Pharmacogenetic analysis combines the principles and tools of classical and molecular genetics. Adherence to the principles of classical (Mendelian) genetics seeks to partition the pharmacological variation into its hereditary and environmental components. To this end, profiles of information on distinct drug responder phenotypes are collected and analyzed for the variation between individuals, between identical and fraternal twins, within families, and in larger populations. A small degree of variation in response within individuals compared to that observed between individuals, within identical twins compared to that in fraternal twins, clustering of phenotypes within families, and segregation of phe-notypes according to Mendelian rules indicates that heritability contributes to phenotypic differences in response. The agreement between the observed numbers of specific drug responder phenotypes and those expected by the Hardy-Weinberg law of population genetics and the association of specific drug responder phenotypes with specific genotypes provides additional support for heritability.
Pharmacogenetic disorders, like genetic diseases, are due to structural lesions of DNA sequences as small as a single base up to an entire chromosome, and DNA technologies are capable of detecting lesions throughout the entire range of interest. These molecular tools enable investigators to produce accurate copies of genes and express the proteins they encode in quantities sufficient for biochemical and pharmacological characterization, permitting an altered response to a therapeutic agent or another exogenous chemical to be associated with its molecular genetic basis.
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