Pharmacogenetics: Implementing personalized medicine

Pharmacogenetics and pharmacogenomics have been widely recognized as fundamental steps toward personalized medicine. They deal with genetically determined variants in how individuals respond to drugs, and hold the promise to revolutionize drug therapy by tailoring it according to individual genotypes. The clinical need for novel approaches to improve drug therapy derives from the high rate of adverse reactions to drugs and their lack of efficacy in many individuals that may be predicted by pharmacogenetic testing. Significant advances in pharmacogenetic research have been made since inherited differences in response to drugs such as isoniazid and succinylcholine were explored in the 1950s. The clinical utility and applications of pharmacogenetics and pharmacogenomics are at present particularly evident in some therapeutic areas (anticancer, psycotrophic, and anticoagulant drugs). Recent evidence derived from several studies includes screening for thiopurine methyl transferase or uridine 5′-diphospho-glucuronosyl-transferase 1A1 gene polymorphisms to prevent mercaptopurine and azathioprine or irinotecan induced myelo-suppression, respectively. Also there is a large body of information concerning cytochrome P450 gene polymorphisms and their relationship to drug toxicity and response. Further examples include screening the presence of the HLA-B*5701 allele to prevent the hypersensitivity reactions to abacavir and the assessment of the human epidermal growth factor receptor (HER- 2) expression for trastuzumab therapy of breast cancer or that of KRAS mutation status for cetuximab or panitumumab therapy in colorectal cancer. Moreover, the application of pharmacogenetics and pharmacogenomics to therapies used in the treatment of osteoarticular diseases (e.g. rheumatoid arthritis, osteoporosis) holds great promise for tailoring therapy with clinically relevant drugs (e.g. disease-modifying antirheumatic drugs, vitamin D, and estrogens). Although the classical candidate gene approach has helped unravel genetic variants that influence clinical drug responsiveness, gene-wide association studies have recently gained attention as they enable to associate specific genetic variants or quantitative differences in gene expression with drug response. Although research findings are accumulating, most of the potential of pharmacogenetics and pharmacogenomics remains to be explored and must be validated in prospective randomized clinical trials. The genetic and molecular foundations of personalized medicine appear solid and evidence indicates its growing importance in healthcare.