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Research Article

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

, &
Pages 187-224 | Published online: 09 Oct 2008
 

Abstract

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.

ABBREVIATIONS
CEPH:=

Centre d'Etude du Polymorphisme Humain

CEU:=

Individuals from Utah, having Caucasian ancestry from northern and western Europe

CHB:=

Han Chinese in Beijing, China

CI:=

Confidence interval

CNVs:=

Copy-number variations

DNaseI:=

E ndonuclease that digests double- or single-stranded DNA into oligonucleotides or mononucleotides

EDP:=

Extreme discordant phenotype

EGP:=

Environmental Genome Project

EM:=

Extensive-metabolizer

ENCODE:=

Encyclopedia of DNA Elements

G6PD:=

Glucose-6-phosphate dehydrogenase

GRR:=

Genotypic relative risk

GWA:=

Genome-wide association

HGP:=

Human Genome Project

hPpM:=

High-penetrance predominantly monogenic

HD:=

Huntington disease

JPT:=

Japanese in Tokyo, Japan

LD:=

Linkage disequilibrium

LOD:=

Logarithm of the odds ratio for linkage

MAF:=

Minor allele frequency

OR:=

Odds ratio

PKU:=

Phenylketonuria

PM:=

Poor-metabolizer

QTLs:=

Quantitative trait loci

SNPs:=

Single-nucleotide polymorphisms

UM:=

Ultrarapid metabolizer

XMEs:=

Xenobiotic-metabolizing enzymes

XRTs:=

XME-related transporters

YRI:=

Yoruba in Ibadan, Nigeria

ACKNOWLEDGMENTS

We thank our many colleagues for a careful reading of this manuscript. This work was supported, in part, by NIH P30 ES06096 (D.W.N.).

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