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INTRODUCTION

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Pharmacogenetics is the study of the genetic basis for variation in drug response. In this broadest sense, pharmacogenetics encompasses pharmacogenomics, which employs tools for surveying the entire genome to assess multigenic determinants of drug response. Individuals differ from each other approximately every 300-1000 nucleotides, with an estimated total of 10 million single nucleotide polymorphisms (SNPs; single base pair substitutions found at frequencies ≥1% in a population) and thousands of copy number variations in the genome. Identifying which of these variants or combinations of variants have functional consequence for drug effects is the task of modern pharmacogenetics.

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IMPORTANCE OF PHARMACOGENETICS TO VARIABILITY IN DRUG RESPONSE

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Drug response is considered to be a gene-by-environment phenotype. An individual's response to a drug depends on the complex interplay between environmental factors (e.g., diet, age, infections, drugs, exercise level, occupation, exposure to toxins, tobacco, and alcohol use) and genetic factors (e.g., gender, variants of drug transporters, and drug metabolizing enzymes expressed). Variation in drug response therefore may be explained by variation in environmental and genetic factors, alone or in combination.

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Drug metabolism is highly heritable, with genetic factors accounting for most of the variation in metabolic rates for many drugs.

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Comparison of intra-twin vs inter-pair variability suggests that ~75-85% of the variability in pharmacokinetic half-lives for drugs that are eliminated by metabolism is heritable. Extended kindreds may be used to estimate heritability. Inter- vs. intra-family variability and relationships among members of a kindred are used to estimate heritability. Using this approach with lymphoblastoid cells, cytotoxicity from chemotherapeutic agents was shown to be heritable, with ~20-70% of the variability in sensitivity to 5-fluorouracil, cisplatin, docetaxel, and other anticancer agents estimated as inherited.

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For "monogenic" phenotypic traits, it is often possible to predict phenotype based on genotype. Several genetic polymorphisms of drug metabolizing enzymes result in monogenic traits. Based on a retrospective study, 49% of adverse drug reactions were associated with drugs that are substrates for polymorphic drug metabolizing enzymes, a proportion larger than estimated for all drugs (22%) or for top-selling drugs (7%). Prospective genotype determinations may result in the ability to prevent adverse drug reactions. Defining multigenic contributors to drug response will be much more challenging. For some multigenic phenotypes, such as response to antihypertensives, the large numbers of candidate genes will necessitate a large patient sample size to produce the statistical power required to solve the "multigene" problem.

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GENOMIC BASIS OF PHARMACOGENETICS

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PHENOTYPE-DRIVEN TERMINOLOGY

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A trait (e.g., CYP2D6 "poor metabolism") is deemed autosomal recessive if the responsible gene is located on an autosome (i.e., it is not sex-linked) and a distinct phenotype is evident only with nonfunctional alleles on both the maternal and paternal chromosomes. An autosomal recessive trait does not appear in heterozygotes. A trait is deemed codominant if heterozygotes exhibit a phenotype that is intermediate to that of ...

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