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Limitations of Genotype-Phenotype Association Studies
Although genotype-phenotype association studies are seemingly simple, in practice,
they are prone to potential diffi culties and problems. Plausible biologic context con-
sistent with allele function, low P values, independent replication of an initial study,
rigorous phenotypic assessment and genotyping, selection of appropriate and suffi -
ciently large populations, and appropriate statistical analysis are all critical to the
confi dence that can be placed in a proposed association. Because such criteria are
not always met, the risk of false-positive or false-negative errors is always possible.
Metabolomics Bridges the Gap Between Genotype and Phenotype
as described in Chap. 6.
Molecular Toxicology in Relation to Personalized Medicines
The term molecular toxicology covers the use of molecular diagnostic methods for
studying the toxic effects of drugs. Toxicology studies are an important part of the
drug development process. During preclinical testing, pharmacogenetics methods
can be applied to determine drug toxicity at the molecular level during animal stud-
ies or to provide an alternative to in vitro/in vivo assays. A number of assays have
been developed to assess toxicity, carcinogenicity, and other genetic responses that
arise when living cells are exposed to various chemical compounds. Two important
categories of molecular toxicology are: toxicogenomics (use of genomic technolo-
gies for the study of toxicology) and toxicoproteomics (see Chap. 5 ). The object of
these studies is to detect suitable drug candidates at an early stage of the discovery
process and to reduce the number of failures in later stages of drug development.
Toxicogenomics
Toxicogenomics is the application of genomic technology to toxicology to study
how the entire genome is involved in biological responses of organisms exposed to
environmental toxicants/stressors. Researchers use toxicogenomic data to determine
how human genes respond and interact with each other during different states of
health, disease and challenges from toxicants. This discipline is the focus of study of
the National Center for Toxicogenomics (Bethesda, MD), a division of the National
Institute of Environmental Health Sciences of the National Institutes of Health of
USA. Technologies to measure and compare gene expression levels are being
increasingly applied to in vitro and in vivo drug toxicology and safety assessment.
Two main technologies for toxicogenomics are those used for measuring gene
expression and SNP genotyping. SNPs and other genetic differences have been
directly linked to variation in drug metabolism. Various technologies for SNP geno-
typing have already been described in Chap. 2. Use of microarray technologies for
toxicogenomics will be described later in this chapter.
4 Pharmacogenetics