms, including humans. The collection of polymorphisms in dbSNP includes not only SNPs but insertions, deletions, and short tandem repeats. Each SNP or polymorphism has an assigned reference SNP accession ID (rs number), which is useful in searching for a particular SNP in the database. For example, the rs number of CYP2C9*2 is rs1799853 and this number can be used to search for information on CYP2C9*2. Other databases, such as ensembl (www.ensembl.org/index.html) and HapMap (www.hapmap.org/cgi-perl/gbrowse/hapmap_B35), can also be used for acquiring individual SNP information. Linkage disequilibrium and haplotype information among SNPs can also be obtained from HapMap. FDA has constructed a website called Genomics at FDA (www.fda.gov/cder/genomics) for individuals who would like to understand the agency’s current thinking on pharmacogenetics. The site also provides education materials on pharmacogenetics. The table of valid genomic biomarkers in the context of approved drug labels (www.fda.gov/cder/genomics/genomic_biomarkers_table.htm) summarizes all pharmacogenetic discoveries included on current drug labeling with a link to the approved package insert. Table 1. Frequency of ImportantCYP2D6Alleles28,a Frequency of Alleles by Race (%) Classification Alleles Caucasian African American Asian aCYP2D6 = gene cytochrome P-450 isoenzyme 2D6. Normal *1, *2, *39 70 50 50 Reduced *10, *17, *29, *41 5 35 45 Nonfunctional *3, *4, *5, *6 25 15 5 Frequency of Alleles by Race (%) Classification Alleles Caucasian African American Asian aCYP2D6 = gene cytochrome P-450 isoenzyme 2D6. Normal *1, *2, *39 70 50 50 Reduced *10, *17, *29, *41 5 35 45 Nonfunctional *3, *4, *5, *6 25 15 5 Table 1. Frequency of ImportantCYP2D6Alleles28,a Frequency of Alleles by Race (%) Classification Alleles Caucasian African American Asian aCYP2D6 = gene cytochrome P-450 isoenzyme 2D6. Normal *1, *2, *39 70 50 50 Reduced *10, *17, *29, *41 5 35 45 Nonfunctional *3, *4, *5, *6 25 15 5 Frequency of Alleles by Race (%) Classification Alleles Caucasian African American Asian aCYP2D6 = gene cytochrome P-450 isoenzyme 2D6. Normal *1, *2, *39 70 50 50 Reduced *10, *17, *29, *41 5 35 45 Nonfunctional *3, *4, *5, *6 25 15 5 Table 2. Frequency ofTPMT*2, TPMT*3A,andTPMT*3CAlleles34,a Frequency of Alleles by Race (%) Allele Caucasian African American Asian aTPMT = thiopurine S-methyltransferase. TPMT*2 0.2 0.4 0 TPMT*3A 3–5 0.4–0.8 0 TPMT*3C 0.2 2–7 2–5 Frequency of Alleles by Race (%) Allele Caucasian African American Asian aTPMT = thiopurine S-methyltransferase. TPMT*2 0.2 0.4 0 TPMT*3A 3–5 0.4–0.8 0 TPMT*3C 0.2 2–7 2–5 Table 2. Frequency ofTPMT*2, TPMT*3A,andTPMT*3CAlleles34,a Frequency of Alleles by Race (%) Allele Caucasian African American Asian aTPMT = thiopurine S-methyltransferase. TPMT*2 0.2 0.4 0 TPMT*3A 3–5 0.4–0.8 0 TPMT*3C 0.2 2–7 2–5 Frequency of Alleles by Race (%) Allele Caucasian African American Asian aTPMT = thiopurine S-methyltransferase. TPMT*2 0.2 0.4 0 TPMT*3A 3–5 0.4–0.8 0 TPMT*3C 0.2 2–7 2–5 Table 3. Frequency ofVKORC1Haplotypes45,a Frequency of Haplotypes by Race (%) Haplotype Caucasian African American Asian aVKORC1 = vitamin k epoxide reductase complex subunit 1. A 37 14 89 B 58 49 10     Total 96 62 99 Frequency of Haplotypes by Race (%) Haplotype Caucasian African American Asian aVKORC1 = vitamin k epoxide reductase complex subunit 1. A 37 14 89 B 58 49 10     Total 96 62 99 Table 3. Frequency ofVKORC1Haplotypes45,a Frequency of Haplotypes by Race (%) Haplotype Caucasian African American Asian aVKORC1 = vitamin k epoxide reductase complex subunit 1. A 37 14 89 B 58 49 10     Total 96 62 99 Frequency of Haplotypes by Race (%) Haplotype Caucasian African American Asian aVKORC1 = vitamin k epoxide reductase complex subunit 1. A 37 14 89 B 58 49 10     Total 96 62 99 Table 4. Noncoding Single Nucleotide Polymorphisms ofVKORC1in Linkage Disequilibrium That Form Haplotypes Associated With Warfarin Dosage Requirements45,a Polymorphism at Indicated Nucleotide Position Haplotype –4931 –1639 1173 1542 2255 aVKORC1 = vitamin k epoxide reductase complex subunit 1. A Cytosine Adenine Thymine Cytosine Thymine B Thymine Guanine Cytosine Guanine Cytosine Polymorphism at Indicated Nucleotide Position Haplotype –4931 –1639 1173 1542 2255 aVKORC1 = vitamin k epoxide reductase complex subunit 1. A Cytosine Adenine Thymine Cytosine Thymine B Thymine Guanine Cytosine Guanine Cytosine Table 4. Noncoding Single Nucleotide Polymorphisms ofVKORC1in Linkage Disequilibrium That Form Haplotypes Associated With Warfarin Dosage Requirements45,a Polymorphism at Indicated Nucleotide Position Haplotype –4931 –1639 1173 1542 2255 aVKORC1 = vitamin k epoxide reductase complex subunit 1. A Cytosine Adenine Thymine Cytosine Thymine B Thymine Guanine Cytosine Guanine Cytosine Polymorphism at Indicated Nucleotide Position Haplotype –4931 –1639 1173 1542 2255 aVKORC1 = vitamin k epoxide reductase complex subunit 1. A Cytosine Adenine Thymine Cytosine Thymine B Thymine Guanine Cytosine Guanine Cytosine Table 5. FDA Positions on Necessity of Pharmacogenetic Testing as Indicated on Drug Labeling77,a Pharmacogenetic Biomarker Drug aDrugs with “information only” pharmacogenetic discoveries are not comprehensively presented. FDA = Food and Drug Administration, EGFR = epidermal growth factor receptor, HER2/NEU = v-erb-b2 erythroblastic leukemia viral oncogene homolog 2, CCR-5 = chemokine C-C motif receptor, HLA = human leukocyte antigen, CYP2C9 = cytochrome P-450 isoenzyme 2C9, VKORC1 = vitamin K epoxide reductase complex subunit 1, TPMT = thiopurine S-methyltransferase, UGT1A1 = uridine diphosphate-glucuronosyltransferase 1A1, c-KIT = v -kit Hardy-Zuckerman 4 feline sarcoma viral oncogene homolog, CYP2C19 = cytochrome P-450 2C19, CYP2D6 = cytochrome P-450 isoenzyme 2D6, DPD deficiency = dihydropyrimidine dehydrogenase, G6PD = glucose -6-phosphate dehydrogenase, NAT = N- acetyltransferase, PML/RAR = promyelocytic leukemia/retinoic acid receptor. Test Required     EGFR expression Cetuximab     HER2/NEU overexpression Trastuzumab     CCR-5-tropic HIV-1 Maraviroc     Presence of Philadelphia chromosome Dasatinib Test Recommended     HLA-B*1502 Carbamazepine     HLA-B*5701 Abacavir     CYP2C9 variants Warfarin     VKORC1 variants Warfarin     Protein C deficiency Warfarin     TPMT variants Azathioprine, mercaptopurine, thioguanine     UGT1A1 variants Irinotecan     G6PD deficiency Rasburicase     Urea cycle disorders Valproic acid Information Only     c-KIT expression Imatinib     CYP2C19 variants Voriconazole     CYP2C9 variants Celecoxib     CYP2D6 variants Atomoxetine, tamoxifen, fluoxetine     DPD deficiency Capecitabine, fluorouracil     EGFR expression Erlotinib     G6PD deficiency Rasburicase, primaquine     NAT variants Isoniazid, rifampin     Philadelphia chromosome deficiency Busulfan     PML/RAR gene expression Tretinoin Pharmacogenetic Biomarker Drug aDrugs with “information only” pharmacogenetic discoveries are not comprehensively presented. FDA = Food and Drug Administration, EGFR = epidermal growth factor receptor, HER2/NEU = v-erb-b2 erythroblastic leukemia viral oncogene homolog 2, CCR-5 = chemokine C-C motif receptor, HLA = human leukocyte antigen, CYP2C9 = cytochrome P-450 isoenzyme 2C9, VKORC1 = vitamin K epoxide reductase complex subunit 1, TPMT = thiopurine S-methyltransferase, UGT1A1 = uridine diphosphate-glucuronosyltransferase 1A1, c-KIT = v -kit Hardy-Zuckerman 4 feline sarcoma viral oncogene homolog, CYP2C19 = cytochrome P-450 2C19, CYP2D6 = cytochrome P-450 isoenzyme 2D6, DPD deficiency = dihydropyrimidine dehydrogenase, G6PD = glucose -6-phosphate dehydrogenase, NAT = N- acetyltransferase, PML/RAR = promyelocytic leukemia/retinoic acid receptor. Test Required     EGFR expression Cetuximab     HER2/NEU overexpression Trastuzumab     CCR-5-tropic HIV-1 Maraviroc     Presence of Philadelphia chromosome Dasatinib Test Recommended     HLA-B*1502 Carbamazepine     HLA-B*5701 Abacavir     CYP2C9 variants Warfarin     VKORC1 variants Warfarin     Protein C deficiency Warfarin     TPMT variants Azathioprine, mercaptopurine, thioguanine     UGT1A1 variants Irinotecan     G6PD deficiency Rasburicase     Urea cycle disorders Valproic acid Information Only     c-KIT expression Imatinib     CYP2C19 variants Voriconazole     CYP2C9 variants Celecoxib     CYP2D6 variants Atomoxetine, tamoxifen, fluoxetine     DPD deficiency Capecitabine, fluorouracil     EGFR expression Erlotinib     G6PD deficiency Rasburicase, primaquine     NAT variants Isoniazid, rifampin     Philadelphia chromosome deficiency Busulfan     PML/RAR gene expression Tretinoin Table 5. FDA Positions on Necessity of Pharmacogenetic Testing as Indicated on Drug Labeling77,a Pharmacogenetic Biomarker Drug aDrugs with “information only” pharmacogenetic discoveries are not comprehensively presented. FDA = Food and Drug Administration, EGFR = epidermal growth factor receptor, HER2/NEU = v-erb-b2 erythroblastic leukemia viral oncogene homolog 2, CCR-5 = chemokine C-C motif receptor, HLA = human leukocyte antigen, CYP2C9 = cytochrome P-450 isoenzyme 2C9, VKORC1 = vitamin K epoxide reductase complex subunit 1, TPMT = thiopurine S-methyltransferase, UGT1A1 = uridine diphosphate-glucuronosyltransferase 1A1, c-KIT = v -kit Hardy-Zuckerman 4 feline sarcoma viral oncogene homolog, CYP2C19 = cytochrome P-450 2C19, CYP2D6 = cytochrome P-450 isoenzyme 2D6, DPD deficiency = dihydropyrimidine dehydrogenase, G6PD = glucose -6-phosphate dehydrogenase, NAT = N- acetyltransferase, PML/RAR = promyelocytic leukemia/retinoic acid receptor. Test Required     EGFR expression Cetuximab     HER2/NEU overexpression Trastuzumab     CCR-5-tropic HIV-1 Maraviroc     Presence of Philadelphia chromosome Dasatinib Test Recommended     HLA-B*1502 Carbamazepine     HLA-B*5701 Abacavir     CYP2C9 variants Warfarin     VKORC1 variants Warfarin     Protein C deficiency Warfarin     TPMT variants Azathioprine, mercaptopurine, thioguanine     UGT1A1 variants Irinotecan     G6PD deficiency Rasburicase     Urea cycle disorders Valproic acid Information Only     c-KIT expression Imatinib     CYP2C19 variants Voriconazole     CYP2C9 variants Celecoxib     CYP2D6 variants Atomoxetine, tamoxifen, fluoxetine     DPD deficiency Capecitabine, fluorouracil     EGFR expression Erlotinib     G6PD deficiency Rasburicase, primaquine     NAT variants Isoniazid, rifampin     Philadelphia chromosome deficiency Busulfan     PML/RAR gene expression Tretinoin Pharmacogenetic Biomarker Drug aDrugs with “information only” pharmacogenetic discoveries are not comprehensively presented. FDA = Food and Drug Administration, EGFR = epidermal growth factor receptor, HER2/NEU = v-erb-b2 erythroblastic leukemia viral oncogene homolog 2, CCR-5 = chemokine C-C motif receptor, HLA = human leukocyte antigen, CYP2C9 = cytochrome P-450 isoenzyme 2C9, VKORC1 = vitamin K epoxide reductase complex subunit 1, TPMT = thiopurine S-methyltransferase, UGT1A1 = uridine diphosphate-glucuronosyltransferase 1A1, c-KIT = v -kit Hardy-Zuckerman 4 feline sarcoma viral oncogene homolog, CYP2C19 = cytochrome P-450 2C19, CYP2D6 = cytochrome P-450 isoenzyme 2D6, DPD deficiency = dihydropyrimidine dehydrogenase, G6PD = glucose -6-phosphate dehydrogenase, NAT = N- acetyltransferase, PML/RAR = promyelocytic leukemia/retinoic acid receptor. Test Required     EGFR expression Cetuximab     HER2/NEU overexpression Trastuzumab     CCR-5-tropic HIV-1 Maraviroc     Presence of Philadelphia chromosome Dasatinib Test Recommended     HLA-B*1502 Carbamazepine     HLA-B*5701 Abacavir     CYP2C9 variants Warfarin     VKORC1 variants Warfarin     Protein C deficiency Warfarin     TPMT variants Azathioprine, mercaptopurine, thioguanine     UGT1A1 variants Irinotecan     G6PD deficiency Rasburicase     Urea cycle disorders Valproic acid Information Only     c-KIT expression Imatinib     CYP2C19 variants Voriconazole     CYP2C9 variants Celecoxib     CYP2D6 variants Atomoxetine, tamoxifen, fluoxetine     DPD deficiency Capecitabine, fluorouracil     EGFR expression Erlotinib     G6PD deficiency Rasburicase, primaquine     NAT variants Isoniazid, rifampin     Philadelphia chromosome deficiency Busulfan     PML/RAR gene expression Tretinoin Table 6. Selected Pharmacogenetic Tests Approved by FDA94,95,a Test (Manufacturer) Gene Drug aFDA = Food and Drug Administration, CYP2C9 = cytochrome P-450 isoenzyme 2C9, VKORC1 = vitamin K epoxide reductase complex subunit 1, UGT1A1 = uridine diphosphate-glucuronosyltransferase 1A1, CYP2C19 = cytochrome P-450 isoenzyme 2C19, CYP2D6 = cytochrome P-450 isoenzyme 2D6. Verigene warfarin metabolism nucleic acid test (Nanosphere, Northbrook, IL) CYP2C9, VKORC1 Warfarin Infiniti 2C9-VKORC1 multiplex assay (AutoGenomics, Carlsbad, CA) CYP2C9, VKORC1 Warfarin Paragon Dx rapid genotyping assay (Paragon Dx, LLC, Morrisville, NC) CYP2C9, VKORC1 Warfarin eSensor warfarin sensitivity (Osmetech Molecular Diagnostics, Pasadena, CA) CYP2C9, VKORC1 Warfarin Invader UGT1A1 molecular assay (Third Wave Technologies, Madison, WI) UGT1A1 Irinotecan AmpliChip CYP450 test (Roche Diagnostics, Indianapolis, IN) CYP2C19, CYP2D6 Voriconazole, atomoxetine, tamoxifen Test (Manufacturer) Gene Drug aFDA = Food and Drug Administration, CYP2C9 = cytochrome P-450 isoenzyme 2C9, VKORC1 = vitamin K epoxide reductase complex subunit 1, UGT1A1 = uridine diphosphate-glucuronosyltransferase 1A1, CYP2C19 = cytochrome P-450 isoenzyme 2C19, CYP2D6 = cytochrome P-450 isoenzyme 2D6. Verigene warfarin metabolism nucleic acid test (Nanosphere, Northbrook, IL) CYP2C9, VKORC1 Warfarin Infiniti 2C9-VKORC1 multiplex assay (AutoGenomics, Carlsbad, CA) CYP2C9, VKORC1 Warfarin Paragon Dx rapid genotyping assay (Paragon Dx, LLC, Morrisville, NC) CYP2C9, VKORC1 Warfarin eSensor warfarin sensitivity (Osmetech Molecular Diagnostics, Pasadena, CA) CYP2C9, VKORC1 Warfarin Invader UGT1A1 molecular assay (Third Wave Technologies, Madison, WI) UGT1A1 Irinotecan AmpliChip CYP450 test (Roche Diagnostics, Indianapolis, IN) CYP2C19, CYP2D6 Voriconazole, atomoxetine, tamoxifen Table 6. Selected Pharmacogenetic Tests Approved by FDA94,95,a Test (Manufacturer) Gene Drug aFDA = Food and Drug Administration, CYP2C9 = cytochrome P-450 isoenzyme 2C9, VKORC1 = vitamin K epoxide reductase complex subunit 1, UGT1A1 = uridine diphosphate-glucuronosyltransferase 1A1, CYP2C19 = cytochrome P-450 isoenzyme 2C19, CYP2D6 = cytochrome P-450 isoenzyme 2D6. Verigene warfarin metabolism nucleic acid test (Nanosphere, Northbrook, IL) CYP2C9, VKORC1 Warfarin Infiniti 2C9-VKORC1 multiplex assay (AutoGenomics, Carlsbad, CA) CYP2C9, VKORC1 Warfarin Paragon Dx rapid genotyping assay (Paragon Dx, LLC, Morrisville, NC) CYP2C9, VKORC1 Warfarin eSensor warfarin sensitivity (Osmetech Molecular Diagnostics, Pasadena, CA) CYP2C9, VKORC1 Warfarin Invader UGT1A1 molecular assay (Third Wave Technologies, Madison, WI) UGT1A1 Irinotecan AmpliChip CYP450 test (Roche Diagnostics, Indianapolis, IN) CYP2C19, CYP2D6 Voriconazole, atomoxetine, tamoxifen Test (Manufacturer) Gene Drug aFDA = Food and Drug Administration, CYP2C9 = cytochrome P-450 isoenzyme 2C9, VKORC1 = vitamin K epoxide reductase complex subunit 1, UGT1A1 = uridine diphosphate-glucuronosyltransferase 1A1, CYP2C19 = cytochrome P-450 isoenzyme 2C19, CYP2D6 = cytochrome P-450 isoenzyme 2D6. Verigene warfarin metabolism nucleic acid test (Nanosphere, Northbrook, IL) CYP2C9, VKORC1 Warfarin Infiniti 2C9-VKORC1 multiplex assay (AutoGenomics, Carlsbad, CA) CYP2C9, VKORC1 Warfarin Paragon Dx rapid genotyping assay (Paragon Dx, LLC, Morrisville, NC) CYP2C9, VKORC1 Warfarin eSensor warfarin sensitivity (Osmetech Molecular Diagnostics, Pasadena, CA) CYP2C9, VKORC1 Warfarin Invader UGT1A1 molecular assay (Third Wave Technologies, Madison, WI) UGT1A1 Irinotecan AmpliChip CYP450 test (Roche Diagnostics, Indianapolis, IN) CYP2C19, CYP2D6 Voriconazole, atomoxetine, tamoxifen Table 7. Selected Clinical Laboratories Offering Pharmacogenetic Tests99,–107 Clinical Laboratorya Pharmacogenetic Tests Offered aAll laboratories listed are certified by the Clinical Laboratory Improvement Amendment of 1988. CYP2C9 = cytochrome P-450 isoenzyme 2C9, CYP2C19 = cytochrome P-450 isoenzyme 2C19, CYP2D6 = cytochrome P-450 isoenzyme 2D6, UGT1A1 = uridine diphosphate-glucuronosyltransferase 1A1, VKORC1 = vitamin K epoxide reductase complex subunit 1, CYP1A2 = cytochrome P-450 isoenzyme 1A2, DPD = dihydropyridine dehydrogenase, NAT = N-acetyltransferase, TPMT = thiopurine S-methyltransferase. bSimultaneous genotyping for multiple genes. Arup Laboratories (Salt Lake City, UT) CYP2C9, CYP2C19, CYP2D6, UGT1A1, CYP2C9/VKORC1b Genelex (Seattle, WA) CYP1A2, CYP2C9, CYP2C19, CYP2D6, DPD, NAT2, UGT1A1, CYP2C9/ VKORC1b Genomas Inc. (Newington, CT) CYP2C9/CYP2C19/CYP2D6,bCYP2C9/ VKORC1b Laboratory Corporation (multiple U.S. locations) CYP2C9, CYP2C19, CYP2D6, CYP2C19/ CYP2D6,bDPD, UGT1A1, CYP2C9/ VKORC1b Molecular Diagnostics Laboratories (Cincinnati, OH) CYP2C9, CYP2C19, CYP2D6, CYP2C9/ CYP2C19/CYP2D6,bDPD, UGT1A1, CYP2C9/VKORC1b PGXL Laboratories (Louisville, KY) CYP1A2, CYP2C9, CYP2C19, CYP2D6, NAT2, VKORC1, CYP2C9/VKORC1b Prometheus Therapeutics & Diagnostics (San Diego, CA) TPMT Quest Diagnostics (multiple U.S. locations) CYP2C9, CYP2D6, CYP2C19/CYP2D6,bTPMT, CYP2C9/VKORC1b Specialty Laboratories (Valencia, CA) CYP2C19, CYP2D6, DPD, TPMT, UGT1A1, CYP2C9/VKORC1b Clinical Laboratorya Pharmacogenetic Tests Offered aAll laboratories listed are certified by the Clinical Laboratory Improvement Amendment of 1988. CYP2C9 = cytochrome P-450 isoenzyme 2C9, CYP2C19 = cytochrome P-450 isoenzyme 2C19, CYP2D6 = cytochrome P-450 isoenzyme 2D6, UGT1A1 = uridine diphosphate-glucuronosyltransferase 1A1, VKORC1 = vitamin K epoxide reductase complex subunit 1, CYP1A2 = cytochrome P-450 isoenzyme 1A2, DPD = dihydropyridine dehydrogenase, NAT = N-acetyltransferase, TPMT = thiopurine S-methyltransferase. bSimultaneous genotyping for multiple genes. Arup Laboratories (Salt Lake City, UT) CYP2C9, CYP2C19, CYP2D6, UGT1A1, CYP2C9/VKORC1b Genelex (Seattle, WA) CYP1A2, CYP2C9, CYP2C19, CYP2D6, DPD, NAT2, UGT1A1, CYP2C9/ VKORC1b Genomas Inc. (Newington, CT) CYP2C9/CYP2C19/CYP2D6,bCYP2C9/ VKORC1b Laboratory Corporation (multiple U.S. locations) CYP2C9, CYP2C19, CYP2D6, CYP2C19/ CYP2D6,bDPD, UGT1A1, CYP2C9/ VKORC1b Molecular Diagnostics Laboratories (Cincinnati, OH) CYP2C9, CYP2C19, CYP2D6, CYP2C9/ CYP2C19/CYP2D6,bDPD, UGT1A1, CYP2C9/VKORC1b PGXL Laboratories (Louisville, KY) CYP1A2, CYP2C9, CYP2C19, CYP2D6, NAT2, VKORC1, CYP2C9/VKORC1b Prometheus Therapeutics & Diagnostics (San Diego, CA) TPMT Quest Diagnostics (multiple U.S. locations) CYP2C9, CYP2D6, CYP2C19/CYP2D6,bTPMT, CYP2C9/VKORC1b Specialty Laboratories (Valencia, CA) CYP2C19, CYP2D6, DPD, TPMT, UGT1A1, CYP2C9/VKORC1b Table 7. Selected Clinical Laboratories Offering Pharmacogenetic Tests99,–107 Clinical Laboratorya Pharmacogenetic Tests Offered aAll laboratories listed are certified by the Clinical Laboratory Improvement Amendment of 1988. CYP2C9 = cytochrome P-450 isoenzyme 2C9, CYP2C19 = cytochrome P-450 isoenzyme 2C19, CYP2D6 = cytochrome P-450 isoenzyme 2D6, UGT1A1 = uridine diphosphate-glucuronosyltransferase 1A1, VKORC1 = vitamin K epoxide reductase complex subunit 1, CYP1A2 = cytochrome P-450 isoenzyme 1A2, DPD = dihydropyridine dehydrogenase, NAT = N-acetyltransferase, TPMT = thiopurine S-methyltransferase. bSimultaneous genotyping for multiple genes. Arup Laboratories (Salt Lake City, UT) CYP2C9, CYP2C19, CYP2D6, UGT1A1, CYP2C9/VKORC1b Genelex (Seattle, WA) CYP1A2, CYP2C9, CYP2C19, CYP2D6, DPD, NAT2, UGT1A1, CYP2C9/ VKORC1b Genomas Inc. (Newington, CT) CYP2C9/CYP2C19/CYP2D6,bCYP2C9/ VKORC1b Laboratory Corporation (multiple U.S. locations) CYP2C9, CYP2C19, CYP2D6, CYP2C19/ CYP2D6,bDPD, UGT1A1, CYP2C9/ VKORC1b Molecular Diagnostics Laboratories (Cincinnati, OH) CYP2C9, CYP2C19, CYP2D6, CYP2C9/ CYP2C19/CYP2D6,bDPD, UGT1A1, CYP2C9/VKORC1b PGXL Laboratories (Louisville, KY) CYP1A2, CYP2C9, CYP2C19, CYP2D6, NAT2, VKORC1, CYP2C9/VKORC1b Prometheus Therapeutics & Diagnostics (San Diego, CA) TPMT Quest Diagnostics (multiple U.S. locations) CYP2C9, CYP2D6, CYP2C19/CYP2D6,bTPMT, CYP2C9/VKORC1b Specialty Laboratories (Valencia, CA) CYP2C19, CYP2D6, DPD, TPMT, UGT1A1, CYP2C9/VKORC1b Clinical Laboratorya Pharmacogenetic Tests Offered aAll laboratories listed are certified by the Clinical Laboratory Improvement Amendment of 1988. CYP2C9 = cytochrome P-450 isoenzyme 2C9, CYP2C19 = cytochrome P-450 isoenzyme 2C19, CYP2D6 = cytochrome P-450 isoenzyme 2D6, UGT1A1 = uridine diphosphate-glucuronosyltransferase 1A1, VKORC1 = vitamin K epoxide reductase complex subunit 1, CYP1A2 = cytochrome P-450 isoenzyme 1A2, DPD = dihydropyridine dehydrogenase, NAT = N-acetyltransferase, TPMT = thiopurine S-methyltransferase. bSimultaneous genotyping for multiple genes. Arup Laboratories (Salt Lake City, UT) CYP2C9, CYP2C19, CYP2D6, UGT1A1, CYP2C9/VKORC1b Genelex (Seattle, WA) CYP1A2, CYP2C9, CYP2C19, CYP2D6, DPD, NAT2, UGT1A1, CYP2C9/ VKORC1b Genomas Inc. (Newington, CT) CYP2C9/CYP2C19/CYP2D6,bCYP2C9/ VKORC1b Laboratory Corporation (multiple U.S. locations) CYP2C9, CYP2C19, CYP2D6, CYP2C19/ CYP2D6,bDPD, UGT1A1, CYP2C9/ VKORC1b Molecular Diagnostics Laboratories (Cincinnati, OH) CYP2C9, CYP2C19, CYP2D6, CYP2C9/ CYP2C19/CYP2D6,bDPD, UGT1A1, CYP2C9/VKORC1b PGXL Laboratories (Louisville, KY) CYP1A2, CYP2C9, CYP2C19, CYP2D6, NAT2, VKORC1, CYP2C9/VKORC1b Prometheus Therapeutics & Diagnostics (San Diego, CA) TPMT Quest Diagnostics (multiple U.S. locations) CYP2C9, CYP2D6, CYP2C19/CYP2D6,bTPMT, CYP2C9/VKORC1b Specialty Laboratories (Valencia, CA) CYP2C19, CYP2D6, DPD, TPMT, UGT1A1, CYP2C9/VKORC1b References 1 Beutler E. Drug-induced hemolytic anemia. Pharmacol Rev . 1969 ; 21 : 73 –103. PubMed 2 Vogel F. [Modern problems of human genetics.] Ergeb Inn Med Kinderheilkd. 1959 ; 12 : 52 –125. In German. 3 Hopkins MM, Ibarreta D, Gaisser S et al. Putting pharmacogenetics into practice. Nat Biotechnol . 2006 ; 24 : 403 –10. 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Copyright © 2009, American Society of Health-System Pharmacists, Inc. All rights reserved.
TI - Pharmacogenetics: from discovery to patient care
JF - American Journal of Health-System Pharmacy
DO - 10.2146/ajhp080170
DA - 2009-04-01
UR - https://www.deepdyve.com/lp/oxford-university-press/pharmacogenetics-from-discovery-to-patient-care-6BpU3ecPi9
SP - 625
VL - 66
IS - 7
DP - DeepDyve
ER -