Pharmacogenomics: a clinician's primer on emerging technologies for improved patient care.

Pharmacogenomics is a term recently coined to embody the concept of individualized and rational drug selection based on the genotype of a particular patient. Customization of drug therapy offers the potential for optimal safety and efficacy in an individual patient. Such a process contrasts current prescribing practices, which use medications shown to be safe and effective in patient populations or based on anecdotal experiences. Within patient populations, medications vary in their efficacy among individual patients. More importantly, a medication that is safe and effective in one patient may be ineffective or even harmful in another. Underlying many of these phenotypic differences are genotypic variants (polymorphisms) of key enzymes and proteins that affect the safety and efficacy of a drug in an individual patient. An understanding of these polymorphisms has the potential to enhance patient care by allowing physicians to customize the selection of medication to meet individual patient needs. Pharmacogenomics may also lead to improved compliance and shorter time to optimal disease management, thereby reducing morbidity and mortality. Significant cost savings could result from reductions in polypharmacy as well as from fewer physician encounters and hospitalizations for exacerbations of underlying illness and because of adverse drug reactions.

[1]  C. P. Nogueira,et al.  Identification of the structural mutation responsible for the dibucaine-resistant (atypical) variant form of human serum cholinesterase. , 1989, Proceedings of the National Academy of Sciences of the United States of America.

[2]  W. McGuire,et al.  Human breast cancer: correlation of relapse and survival with amplification of the HER-2/neu oncogene. , 1987, Science.

[3]  E. Vesell,et al.  Genetic control of dicumarol levels in man. , 1968, The Journal of clinical investigation.

[4]  J. Gummert,et al.  Azathioprine-induced myelosuppression in thiopurine methyltransferase deficient heart transplant recipient , 1993, The Lancet.

[5]  Kyoichi Ohashi,et al.  Effect of Genetic Differences in Omeprazole Metabolism on Cure Rates for Helicobacter pylori Infection and Peptic Ulcer , 1998, Annals of Internal Medicine.

[6]  J. Turgeon,et al.  Influence of CYP2D6 activity on the disposition and cardiovascular toxicity of the antidepressant agent venlafaxine in humans. , 1999, Pharmacogenetics.

[7]  Detection The sixth report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (JNC VI) , 1997 .

[8]  R. Diasio,et al.  Clinical implications of dihydropyrimidine dehydrogenase inhibition. , 1999, Oncology.

[9]  P. Beaune,et al.  Human cytochromes P450 , 1999 .

[10]  E. Smeraldi,et al.  Polymorphism within the promoter of the serotonin transporter gene and antidepressant efficacy of fluvoxamine , 1998, Molecular Psychiatry.

[11]  M. Relling,et al.  Pharmacogenomics: translating functional genomics into rational therapeutics. , 1999, Science.

[12]  P. K. Lunde,et al.  Disease and Acetylation Polymorphism , 1977, Clinical pharmacokinetics.

[13]  J. Turgeon,et al.  Involvement of CYP2D6 activity in the N-oxidation of procainamide in man. , 1999, Pharmacogenetics (London).

[14]  W. Kalow,et al.  A METHOD FOR THE DETECTION OF ATYPICAL FORMS OF HUMAN SERUM CHOLINESTERASE. DETERMINATION OF DIBUCAINE NUMBERS , 1957 .

[15]  G. Discombe Letter: Medical nemesis. , 1974, Lancet.

[16]  W. Kalow,et al.  The relation between dose of succinylcholine and duration of apnea in man. , 1957, The Journal of pharmacology and experimental therapeutics.

[17]  Steven E. Bayer,et al.  A strong candidate for the breast and ovarian cancer susceptibility gene BRCA1. , 1994, Science.

[18]  E. Vesell,et al.  Genetic Control of Drug Levels in Man: Phenylbutazone , 1968, Science.

[19]  S. Shak Overview of the trastuzumab (Herceptin) anti-HER2 monoclonal antibody clinical program in HER2-overexpressing metastatic breast cancer. Herceptin Multinational Investigator Study Group. , 1999, Seminars in oncology.

[20]  D. Thomason,et al.  Impact of genetic polymorphisms of the β2‐adrenergic receptor on albuterol bronchodilator pharmacodynamics , 1999, Clinical pharmacology and therapeutics.

[21]  G. Aithal,et al.  Association of polymorphisms in the cytochrome P450 CYP2C9 with warfarin dose requirement and risk of bleeding complications , 1999, The Lancet.

[22]  B. Vogelstein,et al.  p53 mutations in human cancers. , 1991, Science.

[23]  S. Green,et al.  Genetic polymorphisms of the beta 2-adrenergic receptor in nocturnal and nonnocturnal asthma. Evidence that Gly16 correlates with the nocturnal phenotype. , 1995, The Journal of clinical investigation.

[24]  F. Collins,et al.  Shattuck lecture--medical and societal consequences of the Human Genome Project. , 1999, The New England journal of medicine.

[25]  P. Corey,et al.  Incidence of Adverse Drug Reactions in Hospitalized Patients , 2012 .

[26]  Brian Lipworth,et al.  Association between β2-adrenoceptor polymorphism and susceptibility to bronchodilator desensitisation in moderately severe stable asthmatics , 1997, The Lancet.

[27]  D. Bentley,et al.  Identification of the breast cancer susceptibility gene BRCA2 , 1995, Nature.

[28]  W Godolphin,et al.  Studies of the HER-2/neu proto-oncogene in human breast and ovarian cancer. , 1989, Science.

[29]  U. Meyer,et al.  Molecular mechanisms of genetic polymorphisms of drug metabolism. , 1997, Annual review of pharmacology and toxicology.

[30]  W. Haseltine Not quite pharmacogenomics , 1998, Nature Biotechnology.

[31]  D. Tinkelman,et al.  Take control of high-cost asthma. , 1997, The Journal of asthma : official journal of the Association for the Care of Asthma.

[32]  G. Mayer,et al.  Angiotensin-Converting Enzyme Gene Polymorphism Determines the Antiproteinuric and Systemic Hemodynamic Effect of Enalapril in Patients with Proteinuric Renal Disease , 1998, Kidney and Blood Pressure Research.

[33]  D. Collier,et al.  Analysis of a structural polymorphism in the 5-HT2A receptor and clinical response to clozapine , 1996, Neuroscience Letters.

[34]  R. Prough,et al.  Pharmacogenetics: a laboratory tool for optimizing therapeutic efficiency. , 1997, Clinical chemistry.

[35]  R W Wallace DNA on a chip: serving up the genome for diagnostics and research. , 1997, Molecular medicine today.

[36]  Y. Tanigawara,et al.  CYP2C19 genotype–related efficacy of omeprazole for the treatment of infection caused by Helicobacter pylori , 1999 .

[37]  W. Evans,et al.  Altered mercaptopurine metabolism, toxic effects, and dosage requirement in a thiopurine methyltransferase-deficient child with acute lymphocytic leukemia. , 1991, The Journal of pediatrics.

[38]  W. Weber,et al.  N-acetylation pharmacogenetics. , 1985, Pharmacological reviews.

[39]  P. Talmud,et al.  Effect of angiotensin-converting enzyme (ACE) gene polymorphism on progression of renal disease and the influence of ACE inhibition in IDDM patients: findings from the EUCLID Randomized Controlled Trial. EURODIAB Controlled Trial of Lisinopril in IDDM. , 1998, Diabetes.

[40]  R. Weinshilboum,et al.  Mercaptopurine pharmacogenetics: monogenic inheritance of erythrocyte thiopurine methyltransferase activity. , 1980, American journal of human genetics.

[41]  L. Balant,et al.  High blood concentrations of imipramine or clomipramine and therapeutic failure: a case report study using drug monitoring data. , 1989, Therapeutic drug monitoring.

[42]  R. Branch,et al.  Genetically determined drug‐metabolizing activity and desipramine‐associated cardiotoxicity: A case report , 1993, Clinical pharmacology and therapeutics.

[43]  S. Sindrup,et al.  The pharmacogenetics of codeine hypoalgesia. , 1995, Pharmacogenetics.

[44]  P. Jones,et al.  The therapeutic response to D-penicillamine in rheumatoid arthritis: influence of glutathione S-transferase polymorphisms. , 1999, Rheumatology.

[45]  A. Breckenridge,et al.  The activation of the biguanide antimalarial proguanil co-segregates with the mephenytoin oxidation polymorphism--a panel study. , 1991, British journal of clinical pharmacology.

[46]  P. Seeburg,et al.  Tyrosine kinase receptor with extensive homology to EGF receptor shares chromosomal location with neu oncogene. , 1985, Science.

[47]  M. Ingelman-Sundberg,et al.  Inherited amplification of an active gene in the cytochrome P450 CYP2D locus as a cause of ultrarapid metabolism of debrisoquine. , 1993, Proceedings of the National Academy of Sciences of the United States of America.

[48]  S. Gauthier,et al.  Apolipoprotein E4 allele as a predictor of cholinergic deficits and treatment outcome in Alzheimer disease. , 1995, Proceedings of the National Academy of Sciences of the United States of America.

[49]  M. Kasuga,et al.  Sufficient effect of 1-week omeprazole and amoxicillin dual treatment for Helicobacter pylori eradication in cytochrome P450 2C19 poor metabolizers. , 1999, Journal of gastroenterology.

[50]  W. I. Cranston,et al.  Clinical observations on the effects of debrisoquine sulphate in patients with high blood-pressure. , 1966, British medical journal.

[51]  T. Yamamoto,et al.  The product of the human c-erbB-2 gene: a 185-kilodalton glycoprotein with tyrosine kinase activity. , 1986, Science.

[52]  E. Vicaut,et al.  G894T polymorphism in the endothelial nitric oxide synthase gene is associated with an enhanced vascular responsiveness to phenylephrine. , 1999, Circulation.

[53]  I. Hall Beta 2 adrenoceptor polymorphisms: are they clinically important? , 1996, Thorax.

[54]  W. Kalow,et al.  On distribution and inheritance of atypical forms of human serum cholinesterase, as indicated by dibucaine numbers. , 1957, Canadian journal of biochemistry and physiology.

[55]  P Whelton,et al.  Prevalence of hypertension in the US adult population. Results from the Third National Health and Nutrition Examination Survey, 1988-1991. , 1995, Hypertension.

[56]  O. Lockridge,et al.  Complete amino acid sequence of human serum cholinesterase. , 1987, The Journal of biological chemistry.

[57]  D. Easton,et al.  Risks of cancer in BRCA1-mutation carriers , 1994, The Lancet.

[58]  A. Breckenridge,et al.  In vitro metabolism of the biguanide antimalarials in human liver microsomes: evidence for a role of the mephenytoin hydroxylase (P450 MP) enzyme. , 1990, British journal of clinical pharmacology.

[59]  S. Liggett,et al.  beta2-adrenergic receptor polymorphisms at amino acid 16 differentially influence agonist-stimulated blood pressure and peripheral blood flow in normal individuals. , 2000, American heart journal.

[60]  R. Poland,et al.  The evolving science of pharmacogenetics: clinical and ethnic perspectives. , 1996, Psychopharmacology bulletin.

[61]  R. Weinberg,et al.  p185, a product of the neu proto-oncogene, is a receptorlike protein associated with tyrosine kinase activity , 1986, Molecular and cellular biology.

[62]  C. Hudis,et al.  Phase II study of weekly intravenous trastuzumab (Herceptin) in patients with HER2/neu-overexpressing metastatic breast cancer. , 1999, Seminars in oncology.

[63]  F. Cambien,et al.  Effect of deletion polymorphism of angiotensin converting enzyme gene on progression of diabetic nephropathy during inhibition of angiotensin converting enzyme: observational follow up study , 1996, BMJ.

[64]  J. Connell,et al.  ACE (I/D) genotype as a predictor of the magnitude and duration of the response to an ACE inhibitor drug (enalaprilat) in humans. , 1998, Circulation.

[65]  H. Lehmann,et al.  The familial incidence of low pseudocholinesterase level. , 1956, Lancet.

[66]  C. Watson,et al.  DNA chip technolgy , 1999 .

[67]  F. Goldwasser,et al.  Severe CPT-11 toxicity in patients with Gilbert's syndrome: two case reports. , 1997, Annals of oncology : official journal of the European Society for Medical Oncology.

[68]  K. Ohashi,et al.  Effects of clarithromycin on the metabolism of omeprazole in relation to CYP2C19 genotype status in humans , 1999, Clinical pharmacology and therapeutics.

[69]  W. Evans,et al.  Azathioprine-induced myelosuppression in thiopurine methyltransferase deficient heart transplant recipient , 1993, The Lancet.

[70]  E. Vesell,et al.  Genetic Control of Drug Levels in Man: Antipyrine , 1968, Science.

[71]  R. Erickson,et al.  Association between genetic polymorphisms of the beta2-adrenoceptor and response to albuterol in children with and without a history of wheezing. , 1997, The Journal of clinical investigation.

[72]  R. Kim,et al.  Alpha1A-adrenergic receptor polymorphism: association with ethnicity but not essential hypertension. , 1999, Pharmacogenetics.

[73]  Biochips: an evolving clinical technology. , 1999, Hospital practice.

[74]  J. Idle,et al.  POLYMORPHIC HYDROXYLATION OF DEBRISOQUINE IN MAN , 1977, The Lancet.

[75]  R. Weinshilboum,et al.  Human liver thiopurine methyltransferase pharmacogenetics: biochemical properties, liver-erythrocyte correlation and presence of isozymes. , 1992, Pharmacogenetics.

[76]  H. Perry,et al.  Relationship of acetyl transferase activity to antinuclear antibodies and toxic symptoms in hypertensive patients treated with hydralazine. , 1970, The Journal of laboratory and clinical medicine.

[77]  K. Ohashi,et al.  CYP2C19 genotype status and effect of omeprazole on intragastric pH in humans , 1999 .

[78]  M. Ingelman-Sundberg,et al.  Molecular basis for rational megaprescribing in ultrarapid hydroxylators of debrisoquine , 1993, The Lancet.

[79]  A. Di Rienzo,et al.  Variability at the uridine diphosphate glucuronosyltransferase 1A1 promoter in human populations and primates. , 1999, Pharmacogenetics.

[80]  U. Brinkmann,et al.  Functional polymorphisms of the human multidrug-resistance gene: multiple sequence variations and correlation of one allele with P-glycoprotein expression and activity in vivo. , 2000, Proceedings of the National Academy of Sciences of the United States of America.