Overview of Pharmacogenetics

David A. Katz1, Anahita Bhathena1

1 Abbott Laboratories, Abbott Park, Illinois
Publication Name:  Current Protocols in Human Genetics
Unit Number:  Unit 9.19
DOI:  10.1002/0471142905.hg0919s60
Online Posting Date:  January, 2009
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Abstract

Pharmacogenetics is the study of relationships between genetic variation and inter‐individual differences with respect to drug response. As the field has matured over the past 15 years, a remarkable diversity of pathways, variation types, and mechanisms have been found to be relevant pharmacogenetic factors. Today, pharmacogenetics is becoming more important in pharmacology for target validation, lead optimization, and understanding of idiosyncratic toxicity. This unit provides an overview of the history of pharmacogenetics and current research applications in drug discovery, as well as a discussion of research quality issues relevant for human subjects research in the pharmacogenetics laboratory. Curr. Protoc. Hum. Genet. 60:9.19.1‐9.19.23. © 2009 by John Wiley & Sons, Inc.

Keywords: pharmacogenetics; genotype‐phenotype correlations; drug discovery; toxicogenomics; drug development

     
 
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Table of Contents

  • Introduction
  • The Diversity of Pharmacogenetics
  • Applications in Drug Discovery
  • Applications in Drug Development
  • Clinical Use
  • A Final Word: Technologies
  • Literature Cited
  • Figures
  • Tables
     
 
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Materials

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Figures

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Literature Cited

   Anglicheau, D., Thervet, E., Etienne, I., Hurault De Ligny, B., Le Meur, Y., Touchard, G., Buchler, M., Laurent‐Puig, P., Tregouet, D., Beaune, P., Daly, A., Legendre, C., and Marquet, P. 2004. CYP3A5 and MDR1 genetic polymorphisms and cyclosporine pharmacokinetics after renal transplantation. Clin. Pharmacol. Ther. 75:422‐433.
   Blum, M., Grant, D., McBride, W., Heim, M., and Meyer, U. 1990. Human arylamine N‐acetyltransferase genes: Isolation, chromosomal localization, and functional expression. DNA Cell Biol. 9:193‐203.
   Carson, P., Flanagan, C., Ickes, C., and Alving, A. 1956. Enzymatic deficiancy in primaquine‐sensitive erythrocytes. Science 124:484‐485.
   Chen, K. and Poth, E. 1929. Racial differences as illustrated by the mydriatic action of cocaine, euphthalmine and ephedrine. J. Pharmacol. Exp. Ther. 36:429‐445.
   Dadke, S., Li, H., Kusari, A., Begum, N., and Kusari, J. 2000. Elevated expression and activity of protein‐tyrosine phosphatase 1B in skeletal muscle of insulin‐resistant type II diabetic Goto‐Kakizaki rats. Biochem. Biophys. Res. Commun. 274:583‐589.
   Deguchi, T., Mashimo, M., and Suzuki, T. 1990. Correlation between acetylator phenotypes and genotypes of polymorphic arylamine N‐acetyltransferase in human liver. J. Biol. Chem. 265:12757‐12760.
   Deininger, M., Buchdunger, E., and Druker, B.J. 2005. The development of imatinib as a therapeutic agent for chronic myeloid leukemia. Blood 105:2640‐2653.
   Di Paola, R., Frittitta, L., Miscio, G., Bozzali, M., Baratta, R., Centra, M., Spampinato, D., Grazia Santagati, M., Ercolino, T., Cisternino, C., Soccio, T., Mastroianno, S., Tassi, V., Almgren, P., Pizzuti, A., Vigneri, R., and Trischitta, V. 2002. A variation in 3′ UTR of hPTP1B increases specific gene expression and associates with insulin resistance. Am. J. Hum. Genet. 70:806‐812.
   Ding, Y.‐C., Chi, H.‐C., Grady, D., Morishima, A., Kidd, J., Kidd, K., Flodman, P., Spence, M.A., Schuck, S., Swanson, J.M., Zhang, V.‐P., and Moyzis, R.K. 2002. Evidence of positive selection acting at the human dopamine receptor D4 gene locus. Proc. Natl. Acad. Sci. U.S.A. 99:309‐314.
   Dishy, V., Sofowara, G., Xie, H.‐G., Kim, R., Byrne, D., Stein, C.M., and Wood, A.J. 2001. The effect of common polymorphisms of the beta2‐adrenoceptor on agonist‐mediated vascular desenstization. New Engl. J. Med. 345:1030‐1035.
   Drazen, J., Yandava, C., Dube, L., Szczerback, N., Hippensteel, R., Pillari, A., Israel, E., Schork, N., Silverman, E.S., Katz, D.A., and Drajesk, J. 1999. Pharmacogenetic association between ALOX5 promoter genotype and the response to anti‐asthma treatment. Nat. Genet. 22:168‐170.
   Echwald, S., Bach, H., Vestergaard, H., Richelsen, B., Kristensen, K., Drivsholm, T., Borch‐Johnsen, K., Hansen, T., and Pedersen, O. 2002. A P387L variant in protein tyrosine phosphatase‐1B (PTP‐1B) is associated with Type 2 diabetes and impaired serine phosphorylation of PTP‐1B in vitro. Diabetes 51:1‐6.
   Esteller, M., Gardia‐Foncillas, J., Andion, E., Goodman, S., Hidalgo, O., Vanaclocha, V., Baylin, S.B., and Herman, J.G. 2000. Inactivation of the DNA‐repair gene MGMT and the clinical response of gliomas to alkylating agents. New Engl. J. Med. 343:1350‐1354.
   Evans, F.T., Gray, P.W.S., Lehmann, H., and Silk, E. 1952. Sensitivity to succinylcholine in relation to serum cholinesterase. Lancet 1:1229‐1230.
   Food and Drug Administration (FDA). 2001. Label for PathVysion HER‐2 DNA probe kit. Food and Drug Administration. Bethesda, Md.
   FDA. 2004a. Drug interaction studies: Study design, data analysis, and implications for dosing and labeling. Food and Drug Administration. Bethesda, Md.
   FDA. 2004b. Label for Strattera. Food and Drug Administration. Bethesda, Md.
   FDA. 2005. Guidance for industry: Pharmacogenomic data submission. Food and Drug Administration. Bethesda, Md.
   Finta, C. and Zaphiropoulos, P. 2000. The human cytochrome P450 3A locus: Gene evolution by capture of downstream exons. Gene 260:13‐23.
   Floyd, M., Gervasini, G., Masica, A., Mayo, G., George, A., Bhat, K., Kim, R.B., and Wilkinson, G.R. 2003. Genotype‐phenotype associations for common CYP3A4 and CYP3A5 variants in the basal and induced metabolism of midazolam in European‐ and African‐American men and women. Pharmacogenetics 13:595‐606.
   Garcia‐Martin, E., Martinez, C., Pizarro, R., Garcia‐Gamito, F., Gullsten, H., Raunio, H., and Agundez, J.A. 2002. CYP3A4 variant alleles in white individuals with low CYP3A4 enzyme activity. Clin. Pharmacol. Ther. 71:196‐204.
   Garrod, A. 1902. The incidence of alkaptonuria: A study in chemical individuality. Lancet iii:1616‐1620.
   Gerloff, T., Schaefer, M., Johne, A., Oselin, K., Meisel, C., Cascorbi, I., and Roots, I. 2002. MDR1 genotypes do not influence the absorption of a single oral dose of 1 mg digoxin in healthy white males. Br. J. Clin. Pharmacol. 54:610‐616.
   Goetz, M.P., Kamal, A., and Ames, M.M. 2008. Tamoxifen pharmacogenomics: The role of CYP2D6 as a predictor of drug response. Clin. Pharmacol. Ther. 83:160.
   Goh, B.‐C., Lee, S.‐C., Wang, L.‐Z., Fan, L., Guo, J.‐Y., Lamba, J., Schuetz, E., Lim, R., Lim, H.L., Ong, A.B., and Lee, H.S. 2002. Explaining interindividual variability of docetaxel pharmacokinetics and pharmacodynamics in Asians through phenotyping and genotyping strategies. J. Clin. Oncol. 20:3683‐3690.
   Gonzalez, F. and Kimura, S. 2001. Understanding the role of xenobiotic‐metabolism in chemical carcinogenesis using gene knockout mice. Mutat. Res. 477:79‐87.
   Hauner, H., Meier, M., Jöckel K.‐H., Frey U.H., and Siffert, W. 2003. Prediction of successful weight reduction under sibutramine therapy through genotyping of the G‐protein β3 subunit gene (GNB3) C825T polymorphism. Pharmacogenetics 13:453‐459.
   Hesselink, D., vanSchaik, R., vanderHeiden, I., vanderWerf, M., SmakGregoor, P., Lindemans, J., Weimar, W., and van Gelder, T. 2003. Genetic polymorphisms of the CYP3A4, CYP3A5, and MDR‐1 genes and pharmacokinetics of the calcineurin inhibitors cyclosporine and tacrolimus. Clin. Pharmacol. Ther. 74:245‐254.
   Hoffmeyer, S., Burk, O., von Richter, O., Arnold, H.P., Brockmoller, J., Johne, A., Cascorbi, I., Gerloff, T., Roots, I., Eichelbaum, M., and Brinkmann, U. 2000. Functional polymorphisms of the human multidrug‐resistance gene: Multiple sequence variations and correlation of one allele with P‐glycoprotein expression and activity in vivo. Proc. Natl. Acad. Sci. U.S.A. 97:3473‐3478.
   Israel, E., Chinchilli, V.M., Ford, J.G., Boushey, H.A., Cherniack, R., Craig, T.J., Deykin, A., Fagan, J.K., Fahy, J.V., Fish, J., Kraft, M., Kunselman, S.J., Lazarus, S.C., Lemanske, R.F., Liggett, S.B., Martin, R.J., Mitra, N., Peters, S.P., Silverman, E., Sorkness, C.A., Szefler, S.J., Wechsler, M.E., Weiss, S.T., and Drazen, J.M. 2004. Use of regularly scheduled albuterol treatment in asthma: Genotype‐stratified, randomised, placebo‐controlled cross‐over trial. Lancet 364:1505‐1512.
   Johne, A., Köpke, K., Gerloff, T., Mai, I., Rietbrock, S., Meisel, C., Hoffmeyer, S., Kerb, R., Fromm, M.F., Brinkmann, U., Eichelbaum, M., Brockmoller, J., Cascorbi, I., and Roots, I. 2002. Modulation of steady‐state kinetics of digoxin by haplotypes of the P‐glycoprotein MDR1 gene. Clin. Pharmacol. Ther. 72:584‐594.
   Kang, E.S., Park, S.Y., Kim, H.J., Kim, C.S., Ahn, C.W., Cha, B.S., Lim, S.K., Nam, C.M., and Lee, H.C. 2005. Effects of Pro12Ala polymorphism of peroxisome proliferator‐activated receptor γ2 gene on rosiglitazone response in type 2 diabetes. Clin. Pharmacol. Ther. 78:202‐208.
   Katz, D. 2000. The promise of pharmacogenetics. Pharm. News 7:47‐52.
   Katz, D.A., Gustavson, L.E., Grimm, D.R., Cassar, S.C., Gentile‐Davey, M.C., Rieser, M.J., Gordon, E.F., Polzin, J.E., Driscoll, R.M., O'Dea, R.F., Williams, L.A., and Bukofzer, S. 2004a. Dose‐dependent effect of CYP3A5 genotype on ABT‐773 pharmacokinetics. Clin. Pharmacol. Ther. 75:516‐528.
   Katz, D.A., Grimm, D.R., Carr, R., Xiong, H., Holley‐Shanks, R., Mueller, T., and Allen, A. 2004b. Pharmacogenetic meta‐analysis suggests that atrasentan is an organic anion transport protein C substrate. Clin. Pharmacol. Ther. 75:P94.
   Katz, D.A., Murray, B., Bhathena, A., and Sahelijo, L. 2008. Defining drug disposition determinants: A pharmacogenetic‐pharmacokinetic strategy. Nature Rev. Drug Discov. 7:293‐305.
   Kim, J., Chung, J., Cho, J., Lim, H., Hong, K., Oh, D., Yi, S., Jang, I., and Shin, S. 2003. Identification of the influence of CYP3A5 genetic polymorphism in tacrolimus pharmacokinetics assessed from routine TDM data using population pharmacokinetics approach. Clin. Pharmacol. Ther. 73:P20.
   Kirchheiner, J., Nickchen, K., Bauer, M., Wong, M.L., Licinio, J., Roots, I., and Brockmöller, J. 2004. Pharmacogenetics of antidepressants and antipsychotics: The contribution of allelic variations to the phenotype of drug response. Mol. Psychiatry 9:442‐473.
   Kuehl, P., Zhang, J., Lin, Y., Lamba, J., Assem, M., Schuetz, J., Watkins, P.B., Daly, A., Wrighton, S.A., Hall, S.D., Maurel, P., Relling, M., Brimer, C., Yasuda, K., Venkataramanan, R., Strom, S., Themmel, K., Boguski, M.S., and Schuetz, E. 2001. Sequence diversity in CYP3A promoters and characterization of the genetic basis of polymorphic CYP3A5 expression. Nat. Genet. 27:383‐391.
   Kurata, Y., Ieiri, I., Kimura, M., Morita, T., Irie, S., Urae, A., Ohdo, S., Ohtani, H., Sawada, Y., Higuchi, S., and Otsubo, K. 2002. Role of human MDR1 gene polymorphism in bioavailability and interaction of digoxin, a substrate of P‐glycoprotein. Clin. Pharmacol. Ther. 72:209‐219.
   Lawrence, T.E., Chien, C., Tu, H.C., Phillips, J.M., Donnelly, C.M., and Huang, M.Y. 2005. No effect of concomitant administration of nebivolol and losartan in healthy volunteers genotyped for CYP2D6 status. Clin. Pharmacol. Ther. 77:P82.
   Lehmann, H. 1956. The familial incidence of low pseudocholinesterase level. Lancet 2:1240.
   Li, X., Pequignot, E., Panebianco, D., Majumdar, A., Selverian, D., Rosen, L., and Petty, K. 2005. Lack of effect of aprepitant on the pharmacokinetics of hydrodolasetron in CYP2D6 extensive and poor metabolizers. Clin. Pharmacol. Ther. 77:P47.
   Macphee, I., Fredericks, S., Tai, T., Syrris, P., Carter, N., Johnston, A., Goldberg, L., and Holt, D.W. 2002. Tacrolimus pharmacogenetics: Polymorphisms associated with expression of cytochrome P4503A5 and P‐glycoprotein correlate with dose requirement. Transplantation 74:1486‐1489.
   Mai, I., Störmer, E., Goldammer, M., Johne, A., Krüger, H., Budde, K., and Roots, I. 2003. MDR1 haplotypes do not affect the steady‐state pharmacokinetics of cyclosporine in renal transplant patients. J. Clin. Pharmacol. 43:1101‐1107.
   Martini, G., Toniolo, D., Vulliamy, T., Luzzatto, L., Dono, R., Viglietto, G., Paonessa, G., D'Urso, M., and Persico, M.G. 1986. Structural analysis of the X‐linked gene encoding human glucose 6‐phosphate dehydrogenase. EMBO J. 5:1849‐1855.
   Masellis, M., Basile, V., Ozdemir, V., Meltzer, H., Macciardi, F., and Kennedy, J. 2000. Pharmacogenetics of antipsychotic treatment: Lessons learned from clozapine. Biol. Psychiatry 47:252‐266.
   McGuire, M., Nogueira, C., Bartels, C., Lightstone, H., Hajra, A., Van der Spek, A.F.L., Lockridge, O., and La Du, B.N. 1989. Identification of the structural mutation responsible for the dibucaine‐resistant (atypical) variant form of human serum cholinesterase. Proc. Natl. Acad. Sci. U.S.A. 86:953‐957.
   McTiernan, C., Adkins, S., Chatonnet, A., Vaughan, T., Bartels, C., Kott, M., Rosenberry, T.L., La Du, B.N., and Lockridge, O. 1987. Brain cDNA clone for human cholinesterase. Proc. Natl. Acad. Sci. U.S.A. 84:6682‐6686.
   Michalski, C., Cui, Y., Nies, A., Nuessler, A., Neuhaus, P., Zanger, U., Klein, K., Eichelbaum, M., Keppler, D., and Konig, J. 2002. A naturally occurring mutation in the SLC21A6 gene causing impaired membrane localization of the hepatocyte uptake transporter. J. Biol. Chem. 277:43058‐43063.
   Morita, Y., Sakaeda, T., Horinouchi, M., Nakamura, T., Kuroda, K., Miki, I., Yoshimura, K., Sakai, T., Shirasaka, D., Tamura, T., Aoyama, N., Kasuga, M., and Okumura, K. 2003. MDR1 genotype‐related duodenal absorbtion rate of digoxin in healthy Japanese subjects. Pharm. Res. 20:552‐556.
   Mwinyi, J., Johne, A., Bauer, S., Roots, I., and Gerloff, T. Evidence for inverse effects of OATP‐C (SLC21A6) *5 and *1b haplotypes on pravastatin kinetics. 2004. Clin. Pharmacol. Ther. 75:415‐421.
   Niemi, M., Schaeffeler, E., Lang, T., Fromm, M., Neuvonen, M., Kyrklund, C., Backman, J.T., Kerb, R., Schwab, M., Neuvonen, P.J., Eichelbaum, M., and Kivisto, K.T. 2004. High plasma pravastatin concentrations are associated with single nucleotide polymorphisms and haplotypes of organic anion‐transporting polypeptide‐C(OATP‐C, SLCO1B1). Pharmacogenetics 14:429‐440.
   Nishizato, Y., Ieiri, I., Suzuki, H., Kimura, M., Kawabata, K., Hirota, T., Takane, H., Irie, S., Kusuhara, H., Urasaki, Y., Urae, A., Higuchi, S., Otsubo, K., and Sugiyama, Y. 2003. Polymorphisms of OATP‐C (SLC21A6) and OAT3 (SLC22A8) genes: Consequences for pravastatin pharmacokinetics. Clin. Pharmacol. Ther. 73:554‐565.
   Nozawa, T., Nakajima, M., Tamai, I., Noda, K., Nezu, J.‐I., Sai, Y, Tsuji, A., and Yokoi, T. 2002. Genetic polymorphisms of human organic anion Transporters OATP‐C (SLC21A6) and OATP‐B (SLC21A9): Allele frequencies in the Japanese population and functional analysis. J. Pharmacol. Exp. Ther. 302:804‐813.
   Ozkaya‐Bayazit, E. and Akar, U. 2001. Fixed drug eruption induced by trimethoprim‐sulfomethoxazole: Evidence for a link to HLA‐A30 B13 Cw6 haplotype. J. Am. Acad. Dermatol. 45:712‐717.
   Paskind, H. 1921. Some differences in response to atropine in white and colored races. J. Lab. Clin. Med. 7:104‐108.
   Pellicano, R., Lomuto, M., Ciavarella, G., Giorgio, G.D., and Gasparini, P. 1997. Fixed drug eruptions with feprazone are linked to HLA‐B22. J. Am. Acad. Dermatol. 36:782‐784.
   Price Evans, D., Manley, K., and McKusick, V. 1960. Genetic control of isoniazid metabolism in man. Br. Med. J. 485‐491.
   Prody, C., Zevin‐Sonkin, D., Gnatt, A., Goldberg, O., and Soreq, H. 1987. Isolation and characterization of full‐length cDNA clones coding for cholinesterase from fetal human tissues. Proc. Natl. Acad. Sci. U.S.A. 84:3555‐3559.
   Quiralte, J., Sanchez‐Garcia, F., Torres, M.‐J., Bianco, C., Castillo, R., Ortega, N., Rodriguez de Castro, F., Perez‐Aciego, P., and Carrillo, T. 1999. Association of HLA‐DR11 with the anaphylactoid reaction caused by nonsteroidal anti‐infammatory drugs. J. Allergy Clin. Immunol. 103:685‐689.
   Rendic, S. 2002. Human P450 Metabolism Database. Vol. 2002. Gentest Corporation, Woburn, Mass.
   Sachse, C., Brockmoller, J., Bauer, S., and Roots, I. 1997. Cytochrome P450 2D6 Variants in a caucasian population: Allele frequencies and phenotypic consequences. Am. J. Hum. Genet. 60:284‐295.
   Sahelijo, L., Katz, D.A., and Spear, B.B. 2004. Prediction of successful weight reduction under sibutramine therapy. Pharmacogenetics 14:387.
   Sakaeda, T., Nakamura, T., Horinouchi, M., Kakumoto, M., Ohmoto, N., Sakai, T., Morita, Y., Tamura, T., Aoyama, N., Hirai, M., Kasuga, M., and Okumura, K. 2001. MDR1 Genotype‐related pharmacokinetics of digoxin after single oral administration in healthy Japanese subjects. Pharm. Res. 18:1400‐1404.
   Shih, P.‐S. and Huang, J.‐D. 2002. Pharmacokinetics of midazolam and 1′‐hydroxymidazolam in Chinese with different CYP3A5 genotypes. Drug Metab. Dispos. 30:1491‐1496.
   Siegsmund, M., Brinkmann, U., Schäffeler, E., Weirich, G., Schwab, M., Eichelbaum, M., Fritz, P., Burk, O., Decker, J., Alken, P., Rothenpieler, U., Kerb, R., Hoffmeyer, S., and Brauch, H. 2002. Association of the P‐glycoprotein transporter MDR1 C3435T polymorphism with the susceptibility to renal epithelial tumors. J. Am. Soc. Nephrol. 13:1847‐1854.
   Simon, J., Karnoub, M.C., Devlin, D.J., Arreaza, M.G., Qiu, P., Monks, S.A., Severino, M.E., Deutsch, P., Palmisano, J., Sachs, A.B., Bayne, M.L., Plump, A.S., and Schadt, E.E.. 2005. Sequence variation in NPC1L1 and association with improved LDL‐cholesterol lowering in response to ezetimibe treatment. Genomics 86:648‐656.
   Slamon, D.J., Leyland‐Jones, B., Shak, S., Fuchs, H., Paton, V., Bajamonde, A., Fleming, T., Eiermann, W., Wolter, J., Pegram, M., Baselga, J., and Norton, L. 2001. Use of chemotherapy plus a monoclonal antibody against HER2 for metastatic breast cancer that overexpresses HER2. New Engl. J. Med. 344:783‐792.
   Small, D., Loghin, C., Lucas, R., Knadler, M.P., Zhang, L, Chappell, J., Bergstrom, R., and Callaghan, J.T. 2005. Pharmacokinetic evaluation of combined duloxetine and fluvoxamine dosing in CYP2D6 poor metabolizers. Clin. Pharm. Ther. 77:P37.
   Smits, K.M., Smits, L.J.M., Schouten, J.S.A.G., Stelma, F.F., Nelemans, P., and Prins, M.H. 2004. Influence of SERTPR and Stin2 in the serotonin transporter gene on the effect of selective serotonin reuptake inhibitors in depression: A systematic review. Mol. Psych. 9:433‐441.
   Steen, V., Molven, A., Aarskog, N., and Gulbrandsen, A.‐K. 1995. Homologous unequal cross‐over involving a 2.8 kb direct repeat as a mechanism for the generation of allelic variants of the human cytachrome P450 CYP2D6 gene. Hum. Mol. Genet. 4:2251‐2257.
   Steinbach, G., Lynch, P.M., Phillips, R.K., Wallace, M.H., Hawk, E., Gordon, G.B., Wakabayashi, N., Saunders, B., Shen, Y., Fujimura, T., Su, L.K., and Levin, B. 2000. The effect of celecoxib, a cyclooxygenase‐2 inhibitor, in familial adenomatous polyposis. New Engl. J. Med. 342:1946‐1952.
   Swanson, J., Oosterlaan, J., Murias, M., Schuck, S., Flodman, P., Spence, M.A., Wasdell, M., Ding, Y., Chi, H.‐C., Smith, M., Mann, M., Carlson, C., Kennedy, J.L., Sergeant, J.A., Lieung, P., Zhang, Y.‐P., Sadah, A., Chen, C., Whalen, C.K., Babb, K.A., Moyzis, R., and Posner, M.I. 2000. Attention deficit/hyperactivity disorder children with 7‐repeat allele of the dopamine receptor D4 gene have extreme behavior but normal performance on critical neuropsychological tests of attention. Proc. Natl. Acad. Sci. U.S.A. 97:4754‐4759.
   Tirona, R., Leake, B., Wolkoff, A., and Kim, R. 2003. Human organic anion transporting protein‐c (SLC21A6) is a major determinant of rifampin‐mediated pregnane x receptor activation. J. Pharmacol. Exp. Ther. 304:223‐228.
   Vandenbroucke, J., Koster, T., Briet, E., Reitsma, P., Bertina, R., and Rosendaal, F. 1994. Increased risk of venous thrombosis in oral‐contraceptive users who are carriers of factor V Leiden mutation. Lancet 344:1453‐1456.
   Vogel, C.L., Cobleigh, M.A., Tripathy, D., Gutheil, J.C., Harris, L.N., Fehrenbacher, L., Slamon, D.J., Murphy, M., Novotny, W.F., Burchmore, M., Shak, S., Stewart, S.J., and Press, M. 2002. Efficacy and safety of Trastuzumab as a single agent in first‐line treatment of HER2‐overexpressing metastatic breast cancer. J. Clin. Oncol. 20:719‐726.
   Vogel, F. 1959. Moderne Probleme der Humangenetik. Ergeb. Inn. Med. Kinderheilkd. 12:52‐125.
   von Ahsen, N., Richter, M., Grupp, C., Ringe, B., Oellerich, M., and Armstrong, V.W., 2001. No influence of the MDR‐1 C3435T polymorphism or a CYP3A4 promoter polymorphism (CYP3A4‐V allele) on dose‐adjusted cyclosporin A trough concentrations or rejection incidence in stable renal transplant recipients. Clin. Chem. 47:1048‐1052.
   Vulliamy, T., Beutler, E., and Luzzatto, L. 1993. Variants of glucose‐6‐phosphate dehydrgenase are due to missense mutations spread throughout the coding region of the gene. Hum. Mutat. 2:159‐167.
   Weinshilboum, R. 2000. Thiopurine methyltransferase pharmacogenetics. Pharm. News 7:19‐25.
   Wong, M., Balleine, R.L., Collins, M., Liddle, C., Clarke, C.L., and Gurney, H. 2004. CYP3A5 genotype and midazolam clearance in Australian patients receiving chemotherapy. Clin. Pharm. Ther. 75:529‐538.
   Xie, R., Knuth, D., Tan, L., Polasek, E., Hong, C., Teillol‐Foo, M., et al. 2003. Fexofenidine and midazolam disposition in relation to genetic polymorphisms of CYP3A, PXR and P‐glycoprotein. Clin. Pharm. Ther. 73:P19.
   Yoon, Y., Chun, H., Kim, E., Shon, J., Bae, K., Jang, I., et al. 2002. Genetic and environmental factors influencing on the disposition of digoxin: A population pharmacokinetic approach. Clin. Pharm. Ther. 71:A1.
   Yue, Q., Svensson, J.‐O., Alm, C., Sjoqvist, F., and Sawe, J. 1989. Codeine O‐demethylation co‐segregates with polymorphic debrisoquine hydroxylation. Br. J. Clin. Pharmacol. 28:639‐645.
   Zanger, U., Fischer, J., Raimundo, S., Stuven, T., Evert, B., Schwab, M., and Eichelbaum, M. 2001. Comprehensive analysis of the genetic factors determining expression and function of hepatic CYP2D6. Pharmacogenetics 11:573‐585.
   Zheng, H., Webber, S., Zeevi, A., Schuetz, E., Zhang, J., Bowman, P., Boyle, G., Law, Y., Miller, S., Lamba, J., and Burckart, G.J. 2003. Tacrolimus dosing in pediatric heart transplant patients is related to CYP3A5 and MDR1 gene polymorphisms. Am. J. Transplant. 3:477‐483.
   Zill, P., Baghai, T., Zwanzger, P., Schüle, C., Minov, C., Riedel, M., Neumeier, K., Rupprech, R., and Bondy, B. 2000. Evidence for an association between a G‐protein β3‐gene variant with depression and response to antidepressant treatment. Neuroreport 11:1893‐1897.
Internet Resources
  http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?db=OMIM
  The Online Mendelian Inheritance in Man (OMIM) Web site. An annotated database containing information about genes and genetic variants. From the OMIM entry for a gene, it is possible to link to most other major Internet resources on that gene. This is the best place from which to gather gene‐centric information.
  http://www.pharmgkb.org
  PharmGKB, a database of candidate gene polymorphisms maintained via the NIH Pharmacogenetics Research Network (PRN). This group comprises investigators who are funded by a targeted NIGMS grant program. The site includes information about genes studied by PRN investigators, upcoming scientific meetings and the individual PRN centers.
  http://www.gentest.com/human_p450_database/index.html
  The human cytochrome P450 metabolism database (Rendic, ; see ). This is a searchable database of substrates, inhibitors and inducers of human cytochromes P450.
  http://www.imm.ki.se/CYPalleles
  Homepage of the Human Cytochrome P450 Allele Nomenclature Committee. This is an up‐to‐date catalog of known sequence variants of human cytochromes P450. Unfortunately, it does not include allele frequency, and lists rare alleles, even those that have been observed only once.
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