Drug Targets

Clearly, the extent of exposure to a pharmacological agent has a large impact on clinical outcomes; low exposure compromises efficacy, whereas high exposures result in toxicity. However, there are many examples of varied response to drugs in which the clinical outcomes do not correlate with blood or tissue levels of the drug and, therefore, do not arise from polymorphisms in genes controlling the absorption, distribution, or metabolism of the drug. In such instances, genetic variation might still contribute to varied drug response because polymorphisms can also occur in drug targets, as well as in downstream components of the target's signaling pathway. For a number of reasons, defining associations between drug targets, and drug response has been much more challenging and has seen fewer successes than the pharmacogenetics of drug-metabolizing enzymes.

Complex common disorders arise from the interplay of many factors, including multiple gene-gene and gene-environment interactions, making the role of variation in any given gene difficult to discern. Indeed, the complex common diseases that are the main contributors to society's disease burden are fundamentally different from classical, monogenic, "Mendelian" diseases. Monogenic disorders like cystic fibrosis arise from a defect in a single gene, and the presence of specific defects in the gene results in the expression of the disease phenotype . Conversely, a gene defect associated with complex common diseases is only one of many factors associated with the development of the disease, and although its presence increases the probability of the disease arising, it does not determine the phenotype. In addition, complex diseases are heterogeneous, with related but distinct etiologies. For example, an individual with an inflammatory disease like asthma might, among other gene defects, have a defect in the tumor necrosis factor (TNF) promoter resulting in exaggerated expression of TNF-a. Another asthmatic may share gene defects with the first, but harbor wild-type TNF alleles and express normal levels of TNF-a.

Although tremendous progress has been made in the past decade, our molecular understanding of the pathogenesis of common diseases is limited. Because we cannot define subgroups according the molecular etiology of the disease, complex common diseases are defined according to general phenotypic parameters. As a result, studies that investigate the association between genetic polymorphisms and drug response are confounded by allelic heterogeneity of the study population and often produce results that cannot be reproduced. A recent meta-analysis of 370 pharmacogenetic studies found that results from various studies frequently could not be confirmed in subsequent investigations (58). A number of factors likely contribute to this, including diversity among study populations (3,58).

Although this aspect of the field of pharmacogenetics is still in its infancy, there have been success stories involving the polymorphic drug targets and drug response. One example of variant drug targets influencing response involves the P2-adrenergic receptor and the treatment of asthma. One of the mainstays of asthma treatment is the activation of the P2-adrenergic receptor by specific agonists, which leads to the relaxation of bronchial smooth muscles and, consequently, bronchodilation (59). The P2-adrenergic receptor is coded for by ADRB2, in which multiple functional polymorphisms have been identified (60). Several variants of ADRB2 have been associated with altered response to P2-agonist treatment. Individuals homozygous for the glutamate allele at position 27 of the encoded protein have been found to have higher maximal venodilation in response to isoproternol than those with the glutamine allele (28,61). Individuals carrying two copies of a variant allele that codes for glycine instead of arginine in position 16 have been shown to have fivefold reduced response to P2 adrenergic agonists. Individuals heterozygous for the variant allele had a threefold reduced response (62,63).

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