The Pharmacogenetics Research Network: From SNP Discovery to Clinical Drug Response

The NIH Pharmacogenetics Research Network (PGRN) is a collaborative group of investigators with a wide range of research interests, but all attempting to correlate drug response with genetic variation. Several research groups concentrate on drugs used to treat specific medical disorders (asthma, depression, cardiovascular disease, addiction of nicotine, and cancer), whereas others are focused on specific groups of proteins that interact with drugs (membrane transporters and phase II drug‐metabolizing enzymes). The diverse scientific information is stored and annotated in a publicly accessible knowledge base, the Pharmacogenetics and Pharmacogenomics Knowledge base (PharmGKB). This report highlights selected achievements and scientific approaches as well as hypotheses about future directions of each of the groups within the PGRN. Seven major topics are included: informatics (PharmGKB), cardiovascular, pulmonary, addiction, cancer, transport, and metabolism.

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[44]  Giuseppe Curigliano,et al.  Drug-induced prolongation of the QT interval. , 2004, The New England journal of medicine.

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[48]  S. Weiss,et al.  TBX21: A functional variant predicts improvement in asthma with the use of inhaled corticosteroids , 2004, Proceedings of the National Academy of Sciences of the United States of America.

[49]  Christoph Lange,et al.  Using the noninformative families in family-based association tests: a powerful new testing strategy. , 2003, American journal of human genetics.

[50]  D. Roden,et al.  Polymorphism Screening in the Cardiac K+ Channel Gene KCNA5 , 2005, Clinical pharmacology and therapeutics.

[51]  R. Schilsky,et al.  UGT1A1*28 polymorphism as a determinant of irinotecan disposition and toxicity , 2002, The Pharmacogenomics Journal.

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[53]  E. Boerwinkle,et al.  WNK1 Kinase Polymorphism and Blood Pressure Response to a Thiazide Diuretic , 2005, Hypertension.

[54]  E. Boerwinkle,et al.  Lack of agreement between office and ambulatory blood pressure responses to hydrochlorothiazide. , 2005, American journal of hypertension.

[55]  R. Weinshilboum,et al.  Human thiopurine S-methyltransferase pharmacogenetics: variant allozyme misfolding and aggresome formation. , 2005, Proceedings of the National Academy of Sciences of the United States of America.

[56]  N Franklin Adkinson,et al.  Long-term effects of budesonide or nedocromil in children with asthma. , 2000, The New England journal of medicine.

[57]  E. Cook,et al.  A functional common polymorphism in a Sp1 recognition site of the epidermal growth factor receptor gene promoter. , 2005, Cancer research.

[58]  S. Gabriel,et al.  Corticosteroid pharmacogenetics: association of sequence variants in CRHR1 with improved lung function in asthmatics treated with inhaled corticosteroids. , 2004, Human molecular genetics.

[59]  Joshua M. Stuart,et al.  Integrating genotype and phenotype information: an overview of the PharmGKB project , 2001, The Pharmacogenomics Journal.

[60]  Cheng Cheng,et al.  MDR1 genotype is associated with hepatic cytochrome P450 3A4 basal and induction phenotype , 2006, Clinical pharmacology and therapeutics.

[61]  Andreas Rolfs,et al.  The ABCs of solute carriers: physiological, pathological and therapeutic implications of human membrane transport proteins , 2004, Pflügers Archiv.

[62]  D. Sane,et al.  Aspirin Resistance in Cardiovascular Disease: A Review of Prevalence, Mechanisms, and Clinical Significance , 2002, Thrombosis and Haemostasis.

[63]  W. Zhang,et al.  Expression of drug pathway proteins is independent of tumour type , 2006, The Journal of pathology.

[64]  S. Gabriel,et al.  EGFR Mutations in Lung Cancer: Correlation with Clinical Response to Gefitinib Therapy , 2004, Science.

[65]  I. Zineh,et al.  β1‐Adrenergic Receptor Polymorphisms and Antihypertensive Response to Metoprolol , 2003, Clinical pharmacology and therapeutics.

[66]  N. Risch,et al.  Functional genomics of membrane transporters in human populations. , 2005, Genome research.

[67]  S. Raimondi,et al.  Karyotypic abnormalities create discordance of germline genotype and cancer cell phenotypes , 2005, Nature Genetics.

[68]  J. Hudson,et al.  The human pregnane X receptor: genomic structure and identification and functional characterization of natural allelic variants. , 2001, Pharmacogenetics.

[69]  E. Topol,et al.  A prospective, blinded determination of the natural history of aspirin resistance among stable patients with cardiovascular disease. , 2003, Journal of the American College of Cardiology.

[70]  P Riederer,et al.  Allelic Variation of Human Serotonin Transporter Gene Expression , 1996, Journal of neurochemistry.

[71]  E. Schuetz,et al.  Mdr1 limits CYP3A metabolism in vivo. , 2000, Molecular pharmacology.

[72]  M. Weir,et al.  The Cardiac Arrhythmia Suppression Trial Investigators: Preliminary Report: Effect of Encainide and Flecainide on Mortality in a Randomized Trial of Arrhythmia Suppression After Myocardial Infarction. , 1990 .

[73]  G. Breithardt,et al.  Genetic basis and molecular mechanism for idiopathic ventricular fibrillation , 1998, Nature.

[74]  David B. Witonsky,et al.  CYP3A variation and the evolution of salt-sensitivity variants. , 2004, American journal of human genetics.

[75]  G. Parati,et al.  Lack of placebo effect on ambulatory blood pressure. , 1995, American journal of hypertension.

[76]  R. Weinshilboum,et al.  Pharmacogenetics: Inherited Variation in Amino Acid Sequence and Altered Protein Quantity , 2004, Clinical pharmacology and therapeutics.

[77]  C. Jepson,et al.  Impact of CYP2A6 genotype on pretreatment smoking behaviour and nicotine levels from and usage of nicotine replacement therapy , 2006, Molecular Psychiatry.

[78]  David A. Flockhart,et al.  The impact of cytochrome P450 2D6 metabolism in women receiving adjuvant tamoxifen , 2006, Breast Cancer Research and Treatment.

[79]  E. Silverman,et al.  Heterogeneity of therapeutic responses in asthma. , 2000, British medical bulletin.

[80]  R. Weinshilboum,et al.  Thiopurine S-methyltransferase pharmacogenetics: insights, challenges and future directions , 2006, Oncogene.

[81]  Enrico Smeraldi,et al.  Serotonin transporter gene-linked polymorphic region: possible pharmacogenetic implications of rare variants , 2006, Psychiatric genetics.

[82]  P. Watkins,et al.  CYP3A5 genotype predicts renal CYP3A activity and blood pressure in healthy adults. , 2003, Journal of applied physiology.

[83]  J. Oss,et al.  PROPHYLACTIC IMPLANTATION OF A DEFIBRILLATOR IN PATIENTS WITH MYOCARDIAL INFARCTION AND REDUCED EJECTION FRACTION , 2002 .

[84]  R. Weinshilboum,et al.  Thiopurine S-methyltransferase pharmacogenetics: chaperone protein association and allozyme degradation. , 2003, Pharmacogenetics.

[85]  George A. Mensah,et al.  Sudden Cardiac Death in the United States, 1989 to 1998 , 2001, Circulation.

[86]  E. Cook,et al.  Heritability and Linkage Analysis of Sensitivity to Cisplatin-Induced Cytotoxicity , 2004, Cancer Research.

[87]  Ann Daly,et al.  Sequence diversity in CYP3A promoters and characterization of the genetic basis of polymorphic CYP3A5 expression , 2001, Nature Genetics.

[88]  N. Laird,et al.  Family-based designs in the age of large-scale gene-association studies , 2006, Nature Reviews Genetics.

[89]  E. Boerwinkle,et al.  Multilocus effects of the renin–angiotensin–aldosterone system genes on blood pressure response to a thiazide diuretic , 2004, The Pharmacogenomics Journal.

[90]  C. Lerman,et al.  Nicotine metabolite ratio predicts efficacy of transdermal nicotine for smoking cessation , 2006, Clinical pharmacology and therapeutics.

[91]  T. Skaar,et al.  Pharmacological Characterization of 4-hydroxy-N-desmethyl Tamoxifen, a Novel Active Metabolite of Tamoxifen , 2004, Breast Cancer Research and Treatment.

[92]  Kevin P. Bliden,et al.  Clopidogrel for Coronary Stenting Response Variability, Drug Resistance, and the Effect of Pretreatment Platelet Reactivity , 2003, Circulation.

[93]  E. Cook,et al.  Pharmacogenetic risk factors for osteonecrosis of the hip among children with leukemia. , 2004, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[94]  Conrad C. Huang,et al.  Natural variation in human membrane transporter genes reveals evolutionary and functional constraints , 2003, Proceedings of the National Academy of Sciences of the United States of America.

[95]  Feng Lin,et al.  Phenotypic predictors of response to simvastatin therapy among African-Americans and Caucasians: the Cholesterol and Pharmacogenetics (CAP) Study. , 2006, The American journal of cardiology.

[96]  M. Ratain,et al.  Genetic predisposition to the metabolism of irinotecan (CPT-11). Role of uridine diphosphate glucuronosyltransferase isoform 1A1 in the glucuronidation of its active metabolite (SN-38) in human liver microsomes. , 1998, The Journal of clinical investigation.

[97]  R. Weinshilboum,et al.  Thiopurine S-methyltransferase pharmacogenetics: variant allele functional and comparative genomics , 2005, Pharmacogenetics and genomics.

[98]  David B. Witonsky,et al.  Comparative genomics analysis of human sequence variation in the UGT1A gene cluster , 2006, The Pharmacogenomics Journal.

[99]  E. Cook,et al.  Global gene expression as a function of germline genetic variation. , 2005, Human molecular genetics.

[100]  Fergus J Couch,et al.  Pharmacogenetics of tamoxifen biotransformation is associated with clinical outcomes of efficacy and hot flashes. , 2005, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[101]  D. Schaid,et al.  Genetic diversity and function in the human cytosolic sulfotransferases , 2007, The Pharmacogenomics Journal.

[102]  E. Cook,et al.  Interethnic difference in the allelic distribution of human epidermal growth factor receptor intron 1 polymorphism. , 2003, Clinical cancer research : an official journal of the American Association for Cancer Research.