Clinical relevance of pharmacogenetics

Pharmacogenetics fields of research was initially restricted to drug metabolism enzymes. It has recently progressed to drug transporters, receptors, and any kind of targets that can modulate drug response. This rapid extension of pharmacogenetics to all the different medical specialties is in close relation with the recent completion of the draft sequence of the human genome and the discovery that about 0.1% of its sequence is polymorphic. The goal of pharmacogenetics for the next years is clearly to determine the clinical consequences of these 2-3 million single nucleotide polymorphisms (SNPs). Things can be schematically divided in two situations. (1) Frequent SNPs (allele frequency > 10%) which have a low impact on drug response (odds ratios < 2), even combined with other SNPs in haplotype combinations. Such situations, which are by far the most frequent, have no clinical relevance for a single patient to predict its response to a particular drug. CYP3A and MDR1 allelic variants are good examples of such frequent situations. (2) Rare SNPs, which dramatically alter the expression or the activity of a target protein, can sometimes have a real clinical relevance (odds ratios > 5), usually to predict drug side effects. Only few examples, such as TPMT and CYP2C9 genetic polymorphisms, can illustrate this rare situation. Unfortunately, less than 1% of the population is concerned by these rare SNPs, and genotyping can only explain a small part of the variability of the response to a single drug. Beside the impressive mass of data available for pharmacogenetics, it is surprising to observe its poor development in routine medical practice. This discrepancy relies mainly on educational and methodological problems, which might be solved in the decade. To promote pharmacogenetics in routine medical practice, large prospective randomized trials are needed to demonstrate that pharmacogenetic orientated prescription can sometimes predict drug response without dramatic increase in costs.