FIGURE 4-7 Effect of genotype on response to estrogen hormone replacement therapy. Depicted are pretreatment (base line) and posttreatment (follow-up) high-density lipoprotein (HDL) cholesterol levels in women of the C/C vs. C/T or T/T HMG-CoAreductase genotype.

POLYMORPHISM-MODIFYING DISEASES AND DRUG RESPONSES Some genes may affect the underlying disease being treated without directly interacting with the drug. Modifier polymorphisms are important for the de novo risk of some events and for the risk of drug-induced events. The MTHFR polymorphism, for example, is linked to homocysteinemia, which in turn affects thrombosis risk. The risk of a drug-induced thrombosis is dependent not only on the use of prothrombotic drugs, but on environmental and genetic predisposition to thrombosis, which may be affected by germline polymorphisms in MTHFR, factor V, and prothrombin. These polymorphisms do not directly affect the pharmacokinetics or pharmacodynamics of prothrombotic drugs, such as glucocorticoids, estrogens, and asparaginase, but may modify the risk of the phenotypic event (thrombosis) in the presence of the drug.

Likewise, polymorphisms in ion channels (e.g., HERG, KvLQTl, Mink, and MiRP1) may affect the overall risk of cardiac dysrhythmias, which may be accentuated in the presence of a drug that can prolong the QT interval (e.g., macrolide antibiotics, antihistamines). These modifier polymorphisms may impact on the risk of "disease" phenotypes even in the absence of drug challenges; in the presence of drug, the "disease" phenotype may be elicited.

In addition to the underlying germline variation of the host, tumors also harbor somatically-acquired mutations, and the efficacy of some anticancer drugs depends on the genetics of both the host and the tumor. For example, non-small-cell lung cancer is treated with inhibitors of epidermal growth factor receptor (EGFR), such as gefitinib. Patients whose tumors have activating mutations in the tyrosine kinase domain of EGFR appear to respond better to gefitinib than those without such mutations. Thus, the receptor is altered, and at the same time, individuals with the activating mutations may be considered to have a distinct category of non-small-cell lung cancer.

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