Applications of Toxicogenomic Technologies to Predictive Toxicology and Risk Assessment (2007) / Chapter Skim
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6 Application to Analyzing Variation in Human Susceptibility
6 Application to Analyzing Variation in Human Susceptibility
Pages 92-106
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From page 92... ...
The remarkable advances in our ability to rapidly detect thousands of genetic variations have led to high expectations for the ability to discover and then apply critical new information to understand human susceptibility to disease. More than 6 million single nucleotide polymorphisms (SNPs)
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From page 93... ...
This chapter reviews the state of the art in these areas and assesses future needs and challenges. Variation in Gene Sequence Gene-environment interactions refer to effects in which human genetic variability governs differential responses to environmental exposures such as the examples already discussed in this chapter.
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From page 94... ...
. Moreover, studies of the effects of the Q192R polymorphism in the human PON1 gene introduced into transgenic mice illustrate the power of using animal models to understand the effects of human genetic variations on differential toxic ity to pesticides in genetic subgroups of the human population (Cole et al.
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From page 95... ...
The current emphasis on identifying single gene mutations associated with differential response to environmental exposures only delays understanding the distribution of genetic and genomic risks in human populations. Advances in bioinformatics can play a
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From page 96... ...
. Comparative sequence analysis methods are also becoming increasingly valuable to human genetic studies because they provide a way to rank-order SNPs based on their potential deleterious effects on protein function or gene regulation (Z.
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From page 97... ...
Another way to assess human variability is to look downstream of the gene sequence or its epigenetic modification to the amount of mRNA expressed by the genes, examining differences in amount expressed rather than just differences in what is expressed. The variability in gene expression can reflect individual variability due to mutations in the gene, its promoter or other regulatory regions, and other modifications of expression such as epigenetic effects.
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From page 98... ...
Using Animal Models to Identify and Evaluate Susceptibility Genes Animal models offer important experimental research opportunities to understand how genetic factors influence differential response to toxicologic agents. Animal models are advantageous as a first line of research because they are less expensive, less difficult, and less time-consuming than human studies.
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From page 99... ...
First, inbred and wild-derived inbred mice allow research to focus on the mechanisms of resistance and clear distinctions in susceptibility among inbred strains of mice. Study of inbred mouse strains can also be advantageous because, unlike humans, their polymorphisms often become "fixed" in a population (carried by all the mice)
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From page 100... ...
The goal is to breed current inbred mouse strains to create a more genetically heterogeneous, yet stable, resource for examining polygenic networks and interactions among genes, environment, and other factors. Existing resources optimized to study the actions of isolated genetic loci on a fixed background are less effective for studying the complex interactions among genetic factors that are likely to give rise to a substantial proportion of human susceptibility.
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From page 101... ...
As discussed above, differences in gene expression due to epigenetic factors are increasingly recognized as an important basis for individual variation in susceptibility and disease (Scarano et al.
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From page 102... ...
Second, the understanding of the distribution of SNPs in the human gene pool is only beginning, and accurately typing large numbers of SNPs remains a work in progress. Multistaged research strategies (for example, linkage analysis to identify potential genomic regions followed by positional candidate gene studies or genome scans using tag SNPs followed by fine SNP mapping; see Chapter 2)
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From page 103... ...
Unlike the toxicogenomic studies being carried out in animal models, which often rely on inbred strains, humans have a much higher level of genetic variability. This natural human variability makes largescale epidemiologic studies imperative to scientific and policy development and it makes the understanding of disease risk incredibly complex.
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From page 104... ...
Animal models provide an important experimental method for identifying and characterizing genetic factors associated with increased susceptibility to toxicity from chemical exposure. There is substantial evidence that genetic variations in many genes influence individual response to toxic agents.
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From page 105... ...
Animal Models 3. Use animal models to identify genes associated with variability in toxicity and to validate causal mechanisms underlying human gene-environment interactions.
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From page 106... ...
7. Use existing environmental cohort studies and clinical drug trials to investigate the impact of genetic variations on variation in response to a wide range of chemical exposures and pharmaceutical therapies.
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