From Human Genetics and Genomics to Pharmacogenetics and Pharmacogenomics: Past Lessons, Future Directions

• Published in: Drug metabolism reviews 2008-01, Vol.40 (2), p.187-224
• Main Authors: Nebert, Daniel W., Zhang, Ge, Vesell, Elliot S.
• Format: Article
• Language: English
• Subjects: Binary traits; Biotransformation - genetics; Complex disease; CYP2C19 gene; CYP2D6 gene; Cystic fibrosis; Databases, Genetic; dbGAP; Drug-Related Side Effects and Adverse Reactions; ENCODE; Epigenesis, Genetic; Extreme discordant phenotype design and analysis; GAIN; Gaucher disease; Genetic Association Information Network; Genetic Predisposition to Disease; Genetic Testing; Genetics, Medical - history; Genetics, Medical - trends; Genome, Human; Genomics - history; Genomics - trends; Genotype; History, 19th Century; History, 20th Century; History, 21st Century; Human Genome Project; Humans; Linkage Disequilibrium; Molecular Biology; Multifactorial Inheritance; Oligogenic diseases; Patient Selection; Pharmaceutical Preparations - metabolism; Pharmacogenetics - history; Pharmacogenetics - trends; Phenotype; Polymorphism, Single Nucleotide
• ISSN: 0360-2532; 1097-9883
• DOI: 10.1080/03602530801952864

This review is dedicated to the memory of our dear friend and colleague Professor Werner Kalow (1916-2008) A brief history of human genetics and genomics is provided, comparing recent progress in those fields with that in pharmacogenetics and pharmacogenomics, which are subsets of genetics and genomics, respectively. Sequencing of the entire human genome, the mapping of common haplotypes of single-nucleotide polymorphisms (SNPs), and cost-effective genotyping technologies leading to genome-wide association (GWA) studies-have combined convincingly in the past several years to demonstrate the requirements needed to separate true associations from the plethora of false positives. While research in human genetics has moved from monogenic to oligogenic to complex diseases, its pharmacogenetics branch has followed, usually a few years behind. The continuous discoveries, even today, of new surprises about our genome cause us to question reviews declaring that "personalized medicine is almost here" or that "individualized drug therapy will soon be a reality." As summarized herein, numerous reasons exist to show that an "unequivocal genotype" or even an "unequivocal phenotype" is virtually impossible to achieve in current limited-size studies of human populations. This problem (of insufficiently stringent criteria) leads to a decrease in statistical power and, consequently, equivocal interpretation of most genotype-phenotype association studies. It remains unclear whether personalized medicine or individualized drug therapy will ever be achievable by means of DNA testing alone.