Use of Biological Knowledge to Inform the Analysis of Gene-gene Interactions Involved in Modulating Virologic Failure With Efavirenz-containing Treatment Regimens in Art-naïve Actg Clinical Trials Participants
Year: 2010
Type: book-chapter
Abstract: Personalized medicine is a high priority for the future of health care. The idea of tailoring an individual's 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 treatment-naïve 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.
Source: WORLD SCIENTIFIC eBooks
Language: English
Subfield: Infectious Diseases
Field: Medicine
Domain: Health Sciences
Open Access status: green
Funders: Vanderbilt University, University of Alabama, ACT Government, National Institutes of Health, National Heart, Lung, and Blood Institute, National Human Genome Research Institute, National Institute of General Medical Sciences, National Institute of Allergy and Infectious Diseases, U.S. National Library of Medicine, National Center for Research Resources
Awards: ADULT AIDS CLINICAL TRIALS UNIT (AACTU), G10119098, G1019738922, G1033683653, G1050281965, G1054351029, Units for HIV/AIDS Clinical Trials Networks, G1068660208, G1116104148, G1118287939, G115468880, G1158968046, G1169301292, G119332616, G1225594167, G127535873, G1276011396, G1290643946, G1331000642, G1355238660, G1380633192, G139362660, G1471808148, G1480267329, G1515152346, Stanford AIDS Clinical Trials Unit, G1544706747, G1586133245, G1593133010, G1615307613, G161582775, WASHINGTON UNIVERSITY AIDS CLINICAL TRIALS UNIT, G16708505, G1676560303, G1678638035, G1788832858, G185513119, Vanderbilt HIV Clinical Trials Unit, G1865158448, G1939689254, G1951997798, G1976846336, G1978423557, G200764819, G2027736814, G2049085317, G2069435444, G2093356446, G2135258891, G220168668, G2239548760, G2241242742, G226144467, G2268686290, G232810045, G2370685347, G2381598486, G2394140265, G2416365291, G2463412709, G2501702145, G2539633428, G25420283, G259817324, G2643340084, G2737559749, G2800974659, G2833553957, G2840672922, General Clinical Research Center, G2916982757, ADULT AIDS CLINICAL TRIALS UNIT, G2957799271, G2979570438, G3053192352, Cornell Clinical Trials Unit, G3142995538, G3206835426, G3206931443, G3245214449, G3277483280, G3290139526, G3306674280, Johns Hopkins AIDS Clinical Trials Unit, G3406742890, G3441327761, ADULT AIDS CLINICAL TRIALS UNIT, AIDS CLINICAL TRIALS UNIT, G3483687112, G3508418089, G3604395871, G3667695504, G3672534956, G374818150, G375632836, UW Clinical HIV Integrated Research Program, G3812657198, G3873853564, G390975780, G3922356, ADULT THERAPEUTIC CLINICAL TRIALS PROGRAM FOR AIDS, G3935416247, Philadelphia IMPAACT Clinical Trials Unit, G3955098203, G3964108010, G4099673573, Analysis Tool for Heritable and Envirnonmental Network Associations, G4122054131, Vanderbilt Meharry Center for AIDS Research, AIDS CLINICAL TRIALS UNIT, G4193739534, G4208335746, G45471288, G4553935269, G4565868049, G4597465377, G4614481423, Durban International Clinical Trials Unit, G4649361189, G4674963424, G4699718705, G473273920, G4797509974, Case Clinical Trials Unit, G49554566, University of Pittsburgh Clinical Trials Unit, G5031627105, G5046654427, ADULT THERAPEUTIC CLINICAL TRIALS PROGRAM IN AIDS, Integrated University of Puerto Rico Clinical Trials Unit, G5268332287, G5311218958, G5364003616, G5452137875, ADULT ACTG CENTRAL GROUP, G5469398932, G548399296, G556419284, G5588634031, Improving Antiretroviral Management for HIV, G5647179126, G5686926003, UCSD Department of Medicine HIV/AIDS Clinical Trials Unit, Case AIDS Clinical Trials Unit, G6103943158, G610496905, Philadelphia IMPAACT Clinical Trials Unit, G6186512954, G650174051, G6615853387, G6643580741, University of Cincinnati AIDS Clinical Trials Unit- UC ACTU, G6687940712, G6704488760, G6785868222, G6812155733, UCSF HIV Clinical Trials Unit, AIDS CLINICAL TRIALS UNIT, AIDS CLINICAL TRIALS GROUP - ACTU, Partners Healthcare Systems/Harvard Medical School/Boston Medical Center AIDS CTU, G7401883790, G7403049968, G766489020, G7807354757, G7868490553, G7907723076, G8054576849, G8124278128, Epidemiologic Architecture for Genes Linked to Environment (EAGLE), G83299872, G8487837538, HIV/AIDS Clinical Trials Unit, G857487509, Institute of Human Virology Clinical Trials Unit, ADULT THERAPEUTIC CLINICAL TRIALS PROGRAM FOR HIV/AIDS, Advancing Clinical Therapeutics Globally for HIV/AIDS and Other Infections, San Diego Center for AIDS Research (SD CFAR), Statistical and Data Management Center (SDMC), Advancing Clinical Therapeutics Globally for HIV/AIDS and Other Infections (ACTG), Columbia Collaborative HIV/AIDS Clinical Trials Unit, University of North Carolina Global HIV Prevention and Treatment Clinical Trials Unit, G926868656, ADULT AIDS CLINICAL TRIALS UNIT, G936311976, G939730012, G961682679, Bridging the Gap HIV Trials and Clinical Practice
OpenAlex ID: W1585965485