Insights from Genome-Wide Association Studies of Drug Response
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Abstract:
Early genome-wide association studies (GWAS) using relatively small samples have identified both rare and common genetic variants with large impact on severe adverse drug reactions, dosing, and efficacy. Here we outline the challenges and recent successes of the GWAS approach in disease genetics and the ways in which these can be applied to pharmacogenomics for biological discovery, determination of heritability, and personalized treatment. We highlight that the genetic architecture of drug efficacy reflects a complex trait yet that of adverse drug reactions more closely mirrors the architecture of Mendelian diseases and how this difference affects future study design. Given that multiple layers of biological data are increasingly available on large samples from biorepositories linked to electronic medical records, GWAS will remain a key component of the systems biology approach to uncovering small to moderate genetic determinants of drug response; these discoveries should move us closer to a personalized approach to health care.Keywords:
Genome-wide Association Study
Pharmacogenomics
Genetic architecture
Genetic Association
Mendelian inheritance
Drug response
Missing heritability problem
Trait
Race and ancestry have long been associated with differential risk and outcomes to disease as well as responses to medications. These differences in drug response are multifactorial with some portion associated with genomic variation. The field of pharmacogenomics aims to predict drug response in patients prior to medication administration and to uncover the biological underpinnings of drug response. The field of human genetics has long recognized that genetic variation differs in frequency between ancestral populations, with some single nucleotide polymorphisms found solely in one population. Thus far, most pharmacogenomic studies have focused on individuals of European and East Asian ancestry, resulting in a substantial disparity in the clinical utility of genetic prediction for drug response in US minority populations. In this review, we discuss the genetic factors that underlie variability to drug response and known pharmacogenomic associations and how these differ between populations, with an emphasis on the current knowledge in cardiovascular pharmacogenomics.
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Pharmacogenomics investigates the influence of genetics on drug response, with the ultimate aim of giving patients the right drug at the right dose and at the right time. Almost all patients carry one or more genetic variants which can significantly alter their response to a drug, causing anything from a lack of response to serious, even fatal, drug toxicity. This chapter introduces the reader to this field of precision medicine, using well-characterized examples which are already used in the clinic to optimize drug prescribing. It also introduces the star allele nomenclature system and describes the process of building a solid evidence base for clinical pharmacogenomic guidelines. The importance of working with diverse cohorts is critical when designing pharmacogenomics studies. Finally, it presents several barriers to the implementation of pharmacogenomics in the clinic and discusses methods for overcoming these.
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This chapter contains sections titled: The Promise of Pharmacogenomics Combinatorial Pharmacogenomics Identifying Useful Marker Combinations for the Prediction of Individual Drug Response Data Mining Tools Available to Predict Individual Drug Response from Genetic Data Applications of Data Mining Tools in Pharmacogenomics Conclusion References
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The practice of anesthesia has long been considered an art and a science, with interpatient variability in drug response being the rule, rather than the exception. Pharmacogenomics, which studies the role of genetics in drug response, is emerging as a discipline that may impact anesthetic management. The purpose of this review is to provide clinicians with basic knowledge related to pharmacogenomics and its implications in anesthesia. This review focuses on pharmacogenomics related to commonly used drugs in anesthesia. Pharmacogenomics as a predictor of drug response is increasingly used in medicine and drug development. By expanding the knowledge base of anesthesia providers, pharmacogenomic considerations have the potential to improve therapeutic outcomes and individualize drug therapy, while avoiding toxic effects and treatment failure. However, because pharmacogenomics may not fully explain variability in drug response, implementation should be in conjunction with traditional anesthesia considerations.
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The first observations of inherited differences in drug effects in the 1950s led to the recognition of a genetic basis for drug response. With the development of genetics and molecular biology, it became clear that certain drug responses could be associated with specific genetic variations or polymorphisms. There are now examples of polymorphisms that affect response to drugs ranging from common analgesics to chemotherapeutics. The goal of pharmacogenetics is to identify polymorphisms that can serve as predictive markers of drug response. This review summarizes how existing pharmacogenomic technologies can be applied advantageously throughout drug development to bring drugs successfully to market along with diagnostic tests that ensure their appropriate use.
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