Use of Biological Knowledge to Inform The Analysis of Gene-Gene Interactions Involved in Modulating Virologic Failure with Efavirenz-Containing Treatment Regimens in Art-Naive Actg Clinical Trials Participants

Benjamin J. Grady1, Eric C. Torstenson1, Paul J. Mclaren2, Paul W. De Bakker2, David W. Haas3, Gregory K. Robbins4, Roy M. Gulick5, Richard Haubrich6, Heather Ribaudo7, Marylyn D. Ritchie1*

1Center for Human Genetics Research, Vanderbilt University, Nashville, TN 37232, USA;
2Broad Institute, Harvard University, Cambridge, Massachusetts 02138, USA;
3Departments of Medicine, Microbiology & Immunology, Vanderbilt University, Nashville, TN 37232, USA;
4Department of Medicine, Massachusetts General Hospital, Boston, MA 02114, USA;
5Department of Medicine, Cornell University, New York, NY 10065, USA;
6Department of Medicine, University of California, San Diego, San Diego, CA 92103, USA;
7Department of Biostatistics, Harvard University, Boston, MA 02115, USA;


Pacific Symposium on Biocomputing 16:253-264(2011)


Personalized medicine is a high priority for the future of health care. The idea of tailoring an individualís wellness plan to their unique genetic code is one which we hope to realize through the use of pharmacogenomics. There have been examples of tremendous success in pharmacogenomic associations however there are many such examples in which only a small proportion of trait variance has been explained by the genetic variation. Although the increased use of GWAS could help explain more of this variation, it is likely that a significant proportion of the genetic architecture of these pharmacogenomic traits are due to complex genetic effects such as epistasis, also known as gene-gene interactions, as well as gene-drug interactions. In this study, we utilize the Biofilter software package to look for candidate epistasis contributing to risk for virologic failure with efavirenz-containing antiretroviral therapy (ART) regimens in treatmentnaÔve participants of AIDS Clinical Trials Group (ACTG) randomized clinical trials. A total of 904 individuals from three ACTG trials with data on efavirenz treatment are analyzed after race-stratification into white, black, and Hispanic ethnic groups. Biofilter was run considering 245 candidate ADME (absorption, distribution, metabolism, and excretion) genes and using database knowledge of gene and protein interaction networks to produce approximately 2 million SNP-SNP interaction models within each ethnic group. These models were evaluated within the PLATO software package using pair wise logistic regression models. Although no interaction model remained significant after correction for multiple comparisons, an interaction between SNPs in the TAP1 and ABCC9 genes was one of the top models before correction. The TAP1 protein is responsible for intracellular transport of antigen to MHC class I molecules, while ABCC9 codes for a transporter which is part of the subfamily of ABC transporters associated with multi-drug resistance. This study demonstrates the utility of the Biofilter method to prioritize the search for gene-gene interactions in large-scale genomic datasets, although replication in a larger cohort is required to confirm the validity of this particular TAP1-ABCC9 finding.

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