Polymorphisms in Pharmacogenetics of Personalized Cancer Therapy

Therapy process of personalized cancer management covers surgery, chemotherapy, radiation therapy and targeted therapies. The choice of cancer chemotherapeutic agents and doses depends upon the location and stage of tumor, as well as the general state of the patient. On the chemotherapy, radiotherapy, and targeted therapy processes, pharmacogenetics offers customized solutions according to the personal genetic information. Especially for clinicians, genetic information obtained from polymorphism-based pharmacogenetic tests is highly crucial for the better prediction ability of drug response and life-threatening toxic reactions due to the narrow therapeutic index of cancer chemotherapeutic agents. Pharmacogenotyping utilizes different examination strategies, such as single nucleotide polymorphism analysis, somatic/germline mutation analysis and partial/full genome sequencing. The promising effect of pharmacogenetics on the solving of the individual variability in drug response and toxic reactions is being observed with the accumulation of the information that unravel the human genomic variations from large-scale population and multi-parameter-based pharmacogenetic studies of the post-genomic era. Polymorphisms contribute wide variations in human genome and may define how individuals respond to medications, either by changing the pharmacokinetics and pharmacodynamics of drugs or by altering the cellular response to therapeutic agents. To define the effect of polymorphisms on the targets of chemotherapeutics is necessary for the prediction of altered pharmacokinetics of therapeutic agents

Pharmacogenetics : the science of predictive clinical pharmacology

The study of pharmacogenetics has expanded from what were initially casual family-based clinical drug response observations, to a fully-fledged science with direct therapeutic applications, all within a time-span of less than 60 years. A wide spectrum of polymorphisms, located within several genes, are now recognised to influence the pharmacokinetics and pharmacodynamics of the majority of drugs within our therapeutic armamentarium. This information forms the basis for the new development of pharmacogenetic genotyping tests, which can be used to predict the therapeutic and/or adverse effects of a specific drug in a particular patient. Pharmacogenetic-guided, patient targeted therapy has now become the developing fulcrum of personalized medicine, as it provides the best means to optimize benefit/risk ratio in pharmacological management.peer-reviewe

Polymorphic drug metabolising enzymes:Assessment of activities by phenotyping and genotyping in clinical pharmacology

Drug effects (pharmacodynamics) are determined by drug concentration at target site and the affinity of the drug for a target. Pharmacogenetics describes inherited differences in drug metabolising enzyme activities and differences in drug transporters and receptors.Answers were sought on the following questions:1. What is the value of genotyping on polymorphic drug metabolising enzymes compared to the classical phenotyping stategies?2. What is the situation concerning CYP2D6 and CYP2C19 polymorphism in the Dutch population?3. Is knowledge of the individual metaboliser status of CYP2D6 or CYP2C19 valuable in clinical pharmacological research and practice of pharmacotherap

Harvesting Candidate Genes Responsible for Serious Adverse Drug Reactions from a Chemical-Protein Interactome

Identifying genetic factors responsible for serious adverse drug reaction (SADR) is of critical importance to personalized medicine. However, genome-wide association studies are hampered due to the lack of case-control samples, and the selection of candidate genes is limited by the lack of understanding of the underlying mechanisms of SADRs. We hypothesize that drugs causing the same type of SADR might share a common mechanism by targeting unexpectedly the same SADR-mediating protein. Hence we propose an approach of identifying the common SADR-targets through constructing and mining an in silico chemical-protein interactome (CPI), a matrix of binding strengths among 162 drug molecules known to cause at least one type of SADR and 845 proteins. Drugs sharing the same SADR outcome were also found to possess similarities in their CPI profiles towards this 845 protein set. This methodology identified the candidate gene of sulfonamide-induced toxic epidermal necrolysis (TEN): all nine sulfonamides that cause TEN were found to bind strongly to MHC I (Cw*4), whereas none of the 17 control drugs that do not cause TEN were found to bind to it. Through an insight into the CPI, we found the Y116S substitution of MHC I (B*5703) enhances the unexpected binding of abacavir to its antigen presentation groove, which explains why B*5701, not B*5703, is the risk allele of abacavir-induced hypersensitivity. In conclusion, SADR targets and the patient-specific off-targets could be identified through a systematic investigation of the CPI, generating important hypotheses for prospective experimental validation of the candidate genes

Forensic Pharmacogenetics

Current pharmacogenetics research in the clinical and medico-legal settings provides new options for disease treatment and prevention of ADR avoiding correlated death, and for screening interactions with the polymorphic P450 enzymes early on in drug development

A Structure-Based Approach for Mapping Adverse Drug Reactions to the Perturbation of Underlying Biological Pathways

Adverse drug reactions (ADR), also known as side-effects, are complex undesired physiologic phenomena observed secondary to the administration of pharmaceuticals. Several phenomena underlie the emergence of each ADR; however, a dominant factor is the drug's ability to modulate one or more biological pathways. Understanding the biological processes behind the occurrence of ADRs would lead to the development of safer and more effective drugs. At present, no method exists to discover these ADR-pathway associations. In this paper we introduce a computational framework for identifying a subset of these associations based on the assumption that drugs capable of modulating the same pathway may induce similar ADRs. Our model exploits multiple information resources. First, we utilize a publicly available dataset pairing drugs with their observed ADRs. Second, we identify putative protein targets for each drug using the protein structure database and in-silico virtual docking. Third, we label each protein target with its known involvement in one or more biological pathways. Finally, the relationships among these information sources are mined using multiple stages of logistic-regression while controlling for over-fitting and multiple-hypothesis testing. As proof-of-concept, we examined a dataset of 506 ADRs, 730 drugs, and 830 human protein targets. Our method yielded 185 ADR-pathway associations of which 45 were selected to undergo a manual literature review. We found 32 associations to be supported by the scientific literature

GENOTYPES FREQUENCIES OF RS9923231 AND RS7294 SNPS IN THE VKORC1 GENE AMONG EMIRATIS AND THEIR IMPLICATIONS FOR WARFARIN DOSAGE

Warfarin is the most commonly used oral anticoagulant medication given as a prophylaxis and/or treatment of venous and arterial thromboembolic disorders. Warfarin doses vary up to 10-fold among patients due to pharmacokinetics, pharmacodynamics and pharmacogenomics factors. In addition, Warfarin has a low therapeutic index with the risk of developing serious side effects such as severe bleeding or failure of therapy. Therefore, the main challenge to achieve the therapeutic goal in Warfarin treatment is estimating the appropriate dose for each patient. It is estimated that pharmacogenomic factors contribute to more than 60% of dose variability. The gene encoding for the target enzyme of Warfarin, vitamin K epoxide reductase complex 1 (VKORC1), is a highly polymorphic gene and contributes to about 30% of this variability. The US Food and Drug Administration (FDA) recommends genetic testing to determine the VKORC1 genotype prior to using Warfarin. However, there are no data on VKORC1 alleles and genotypes or their frequencies among Emiratis. Therefore, the current approach is trial and error with warfarin doses which might lead to some serious complications for patients receiving this medication. In this thesis, we used PCR amplification and direct DNA Sanger sequencing to genotype the two most important variants in VKORC1 genes (namely, rs9923231 and rs7294). The sample consisted of 117 healthy Emirati nationals as control and 96 patients on stable Warfarin therapy. The alleles and genotypes frequencies were determined for both groups. In addition, the daily Warfarin maintenance dose for patients was examined for associations with the VKORC1 genotypes at the rs9923231 and rs7294positions. There was no significant difference in allele frequencies between the controls and patients for either SNP. The vii genotypes frequencies for rs9923231 were 25%, 48.4%, 26% for GG, GA, AA genotypes, respectively. In addition, genotypes frequencies for rs7294 variant were 44%, 44%, 12% for GG, GA, AA genotypes, respectively. Crucially, both VKORC1 polymorphisms were found to be strongly associated with the Warfarin doses required to achieve the target international normalized ratio INR (p \u3c 0.0001). The results of this study confirm the suitability of VKORC1 genotyping to guide the use of the appropriate Warfarin dosage for Emiratis

Serotonin System Gene Polymorphisms Are Associated with Impulsivity in a Context Dependent Manner

Impulsivity is a risk factor for adverse outcomes and characterizes several psychiatric disorders and risk for suicide. There is strong evidence that genetic variation influences individual differences in impulsivity, but the details are not yet understood. There is growing interest in better understanding the context dependency of genetic effects that is reflected in studies examining gender specificity, gene × environment interaction and epistasis (gene-gene interaction). In a cross-sectional study we examined whether polymorphisms in six serotonin system candidate genes and the experience of early life trauma (age 0–12) were associated with individual differences in impulsivity in a nonclinical sample of Caucasian university students (N = 424). We specifically tested potential gender specific, gene-gene, and gene × environment (early life trauma) effects. In our main analyses with Barratt Impulsiveness Scale (BIS-11) total score, there were significant (i.e., p \u3c .01 and False Discovery Rate \u3c .10) interactions between (1) gender and TPH2 (rs1386483) genotype; (2) gender and HTR2A (rs6313) genotype; and epistatic interactions among (3) 5-HTTLPR and MAOA uVNTR; (4) 5-HTTLPR and rs6313 and (5) HTR1B (rs6296) and rs6313 genotypes. Our results strongly support the explicit investigation of context-dependent genetic effects on impulsivity and may help to resolve some of the conflicting reports in the literature

Impact of Transporter Polymorphisms on Drug Development: Is It Clinically Significant?

Drug transporters are becoming increasingly recognized as relevant to the drug development process. This may be a reflection of increasing target complexity and the need for high-affinity interaction with drug targets that minimize off-target side effects. Moreover, as new molecular entities (NMEs) become larger in size and amphipathic in nature, interaction with drug transporters, both uptake as well as efflux, becomes increasingly likely. In some cases transporters may limit the absorption or organ-specific entry of NMEs, whereas in other cases transporters may enhance their absorption or tissue accumulation. Indeed, in some cases, transporters may prove to be a therapeutic target. Accordingly, a better understanding of potentially clinically relevant drug transporter polymorphisms earlier in the drug development process is highly desirable. In this review we examine key transporters that are important to the absorption, distribution, and excretion of a large number of drugs in clinical use. Importantly, we provide our assessment of the potential impact of known polymorphisms in such transporters and discuss whether there is sufficient evidence to incorporate these polymorphisms in the drug development process