Pharmacogenomics Of Adverse Drug Reactions Research Articles

Genomic variations associated with risk and protection against vincristine-induced peripheral neuropathy in pediatric cancer patients

Vincristine-induced peripheral neuropathy is a common and highly debilitating toxicity from vincristine treatment that affects quality of life and often requires dose reduction, potentially affecting survival. Although previous studies demonstrated genetic factors are associated with vincristine neuropathy risk, the clinical relevance of most identified variants is limited by small sample sizes and unclear clinical phenotypes. A genome-wide association study was conducted in 1100 cases and controls matched by vincristine dose and genetic ancestry, uncovering a statistically significant (p < 5.0 × 10−8) variant in MCM3AP gene that substantially increases the risk of neuropathy and 12 variants protective against neuropathy within/near SPDYA, METTL8, PDE4D, FBN2, ZFAND3, NFIB, PAPPA, LRRTM3, NRG3, VTI1A, ARHGAP5, and ACTN1. A follow-up pathway analysis reveals the involvement of four key pathways, including nerve structure and development, myelination, neuronal transmission, and cytoskeleton/microfibril function pathways. These findings present potential actionable genomic markers of vincristine neuropathy and offer opportunities for tailored interventions to improve vincristine safety in children with cancer. This study is registered with ClinicalTrials.gov under the title National Active Surveillance Network and Pharmacogenomics of Adverse Drug Reactions in Children (ID NCT00414115, registered on December 21, 2006).

Review on Databases and Bioinformatic Approaches on Pharmacogenomics of Adverse Drug Reactions.

Pharmacogenomics has been used effectively in studying adverse drug reactions by determining the person-specific genetic factors associated with individual response to a drug. Current approaches have revealed the significant importance of sequencing technologies and sequence analysis strategies for interpreting the contribution of genetic variation in developing adverse reactions. Advance in next generation sequencing and platform brings new opportunities in validating the genetic candidates in certain reactions, and could be used to develop the preemptive tests to predict the outcome of the variation in a personal response to a drug. With the highly accumulated available data recently, the in silico approach with data analysis and modeling plays as other important alternatives which significantly support the final decisions in the transformation from research to clinical applications such as diagnosis and treatments for various types of adverse responses.

Advances in the Pharmacogenomics of Adverse Drug Reactions.

Rapid developments in pharmacogenomics have been noticeable in recent years, and much of this knowledge has improved understanding of adverse drug reactions. This improved knowledge has largely been the result of improved sequencing technologies and falling costs in this area, as well as improved statistical techniques to analyse the data derived from studies. While the genetic reasons behind adverse drug reactions are becoming better understood, translation of this knowledge, particularly in terms of biomarkers that might be clinically applicable at the bedside, has been more difficult. Understanding of the technologies and their application is limited among practising clinicians. The cost of some of the technologies available may also be prohibitive in stretched healthcare economies. As education about the potential for applying pharmacogenomics improves and costs fall, understanding of adverse drug reactions and application of this knowledge in a clinical setting should improve.

Pharmacogenomics of adverse drug reactions

Considerable progress has been made in identifying genetic risk factors for idiosyncratic adverse drug reactions in the past 30 years. These reactions can affect various tissues and organs, including liver, skin, muscle and heart, in a drug-dependent manner. Using both candidate gene and genome-wide association studies, various genes that make contributions of varying extents to each of these forms of reactions have been identified. Many of the associations identified for reactions affecting the liver and skin involve human leukocyte antigen (HLA) genes and for reactions relating to the drugs abacavir and carbamazepine, HLA genotyping is now in routine use prior to drug prescription. Other HLA associations are not sufficiently specific for translation but are still of interest in relation to underlying mechanisms for the reactions. Progress on non-HLA genes affecting adverse drug reactions has been less, but some important associations, such as those of SLCO1B1 and statin myopathy, KCNE1 and drug-induced QT prolongation and NAT2 and isoniazid-induced liver injury, are considered. Future prospects for identification of additional genetic risk factors for the various adverse drug reactions are discussed.

Pharmacogenomics of adverse drug reactions: implementing personalized medicine

Pharmacogenomics aims to investigate the genetic basis of inter-individual differences in drug responses, such as efficacy, dose requirements and adverse events. Research in pharmacogenomics has grown over the past decade, evolving from a candidate-gene approach to genome-wide association studies (GWASs). Genetic variants in genes coding for drug metabolism, drug transport and more recently human-leukocyte antigens (HLAs) have been linked to inter-individual differences in the risk of adverse drug reactions (ADRs). The tight association of specific HLA alleles with Stevens-Johnson syndrome, toxic epidermal necrolysis, drug hypersensitivity syndrome and drug-induced liver injury underscore the importance of HLA in the pathogenesis of these idiosyncratic drug hypersensitivity reactions. However, as with the search for the genetic basis for common diseases, pharmacogenomic research, including GWAS, has so far been a disappointment in discovering major gene variants responsible for the efficacy of drugs used to treat common diseases. This review focuses on the pharmacogenomics of ADRs, the underlying mechanisms and the potential use of genomic biomarkers in clinical practice for dose adjustment and the avoidance of drug toxicity. We also discuss obstacles to the implementation of pharmacogenomics and the direction of future translational research.

Pharmacogenomics of Adverse Drug Reactions: Practical Applications and Perspectives

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. During the last few years, regulatory agencies introduced pharmacogenomics labels for several drugs, but although a priori genetic testing remains advised or recommended, it is seldom compulsory due to poor evidence-based medicine knowledge. 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.

Pharmacogenetics and Pharmacogenomics: Adverse Drug Reactions

The European Science Foundation and University of Barcelona (ESF-UB) conference on pharmacogenetics and pharmacogenomics of adverse drug reactions (ADRs) held in the sunny Spanish town of St Feliu De Guixols in June 2008 was a great opportunity to exchange views on current issues in pharmacogenetics, particularly its role in the difficult task of predicting and preventing ADRs. The meeting was chaired by Professor Munir Pirmohamed (University of Liverpool, UK), with Professor Laurent Becquemont (University Paris Sud, France) as vicechair. Apart from meeting researchers from 27 countries (66% from 15 EU countries) and fruitful scientific and clinical discussions in a friendly atmosphere, added pleasure came from the beautiful setting of the dramatic Eden Roc sea resort and delicious Mediterranean food. The conference was opened by Munir Pirmohamed who highlighted several questions currently being addressed by pharmacogenetic researchers interested in ADRs, which were discussed through various sessions at the conference:

Defining Targets for Investigating the Pharmacogenomics of Adverse Drug Reactions to Antifungal Agents

Adverse drug reactions (ADRs) associated with antifungal therapy are major problems in patients with invasive fungal infections. Whether by clinical history or patterns of genetic variation, the identification of patients at risk for ADRs should result in improved outcomes while minimizing deleterious side effects. A major contributing factor to ADRs with antifungal agents relates to drug distribution, metabolism and excretion. Genetic variation in key genes can alter the structure and expression of genes and gene products (e.g., proteins). Thus far, the effort has focused on identifying polymorphisms with either empirical or predicted in silico functional consequences; the best candidate genes encode phase I and II drug-metabolizing enzymes (e.g., CYP2C19 and N-acetyltransferase), plasma proteins (albumin and lipoproteins) and drug transporters (P-glycoprotein and multidrug resistance proteins), which can affect the disposition of antifungal agents, eventually leading to dose-dependent (type A) toxicity. Less is known regarding the key genes that interact with antifungal agents, resulting in idiosyncratic (type B) ADRs. The possible role of certain gene products and genetic polymorphisms in the toxicities of antifungal agents are discussed in this review. The preliminary data address the following: low-density lipoproteins and cholesteryl ester transfer protein in amphotericin B renal toxicity; toll-like receptor 1 and 2 in amphotericin B infusion-related ADRs; phosphodiesterase 6 in voriconazole visual adverse events; flavin-containing monooxygenase, glutathione transferases and multidrug resistance proteins 1 and 2 in ketoconazole and terbinafine hepatotoxicity; CYP enzymes and P-glycoprotein in drug interactions between azoles and coadministered medications; multidrug resistance proteins 8 and 9 on 5-flucytosine bone marrow toxicity; and mast cell activation in caspofungin histamine release. This will focus on high-priority candidate genes, which could provide a starting point for molecular studies to elucidate the potential mechanisms for understanding toxicity associated with antifungal drugs as well as identifying candidate genes for large population prospective genetic association studies.