Personalized medicine: hope or hype?

Medicine has always been personalized. For years, physicians have incorporated environmental, behavioural, and genetic factors that affect disease and drug response into patient management decisions. However, until recently, the 'genetic' data took the form of family history and self-reported race/ethnicity. As genome sequencing declines in cost, the availability of specific genomic information will no longer be limiting. Rather, our ability to parse these data and our decision whether to use it will become primary. As our understanding of genetic association with drug responses and diseases continues to improve, clinically useful genetic tests may emerge to improve upon our previous methods of assessing genetic risks. Indeed, genetic tests for monogenic disorders have already proven useful. Such changes may usher in a new era of personalized medicine. In this review, we will discuss the utility and limitations of personal genomic data in three domains: pharmacogenomics, assessment of genetic predispositions for common diseases, and identification of rare disease-causing genetic variants.

[1]  Naomi R. Wray,et al.  Synthetic Associations Created by Rare Variants Do Not Explain Most GWAS Results , 2011, PLoS biology.

[2]  S. Humphries,et al.  Utility of genetic and non-genetic risk factors in prediction of type 2 diabetes: Whitehall II prospective cohort study , 2010, BMJ : British Medical Journal.

[3]  E. Antman,et al.  Cytochrome p-450 polymorphisms and response to clopidogrel. , 2009, The New England journal of medicine.

[4]  R. Collins,et al.  No impact of KIF6 genotype on vascular risk and statin response among 18,348 randomized patients in the heart protection study. , 2011, Journal of the American College of Cardiology.

[5]  M. Ritchie,et al.  Different contributions of polymorphisms in VKORC1 and CYP2C9 to intra- and inter-population differences in maintenance dose of warfarin in Japanese, Caucasians and African-Americans , 2006, Pharmacogenetics and genomics.

[6]  F.A.M. Bordonaba,et al.  Wild-Type KRAS Is Required for Panitumumab Efficacy in Patients With Metastatic Colorectal Cancer , 2009 .

[7]  R. Altman,et al.  Estimation of the warfarin dose with clinical and pharmacogenetic data. , 2009, The New England journal of medicine.

[8]  L. Lazzeroni,et al.  A polymorphism within a conserved beta(1)-adrenergic receptor motif alters cardiac function and beta-blocker response in human heart failure. , 2006, Proceedings of the National Academy of Sciences of the United States of America.

[9]  Deepak L. Bhatt,et al.  Effects of CYP2C19 genotype on outcomes of clopidogrel treatment. , 2010, The New England journal of medicine.

[10]  田中 俊典 National Center for Biotechnology Information (NCBI) , 2012 .

[11]  E. Zeggini,et al.  Synthetic Associations Are Unlikely to Account for Many Common Disease Genome-Wide Association Signals , 2011, PLoS biology.

[12]  Euan A Ashley,et al.  Challenges in the clinical application of whole-genome sequencing , 2010, The Lancet.

[13]  Steven Henikoff,et al.  SIFT: predicting amino acid changes that affect protein function , 2003, Nucleic Acids Res..

[14]  P. Stankiewicz,et al.  Whole-genome sequencing in a patient with Charcot-Marie-Tooth neuropathy. , 2010, The New England journal of medicine.

[15]  Tanya M. Teslovich,et al.  Biological, Clinical, and Population Relevance of 95 Loci for Blood Lipids , 2010, Nature.

[16]  Timothy B. Stockwell,et al.  The Diploid Genome Sequence of an Individual Human , 2007, PLoS biology.

[17]  Christian Gilissen,et al.  De novo mutations of SETBP1 cause Schinzel-Giedion syndrome , 2010, Nature Genetics.

[18]  F. Collins,et al.  Potential etiologic and functional implications of genome-wide association loci for human diseases and traits , 2009, Proceedings of the National Academy of Sciences.

[19]  J. Ferrières,et al.  Genetic determinants of response to clopidogrel and cardiovascular events. , 2009, The New England journal of medicine.

[20]  Jing Chen,et al.  PolyDoms: a whole genome database for the identification of non-synonymous coding SNPs with the potential to impact disease , 2006, Nucleic Acids Res..

[21]  H. Hod,et al.  Clopidogrel Resistance Is Associated With Increased Risk of Recurrent Atherothrombotic Events in Patients With Acute Myocardial Infarction , 2004, Circulation.

[22]  Deborah A Nickerson,et al.  Effect of VKORC1 haplotypes on transcriptional regulation and warfarin dose. , 2005, The New England journal of medicine.

[23]  L. Peltonen,et al.  A multilocus genetic risk score for coronary heart disease: case-control and prospective cohort analyses , 2010, The Lancet.

[24]  Jake K. Byrnes,et al.  Genome-wide association study of copy number variation in 16,000 cases of eight common diseases and 3,000 shared controls , 2010 .

[25]  Thomas W. Mühleisen,et al.  Large-scale association analysis identifies 13 new susceptibility loci for coronary artery disease , 2011, Nature Genetics.

[26]  S. Kathiresan,et al.  Polymorphisms Associated With Cholesterol and Risk of Cardiovascular Events , 2008 .

[27]  Alexander A. Morgan,et al.  Clinical assessment incorporating a personal genome , 2010, The Lancet.

[28]  P. Shannon,et al.  Analysis of Genetic Inheritance in a Family Quartet by Whole-Genome Sequencing , 2010, Science.

[29]  R. Collins,et al.  SLCO1B1 variants and statin-induced myopathy--a genomewide study. , 2008, The New England journal of medicine.

[30]  Peter Almgren,et al.  Clinical risk factors, DNA variants, and the development of type 2 diabetes. , 2008, The New England journal of medicine.

[31]  E. Antman,et al.  Genetic variants in ABCB1 and CYP2C19 and cardiovascular outcomes after treatment with clopidogrel and prasugrel in the TRITON–TIMI 38 trial: a pharmacogenetic analysis , 2010, The Lancet.

[32]  Paul M. Ridker,et al.  Association Between a Literature-Based Genetic Risk Score and Cardiovascular Events in Women , 2010 .

[33]  Judy H. Cho,et al.  Finding the missing heritability of complex diseases , 2009, Nature.

[34]  Tomas W. Fitzgerald,et al.  Origins and functional impact of copy number variation in the human genome , 2010, Nature.

[35]  Emily H Turner,et al.  Targeted Capture and Massively Parallel Sequencing of Twelve Human Exomes , 2009, Nature.

[36]  B. J. Barratt,et al.  Effect of CYP2C19 and ABCB1 single nucleotide polymorphisms on outcomes of treatment with ticagrelor versus clopidogrel for acute coronary syndromes: a genetic substudy of the PLATO trial , 2010, The Lancet.

[37]  Alan Ashworth,et al.  Targeting the DNA repair defect in BRCA mutant cells as a therapeutic strategy , 2005, Nature.

[38]  L. Lazzeroni,et al.  A polymorphism within a conserved β1-adrenergic receptor motif alters cardiac function and β-blocker response in human heart failure , 2006 .

[39]  Rong Chen,et al.  The Reference Human Genome Demonstrates High Risk of Type 1 Diabetes and Other Disorders , 2011, Pacific Symposium on Biocomputing.

[40]  J. Lupski,et al.  The complete genome of an individual by massively parallel DNA sequencing , 2008, Nature.

[41]  Thomas Helleday,et al.  Specific killing of BRCA2-deficient tumours with inhibitors of poly(ADP-ribose) polymerase , 2007, Nature.

[42]  R. Pearson,et al.  Cetuximab and Chemotherapy as Initial Treatment for Metastatic Colorectal Cancer , 2010 .

[43]  Y. Turpaz,et al.  CYP4F2 genetic variant alters required warfarin dose. , 2008, Blood.

[44]  P. Visscher,et al.  Common SNPs explain a large proportion of heritability for human height , 2011 .

[45]  P. Shannon,et al.  Exome sequencing identifies the cause of a Mendelian disorder , 2009, Nature Genetics.

[46]  P. Bork,et al.  Human non-synonymous SNPs: server and survey. , 2002, Nucleic acids research.

[47]  Dawei Li,et al.  The diploid genome sequence of an Asian individual , 2008, Nature.

[48]  N. Mehta Large-scale association analysis identifies 13 new susceptibility loci for coronary artery disease. , 2011, Circulation. Cardiovascular genetics.

[49]  M. Simoons,et al.  Controversies in cardiovascular medicine A systematic review on pharmacogenetics in cardiovascular disease : is it ready for clinical application ? , 2011 .

[50]  N. Cook Statistical evaluation of prognostic versus diagnostic models: beyond the ROC curve. , 2008, Clinical chemistry.

[51]  Robert B. Hartlage,et al.  This PDF file includes: Materials and Methods , 2009 .

[52]  A. Bura,et al.  Cytochrome P450 2C19 loss-of-function polymorphism is a major determinant of clopidogrel responsiveness in healthy subjects. , 2006, Blood.

[53]  M. Gordon Warfarin Genotyping Reduces Hospitalization Rates: Results From the MM-WES (Medco-Mayo Warfarin Effectiveness Study) , 2010 .

[54]  A. Uitterlinden,et al.  Genetic determinants of treatment benefit of the angiotensin-converting enzyme-inhibitor perindopril in patients with stable coronary artery disease. , 2010, European heart journal.

[55]  Nancy R. Cook,et al.  Use and Misuse of the Receiver Operating Characteristic Curve in Risk Prediction , 2007, Circulation.

[56]  M. Sabatine,et al.  Polymorphism in KIF6 gene and benefit from statins after acute coronary syndromes: results from the PROVE IT-TIMI 22 study. , 2008, Journal of the American College of Cardiology.

[57]  P. Stenson,et al.  The Human Gene Mutation Database: 2008 update , 2009, Genome Medicine.

[58]  Omar E. Cornejo,et al.  Phased Whole-Genome Genetic Risk in a Family Quartet Using a Major Allele Reference Sequence , 2011, PLoS genetics.

[59]  Stephan J Sanders,et al.  Whole exome sequencing identifies recessive WDR62 mutations in severe brain malformations , 2010, Nature.

[60]  J. Brooks Why most published research findings are false: Ioannidis JP, Department of Hygiene and Epidemiology, University of Ioannina School of Medicine, Ioannina, Greece , 2008 .

[61]  N. Cook Use and Misuse of the Receiver Operating Characteristic Curve in Risk Prediction , 2007, Circulation.

[62]  V. Salomaa,et al.  Excess of rare variants in genes identified by genome-wide association study of hypertriglyceridemia , 2010, Nature Genetics.

[63]  A. Zwinderman,et al.  CETP genotype predicts increased mortality in statin-treated men with proven cardiovascular disease: an adverse pharmacogenetic interaction. , 2008, European heart journal.

[64]  The UniProt Consortium,et al.  The Universal Protein Resource (UniProt) 2009 , 2008, Nucleic Acids Res..

[65]  M. Thun,et al.  Performance of Common Genetic Variants in Breast-cancer Risk Models , 2022 .

[66]  Alexander A. Morgan,et al.  Likelihood ratios for genome medicine , 2010, Genome Medicine.

[67]  J. Belmont,et al.  Rare copy number variations in congenital heart disease patients identify unique genes in left-right patterning , 2011, Proceedings of the National Academy of Sciences.

[68]  Michael Krawczak,et al.  The human gene mutation database , 1998, Nucleic Acids Res..

[69]  J. Catanese,et al.  KIF6 Trp719Arg polymorphism and the effect of statin therapy in elderly patients: results from the PROSPER study , 2010, European journal of cardiovascular prevention and rehabilitation : official journal of the European Society of Cardiology, Working Groups on Epidemiology & Prevention and Cardiac Rehabilitation and Exercise Physiology.

[70]  R. D'Agostino,et al.  Genotype score in addition to common risk factors for prediction of type 2 diabetes. , 2008, The New England journal of medicine.

[71]  Peter Wood,et al.  The impact of CYP2C9 and VKORC1 genetic polymorphism and patient characteristics upon warfarin dose requirements: proposal for a new dosing regimen. , 2005, Blood.

[72]  Ayellet V. Segrè,et al.  Hundreds of variants clustered in genomic loci and biological pathways affect human height , 2010, Nature.

[73]  Cathy H. Wu,et al.  The Universal Protein Resource (UniProt) , 2004, Nucleic Acids Res..

[74]  D. Goldstein Common genetic variation and human traits. , 2009, The New England journal of medicine.

[75]  R. Collins,et al.  Genetic variants associated with Lp(a) lipoprotein level and coronary disease. , 2009, The New England journal of medicine.

[76]  M. Pepe,et al.  Limitations of the odds ratio in gauging the performance of a diagnostic, prognostic, or screening marker. , 2004, American journal of epidemiology.

[77]  Dongsheng Tu,et al.  K-ras mutations and benefit from cetuximab in advanced colorectal cancer. , 2008, The New England journal of medicine.

[78]  A. Ashworth,et al.  Inhibition of poly(ADP-ribose) polymerase in tumors from BRCA mutation carriers. , 2009, The New England journal of medicine.

[79]  Emily H Turner,et al.  Exome sequencing identifies MLL2 mutations as a cause of Kabuki syndrome , 2010, Nature Genetics.

[80]  Keyan Salari,et al.  The Dawning Era of Personalized Medicine Exposes a Gap in Medical Education , 2009, PLoS medicine.

[81]  David B. Goldstein,et al.  Rare Variants Create Synthetic Genome-Wide Associations , 2010, PLoS biology.

[82]  Marc A Pfeffer,et al.  Association of the Trp719Arg polymorphism in kinesin-like protein 6 with myocardial infarction and coronary heart disease in 2 prospective trials: the CARE and WOSCOPS trials. , 2008, Journal of the American College of Cardiology.