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Journal of Clinical and Experimental Toxicology | Volume: 3
February 21-22, 2019 | Paris, France
International Conference on
Environmental Toxicology and Pharmacology
Computational integration of Human genetic data to evaluate AOP- specific susceptibility
Holly MMortensen
National Health and Environmental Effects Research Laboratory, USA
T
here is a need for approaches to define human variability
and susceptibility in response to environmental chemical
exposure. Direct estimation of the genetic contribution to
variability in susceptibility to environmental chemicals is
only possible in special cases where there is an observed
association between exposure and effect (e.g. genotype
and phenotype information). The availability of genetic data
sources makes it possible to indirectly estimate the relative
contribution of genetic variability to differential human
susceptibility. We developed a computational workflow
that integrates genetic and toxicological resources. This
approach implements the Adverse Outcome Pathway
(AOP) framework in order to integrate molecular targets
associated with AOPs with functional genomic annotations
and population allele frequencies. Resources include the EPA
internal Adverse Outcome Database (AOP-DB), and publicly
available resources, such as the AOP-wiki, Ensembl genomic
annotations, expression Quantitative Trait loci identified by
the GTEx consortium, and 1000 Genomes Project. With this
information it is possible to formulate predictions of genetic
susceptibility built upon established toxicological and
genetic knowledge that are specific to an adverse outcome.
The computational workflow was developed in R and built
around the Ensembl database interfaces (REST API and
biomaRt R package). It downloads, integrates, and analyzes
the available data sources when an AOP is given as input. Data
is processed in four steps: 1. Genetic identities of AOP key
events are extracted from the AOP-DB; 2. Nearby regulatory
annotations are downloaded from the Ensembl regulatory
build; 3. GTEx Expression quantitative trait loci are imported
for AOP-relevant tissue types; and 4. Allele and haplotype
frequency information is retrieved from the 1000 Genomes
Project stage 3 dataset. The analysis provides an estimate of
the degree of genetic variation at functionally relevant loci.
With ongoing AOP development, this automated workflow
will allow rapid assessment of outcome specific human
genetic susceptibility. This abstract does not reflect EPAPolicy.
e:
mortensen.holly@epa.govJ Clin Exp Tox, Volume 3
DOI: 10.4066/2630-4570-C1-006