From human genetics and genomics to pharmacogenetics and pharmacogenomics: past lessons, future directions

Abstract

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.

Figure 1

General examples of phenotypes in pharmacogenetic studies. A, slow metabolism inherited as a predominantly autosomal recessive trait (a allele). B, efficient metabolism inherited as a predominantly autosomal dominant trait. C, gradient of slow-to-rapid metabolism involving multiple genes and showing a unimodal distribution possibly inherited as a codominant, gene-dose or additive trait; this could also reflect a complex disorder. The amount of “scatter”, typical in studies such as those depicted in parts A, B and C, most likely represents contributions from modifier genes, gene-gene interactions, and/or environmental factors. Another interesting example (not shown) is the CYP2D6 polymorphism in which the poor-metabolizer (PM), intermediate-metabolizer (IM), efficient-metabolizer (EM), and ultra-rapid-metabolizer (UM) phenotypes can sometimes be distinguished as four distinct peaks (Ingelman-Sundberg, 2005).

Figure 2

Theoretical scheme showing the number of genes and extent of their contribution to the trait. A monogenic human disease (A) and an hPpM pharmacogenetic disorder (B) are compared with an oligogenic (C) and a complex disease (D). The gene responsible for a monogenic human disease contributes much more to expression of that disease (A) than does an hPpM gene responsible for expression of a pharmacogenetic disorder (B). If we use the same measure for genetic “contribution”, the allelic architecture (number of risk loci, inheritance mode, allele frequency, etc.) of complex diseases should be determined by both evolution and selective pressures. Thus, the dissimilar patterns in A versus B (and in fact in all four panels) represent different roles during human evolution and environmental adaptations (see text). HuGEN, human genetics; PhGEN, pharmacogenetics.

Figure 3

Scheme proposing an “up-front” (or “early-response”) network of hPpM genes involved in pharmacokinetics, followed by downstream targets involving a network of innumerable low-penetrance genes responsible for pharmacodynamics. This diagram assumes that the parent drug possesses efficacy but that its accumulation can cause toxicity. Some examples of drugs occur wherein the metabolite rather than the parent drug is the active agent.