There is great variation in drug-response phenotypes, and a “one size fits all” paradigm for drug delivery is flawed. Pharmacogenomics is the study of how human genetic information impacts drug response, and it aims to improve efficacy and reduced side effects. In this article, we provide an overview of pharmacogenetics, including pharmacokinetics (PK), pharmacodynamics (PD), gene and pathway interactions, and off-target effects. We describe methods for discovering genetic factors in drug response, including genome-wide association studies (GWAS), expression analysis, and other methods such as chemoinformatics and natural language processing (NLP). We cover the practical applications of pharmacogenomics both in the pharmaceutical industry and in a clinical setting. In drug discovery, pharmacogenomics can be used to aid lead identification, anticipate adverse events, and assist in drug repurposing efforts. Moreover, pharmacogenomic discoveries show promise as important elements of physician decision support. Finally, we consider the ethical, regulatory, and reimbursement challenges that remain for the clinical implementation of pharmacogenomics.
References
[1]
Abbott A (2003) With your genes? Take one of these, three times a day. Nature 425: 760–762. doi: 10.1038/425760a
[2]
Katzung BG, Masters SB, and Trevor AJ (2012) Basic & clinical pharmacology. New York: McGraw-Hill Medical.
[3]
Yu I-W, Bukaveckas BL (2008) Pharmacogenetic tests in asthma therapy. Clin Lab Med 28: 645–665. doi: 10.1016/j.cll.2008.05.001
[4]
Azuma J, Nonen S (2009) Chronic heart failure: beta-blockers and pharmacogenetics. Eur J Clin Pharmacol 65: 3–17. doi: 10.1007/s00228-008-0566-7
[5]
Smith WL, DeWitt DL, Garavito RM (2000) Cyclooxygenases: structural, cellular, and molecular biology. Annu Rev Biochem 69: 145–182. doi: 10.1146/annurev.biochem.69.1.145
[6]
Rome LH, Lands WE (1975) Structural requirements for time-dependent inhibition of prostaglandin biosynthesis by anti-inflammatory drugs. Proc Natl Acad Sci USA 72: 4863–4865. doi: 10.1073/pnas.72.12.4863
[7]
DeWitt DL, el-Harith EA, Kraemer SA, Andrews MJ, Yao EF, et al. (1990) The aspirin and heme-binding sites of ovine and murine prostaglandin endoperoxide synthases. J Biol Chem 265: 5192–5198.
[8]
Volpato JP, Yachnin BJ, Blanchet J, Guerrero V, Poulin L, et al. (2009) Multiple conformers in active site of human dihydrofolate reductase F31R/Q35E double mutant suggest structural basis for methotrexate resistance. J Biol Chem 284: 20079–20089. doi: 10.1074/jbc.m109.018010
[9]
Giacomini KM, Brett CM, Altman RB, Benowitz NL, Dolan ME, et al.. (2007) The pharmacogenetics research network: from SNP discovery to clinical drug response. Clin Pharmacol Ther. pp. 328–345.
[10]
Dietrich CG, Geier A, Oude Elferink RPJ (2003) ABC of oral bioavailability: transporters as gatekeepers in the gut. Gut 52: 1788–1795. doi: 10.1136/gut.52.12.1788
Ingelman-Sundberg M, Sim SC, Gomez A, Rodriguez-Antona C (2007) Influence of cytochrome P450 polymorphisms on drug therapies: pharmacogenetic, pharmacoepigenetic and clinical aspects. Pharmacol Ther 116: 496–526. doi: 10.1016/j.pharmthera.2007.09.004
[13]
Rettie AE, Korzekwa KR, Kunze KL, Lawrence RF, Eddy AC, et al. (1992) Hydroxylation of warfarin by human cDNA-expressed cytochrome P-450: a role for P-4502C9 in the etiology of (S)-warfarin-drug interactions. Chem Res Toxicol 5: 54–59. doi: 10.1021/tx00025a009
[14]
Goldstein JA, de Morais SM (1994) Biochemistry and molecular biology of the human CYP2C subfamily. Pharmacogenetics. pp. 285–299.
[15]
Consortium IWP, Klein TE, Altman RB, Eriksson N, Gage BF, et al. (2009) Estimation of the warfarin dose with clinical and pharmacogenetic data. N Engl J Med 360: 753–764. doi: 10.1056/nejmoa0809329
[16]
Jones PM, George AM (2004) The ABC transporter structure and mechanism: perspectives on recent research. Cell Mol Life Sci 61: 682–699. doi: 10.1007/s00018-003-3336-9
[17]
Leschziner GD, Andrew T, Pirmohamed M, Johnson MR (2007) ABCB1 genotype and PGP expression, function and therapeutic drug response: a critical review and recommendations for future research. Pharmacogenomics J 7: 154–179. doi: 10.1038/sj.tpj.6500413
[18]
Thomas H, Coley HM (2003) Overcoming multidrug resistance in cancer: an update on the clinical strategy of inhibiting p-glycoprotein. Cancer Control 10: 159–165.
[19]
Zimmermann A, Matschiner JT (1974) Biochemical basis of hereditary resistance to warfarin in the rat. Biochem Pharmacol 23: 1033–1040. doi: 10.1016/0006-2952(74)90002-1
Owen RP, Altman RB, Klein TE (2008) PharmGKB and the International Warfarin Pharmacogenetics Consortium: the changing role for pharmacogenomic databases and single-drug pharmacogenetics. Human mutation 29: 456–460. doi: 10.1002/humu.20731
[22]
Rost S, Fregin A, Ivaskevicius V, Conzelmann E, H？rtnagel K, et al. (2004) Mutations in VKORC1 cause warfarin resistance and multiple coagulation factor deficiency type 2. Nature 427: 537–541. doi: 10.1038/nature02214
[23]
Bland AE, Calingaert B, Secord AA, Lee PS, Valea FA, et al. (2009) Relationship between tamoxifen use and high risk endometrial cancer histologic types. Gynecol Oncol 112: 150–154. doi: 10.1016/j.ygyno.2008.08.035
[24]
Xie L, Wang J, Bourne PE (2007) In silico elucidation of the molecular mechanism defining the adverse effect of selective estrogen receptor modulators. PLoS Comput Biol 3: e217 doi:10.1371/journal.pcbi.0030217.
[25]
Voora D, Koboldt DC, King CR, Lenzini PA, Eby CS, et al. (2010) A polymorphism in the VKORC1 regulator calumenin predicts higher warfarin dose requirements in African Americans. Clin Pharmacol Ther 87: 445–451.
[26]
Tatonetti NP, Dudley JT, Sagreiya H, Butte AJ, Altman RB (2010) An integrative method for scoring candidate genes from association studies: application to warfarin dosing. BMC Bioinformatics 11 Suppl 9: S9. doi: 10.1186/1471-2105-11-s9-s9
[27]
Thorn CF, Whirl-Carrillo M, Klein TE, Altman RB (2007) Pathway-based approaches to pharmacogenomics. Current Pharmacogenomics 5: 79–86. doi: 10.2174/157016007780077167
[28]
Lamb J, Crawford ED, Peck D, Modell JW, Blat IC, et al. (2006) The Connectivity Map: using gene-expression signatures to connect small molecules, genes, and disease. Science 313: 1929–1935. doi: 10.1126/science.1132939
[29]
Gamazon ER, Huang RS, Cox NJ, Dolan ME (2010) Chemotherapeutic drug susceptibility associated SNPs are enriched in expression quantitative trait loci. Proc Natl Acad Sci USA 107: 9287–9292. doi: 10.1073/pnas.1001827107
[30]
Chen Y, Shoichet BK (2009) Molecular docking and ligand specificity in fragment-based inhibitor discovery. Nat Chem Biol 5: 358–364. doi: 10.1038/nchembio.155
[31]
Kolb P, Ferreira RS, Irwin JJ, Shoichet BK (2009) Docking and chemoinformatic screens for new ligands and targets. Curr Opin Biotechnol 20: 429–436. doi: 10.1016/j.copbio.2009.08.003
[32]
Keiser MJ, Roth BL, Armbruster BN, Ernsberger P, Irwin JJ, et al. (2007) Relating protein pharmacology by ligand chemistry. Nat Biotechnol 25: 197–206. doi: 10.1038/nbt1284
[33]
Keiser MJ, Setola V, Irwin JJ, Laggner C, Abbas AI, et al. (2009) Predicting new molecular targets for known drugs. Nature 462: 175–181. doi: 10.1038/nature08506
[34]
Garten Y, Coulet A, Altman RB (2010) Recent progress in automatically extracting information from the pharmacogenomic literature. Pharmacogenomics 11: 1467–1489. doi: 10.2217/pgs.10.136
[35]
Roses AD (2004) Pharmacogenetics and drug development: the path to safer and more effective drugs. Nat Rev Genet 5: 645–656. doi: 10.1038/nrg1432
[36]
Kinnings SL, Liu N, Buchmeier N, Tonge PJ, Xie L, et al. (2009) Drug discovery using chemical systems biology: repositioning the safe medicine Comtan to treat multi-drug and extensively drug resistant tuberculosis. PLoS Comput Biol 5: e1000423 doi:10.1371/journal.pcbi.1000423.
[37]
Ashley EA, Butte AJ, Wheeler MT, Chen R, Klein TE, et al. (2010) Clinical assessment incorporating a personal genome. Lancet 375: 1525–1535. doi: 10.1016/s0140-6736(10)60452-7
[38]
Indermaur MD, Xiong Y, Kamath SG, Boren T, Hakam A, et al. (2010) Genomic-directed targeted therapy increases endometrial cancer cell sensitivity to doxorubicin. Am J Obstet Gynecol 203: 158.e151–140. doi: 10.1016/j.ajog.2010.02.003
[39]
Donnelly LA, Doney ASF, Dannfald J, Whitley AL, Lang CC, et al. (2008) A paucimorphic variant in the HMG-CoA reductase gene is associated with lipid-lowering response to statin treatment in diabetes: a GoDARTS study. Pharmacogenetics and Genomics 18: 1021–1026. doi: 10.1097/fpc.0b013e3283106071
[40]
Donnelly LA, Palmer CNA, Whitley AL, Lang CC, Doney ASF, et al. (2008) Apolipoprotein E genotypes are associated with lipid-lowering responses to statin treatment in diabetes: a Go-DARTS study. Pharmacogenetics and Genomics 18: 279–287. doi: 10.1097/fpc.0b013e3282f60aad
[41]
Giacomini KM, Krauss RM, Roden DM, Eichelbaum M, Hayden MR, et al. (2007) When good drugs go bad. Nature 446: 975–977. doi: 10.1038/446975a
[42]
Group SC, Link E, Parish S, Armitage J, Bowman L, et al. (2008) SLCO1B1 variants and statin-induced myopathy–a genomewide study. N Engl J Med 359: 789–799. doi: 10.1056/nejmoa0801936
[43]
Donnelly LA, Doney ASF, Tavendale R, Lang CC, Pearson ER, et al. (2011) Common nonsynonymous substitutions in SLCO1B1 predispose to statin intolerance in routinely treated individuals with type 2 diabetes: a go-DARTS study. Clin Pharmacol Ther 89: 210–216.
[44]
Mallal S, Phillips E, Carosi G, Molina J-M, Workman C, et al. (2008) HLA-B*5701 screening for hypersensitivity to abacavir. N Engl J Med 358: 568–579. doi: 10.1056/nejmoa0706135
[45]
Surh LC, Pacanowski MA, Haga SB, Hobbs S, Lesko LJ, et al. (2010) Learning from product labels and label changes: how to build pharmacogenomics into drug-development programs. Pharmacogenomics 11: 1637–1647. doi: 10.2217/pgs.10.138
[46]
Altman RB (2011) Pharmacogenomics: ‘noninferiority’ is sufficient for initial implementation. Clin Pharmacol Ther 89: 348–350.
[47]
Worthey EA, Mayer AN, Syverson GD, Helbling D, Bonacci BB, et al.. (2010) Making a definitive diagnosis: Successful clinical application of whole exome sequencing in a child with intractable inflammatory bowel disease. Genetics in medicine : official journal of the American College of Medical Genetics.
[48]
Mallal S, Nolan D, Witt C, Masel G, Martin AM, et al. (2002) Association between presence of HLA-B*5701, HLA-DR7, and HLA-DQ3 and hypersensitivity to HIV-1 reverse-transcriptase inhibitor abacavir. Lancet 359: 727–732. doi: 10.1016/s0140-6736(02)07873-x
[49]
Link E, Parish S, Armitage J, Bowman L, Heath S, et al. (2008) SLCO1B1 variants and statin-induced myopathy–a genomewide study. N Engl J Med 359: 789–799. doi: 10.1056/nejmoa0801936
[50]
Rebecchi IM, Rodrigues AC, Arazi SS, Genvigir FD, Willrich MA, et al. (2009) ABCB1 and ABCC1 expression in peripheral mononuclear cells is influenced by gene polymorphisms and atorvastatin treatment. Biochem Pharmacol 77: 66–75. doi: 10.1016/j.bcp.2008.09.019
[51]
Voora D, Koboldt DC, King CR, Lenzini PA, Eby CS, et al. A polymorphism in the VKORC1 regulator calumenin predicts higher warfarin dose requirements in African Americans. Clin Pharmacol Ther 87: 445–451.
[52]
D'Andrea G, D'Ambrosio RL, Di Perna P, Chetta M, Santacroce R, et al. (2005) A polymorphism in the VKORC1 gene is associated with an interindividual variability in the dose-anticoagulant effect of warfarin. Blood 105: 645–649. doi: 10.1182/blood-2004-06-2111
[53]
Aithal GP, Day CP, Kesteven PJ, Daly AK (1999) Association of polymorphisms in the cytochrome P450 CYP2C9 with warfarin dose requirement and risk of bleeding complications. Lancet 353: 717–719. doi: 10.1016/s0140-6736(98)04474-2
[54]
Rettie AE, Wienkers LC, Gonzalez FJ, Trager WF, Korzekwa KR (1994) Impaired (S)-warfarin metabolism catalysed by the R144C allelic variant of CYP2C9. Pharmacogenetics 4: 39–42. doi: 10.1097/00008571-199402000-00005
[55]
Crespi CL, Miller VP (1997) The R144C change in the CYP2C9*2 allele alters interaction of the cytochrome P450 with NADPH:cytochrome P450 oxidoreductase. Pharmacogenetics 7: 203–210. doi: 10.1097/00008571-199706000-00005
[56]
Hughes LB, Beasley TM, Patel H, Tiwari HK, Morgan SL, et al. (2006) Racial or ethnic differences in allele frequencies of single-nucleotide polymorphisms in the methylenetetrahydrofolate reductase gene and their influence on response to methotrexate in rheumatoid arthritis. Ann Rheum Dis 65: 1213–1218. doi: 10.1136/ard.2005.046797
[57]
Johnson JA, Zineh I, Puckett BJ, McGorray SP, Yarandi HN, et al. (2003) Beta 1-adrenergic receptor polymorphisms and antihypertensive response to metoprolol. Clin Pharmacol Ther 74: 44–52.
[58]
Israel E, Chinchilli VM, Ford JG, Boushey HA, Cherniack R, et al. (2004) Use of regularly scheduled albuterol treatment in asthma: genotype-stratified, randomised, placebo-controlled cross-over trial. Lancet 364: 1505–1512. doi: 10.1016/s0140-6736(04)17273-5
[59]
Shuldiner AR, O'Connell JR, Bliden KP, Gandhi A, Ryan K, et al. (2009) Association of cytochrome P450 2C19 genotype with the antiplatelet effect and clinical efficacy of clopidogrel therapy. JAMA 302: 849–857. doi: 10.1001/jama.2009.1232
[60]
Barclay ML, Sawyers SM, Begg EJ, Zhang M, Roberts RL, et al. (2003) Correlation of CYP2D6 genotype with perhexiline phenotypic metabolizer status. Pharmacogenetics 13: 627–632. doi: 10.1097/00008571-200310000-00006
[61]
Nogueira CP, Bartels CF, McGuire MC, Adkins S, Lubrano T, et al. (1992) Identification of two different point mutations associated with the fluoride-resistant phenotype for human butyrylcholinesterase. Am J Hum Genet 51: 821–828.
[62]
Otterness DM, Szumlanski CL, Wood TC, Weinshilboum RM (1998) Human thiopurine methyltransferase pharmacogenetics. Kindred with a terminal exon splice junction mutation that results in loss of activity. J Clin Invest 101: 1036–1044. doi: 10.1172/jci1004
[63]
Stocco G, Cheok MH, Crews KR, Dervieux T, French D, et al. (2009) Genetic polymorphism of inosine triphosphate pyrophosphatase is a determinant of mercaptopurine metabolism and toxicity during treatment for acute lymphoblastic leukemia. Clin Pharmacol Ther 85: 164–172.
[64]
Takeuchi F, McGinnis R, Bourgeois S, Barnes C, Eriksson N, et al. (2009) A genome-wide association study confirms VKORC1, CYP2C9, and CYP4F2 as principal genetic determinants of warfarin dose. PLoS Genet 5: e1000433 doi:10.1371/journal.pgen.1000433.
[65]
Pulley JM, Denny JC, Peterson JF, Bernard GR, Vnencak-Jones CL, et al. (2012) Operational implementation of prospective genotyping for personalized medicine: the design of the Vanderbilt PREDICT project. Clin Pharmacol Ther 92: 87–95.
