Pharmacogenetics – Challenges and Opportunities Ahead

Pharmacogenetics, the study of the influence of genetic variation on drug response, and pharmacogenomics, the genome-wide and multifactorial extension of the term (the inclusive code PGx is used from here on), are central to the modern concept of personalized medicine. Although a " person-alized " approach has always been a hallmark of good medical practice, the new aspect is the extensive use of molecular data to tailor drug therapy to the individual patient, in order to maximize therapeutic benefit and to minimize adverse events. PGx developed as an academic discipline over the past six decades, during which a significant amount of astounding examples for pharmacologically relevant genotype-phenotype relationships have been worked out. Basic principles were established, technologies developed, and dozens of genes characterized that have to do with absorption, distribution, metabolism , and excretion (ADME) of drugs, but also receptors and other drug targets. Only during the past decade first serious attempts have been made to translate this knowledge into clinical practice. Rather suddenly, it became clear that translation is everything but easy. The reasons for these problems are manifold. It will require deeper scientific advances in various directions but also concerted medical, regulatory and social actions to realize the opportunities of PGx for better medical treatment. PGx is nurtured by two major streams of research, a basic one that aims to discover genetic variation and to understand biological genotype–phenotype correlations, and a clinically oriented one that builds up on basic knowledge to investigate genetic factors in relation to drug response phenotypes and to apply novel diagnostic tools to translate this into clinical care. Modern technology has revolutionized the speed and output of molecular discovery, providing us with new armament for research. Undoubtedly this will open up great opportunities. However, great challenges must be met in order to realize this potential for basic and clinical PGx. In basic PGx we would like to understand how genetic variation contributes to biological phenotypic variation. Over 300 ADME genes and even more drug target genes have been identified in the human genome 1. Only few of these have so far been systematically investigated, but even for the well characterized CYP, UGT, or some drug transporter genes, our knowledge is often fragmentary regarding both genetic and phenotypic variation. The current large-scale endeavors like the 1000-genomes project will uncover the existing genetic variation in all our genes across various racial groups within a few years. …