Pharmacogenomics
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Stroke remains a leading cause of death worldwide and the first cause of disability in the western world. Ischemic stroke (IS) accounts for almost 80% of the total cases of strokes and is a complex and multifactorial disease caused by the combination of vascular risk factors, environment and genetic factors. ⋯ In this article we sought to review common single-gene disorders relevant to IS, summarize candidate gene and genome-wide studies aimed at discovering genetic stroke risk factors and subclinical phenotypes, and to briefly discuss pharmacogenetics related to stroke treatments. Genetics of IS is, in fact, one of the most promising research frontiers and genetic testing may be helpful for novel drug discoveries as well as for appropriate drug and dose selection for treatment of patients with cerebrovascular disease.
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The µ-opioid receptor is a primary target for clinically important opioid analgesics, including morphine, fentanyl and methadone. Many genetic variations have been identified in the human µ-opioid receptor MOP gene (OPRM1), and their implications have been reported in the effects of opioid drugs and susceptibility to drug dependence. Interestingly, agonistic and antagonistic opioid effects are inversely associated with the A118G polymorphism genotype. ⋯ The IVS1+A21573G, IVS1-T17286C, and TAA+A5359G polymorphisms in the OPRM1 gene may be associated with alcohol, opioid and tobacco dependence, respectively. However, some studies have failed to confirm the correlations between the polymorphisms and opioid effects and substance dependence. Further studies are needed to elucidate the molecular mechanisms underlying the effects of OPRM1 polymorphisms.
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Genomic variations influencing response to pharmacotherapy of pain are currently under investigation. Drug-metabolizing enzymes represent a major target of ongoing research in order to identify associations between an individual's drug response and genetic profile. Polymorphisms of the cytochrome P450 enzymes (CYP2D6) influence metabolism of codeine, tramadol, hydrocodone, oxycodone and tricyclic antidepressants. ⋯ Other candidate genes, such as those encoding (opioid) receptors, transporters and other molecules important for pharmacotherapy in pain management, are discussed; however, study results are often equivocal. Besides genetic variants, further variables, for example, age, disease, comorbidity, concomitant medication, organ function as well as patients' compliance, may have an impact on pharmacotherapy and need to be addressed when pain therapists prescribe medication. Although pharmacogenetics as a diagnostic tool has the potential to improve patient therapy, well-designed studies are needed to demonstrate superiority to conventional dosing regimes.
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The 1000 Genomes Project aims to provide detailed genetic variation data on over 1000 genomes from worldwide populations using the next-generation sequencing technologies. Some of the samples utilized for the 1000 Genomes Project are the International HapMap samples that are composed of lymphoblastoid cell lines derived from individuals of different world populations. ⋯ Although the coverage of the current HapMap data is generally high, the detailed map of human genetic variation promised by the 1000 Genomes Project will allow a more in-depth analysis of the contribution of genetic variation to drug response. Future studies utilizing this new resource may greatly enhance our understanding of the genetic basis of drug response and other complex traits (e.g., gene expression), therefore, help advance personalized medicine.
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Serious adverse drug reactions represent the sixth major cause of death in the USA, are the main reason for postmarketing drug withdrawal and represent billions of US dollars in costs every year in all developed countries. Some of these serious adverse drug reactions might be avoided by systematically screening for pharmacogenomic risk factors. ⋯ Recently published pharmacogenomic randomized, controlled and ongoing trials will progressively make genotyping tests, such as those for HLA-B*5701 (abacavir), TPMT (6-mercaptopurine), CYP2C9 plus VKORC1 (warfarin) and CYP3A5 (tacrolimus), mandatory. Parallel development of pharmacogenomic bed tests will certainly establish genetically-based prescriptions in routine medical practice.