Multilocus genetic interactions and response to efavirenz-containing regimens: An Adult AIDS Clinical Trials Group study

Vanderbilt University School of Medicine, Nashville, Tennessee 37203, USA.
Pharmacogenetics and Genomics (Impact Factor: 3.48). 12/2006; 16(11):837-45. DOI: 10.1097/01.fpc.0000230413.97596.fa
Source: PubMed


For the HIV-1 reverse transcriptase inhibitor efavirenz, variant drug transporter gene ABCB1 may predict virologic response but not plasma efavirenz exposure. Conversely, variant drug metabolizing enzyme gene CYP2B6 predicts greater plasma efavirenz exposure but not virologic response. We examined whether long-term responses to efavirenz, and/or plasma efavirenz exposure, are better predicted by multilocus genetic interactions than by individual polymorphisms.
We studied antiretroviral-naïve study participants randomized to receive efavirenz (with or without nelfinavir) plus two nucleoside analogues in study ACTG 384, and who had DNA available for analysis. Participants were followed up for up to 3 years. Nine single nucleotide polymorphisms in ABCB1, CYP2B6, CYP3A4, CYP3A5 and CYP2C19 were identified. Gene-gene interactions were identified using multifactor dimensionality reduction.
Among 340 efavirenz recipients, higher efavirenz AUC24 h values were associated with a single locus model involving CYP2B6 516G>T (73% accuracy; P<0.001). This was also the best model among blacks (69% accuracy; P<0.001), whereas among whites the best model involved a gene-gene interaction between CYP2B6 516G>T and ABCB1 2677G>T (82% accuracy, P<0.001). Among 155 participants who received efavirenz without nelfinavir, virologic failure was associated with a two-locus interaction between ABCB1 2677G>T and CYP2B6 516G>T (65% accuracy, P<0.001). Toxicity failure was best predicted by an interaction between ABCB1 2677G>T and ABCB1 3435C>T (71% accuracy, P<0.001).
Multilocus genetic interactions between variant drug metabolism and transporter genes may predict efavirenz pharmacokinetics and treatment responses. This finding may have implications for better individualizing antiretroviral therapy.

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    • "Large inter-ethnic variability has been reported for the 3435C>T SNP with the ABCB1 3435C variant being the most frequent at 83, 58, 57, and 11% among Africans (Kenyans and Ghanaians), Asians (Chinese), Caucasians, and Yoruba individuals, respectively (Ameyaw et al., 2001). The ABCB1 3435T variant has been linked with good immune recovery in HIV/AIDS individuals, while the presence of the ABCB1 2677T variant has been strongly associated with virological failure (Motsinger et al., 2006). A few studies have suggested associations between ABCB1 gene polymorphisms and variability in plasma efavirenz concentrations (Fellay et al., 2002; Mukonzo et al., 2009), but all the studies lack adequate sample size. "
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    ABSTRACT: The ABCB1 gene encodes P-glycoprotein, an ATP-dependent drug efflux pump, which is responsible for drug transport across extra- and intra-cellular membranes. The variability in the expression of ABCB1 may contribute to variable plasma efavirenz concentration which results in variability in the levels of suppression of the human immunodeficiency syndrome virus (HIV). The aim of the study was to evaluate the role of polymorphisms in ABCB1 gene on plasma efavirenz levels and treatment response in the form of change in viral load and CD-4 cell count in HIV/AIDS patients receiving efavirenz-containing highly active antiretroviral treatment regimens. Two hundred and eighty-two HIV-infected patients were recruited from Themba Lethu Clinic in Johannesburg and plasma efavirenz drug concentration levels were measured using LC-MS/MS. SNaPshot was used to genotype five known ABCB1 single nucleotide polymorphisms (SNPs). Genotype-phenotype correlations were computed. The ABCB1 4036A/G and 4036G/G genotypes were significantly associated with low plasma efavirenz concentrations (P = 0.0236), while the ABCB1 1236C/T and 1236T/T genotypes were associated with high efavirenz concentrations (P = 0.0282). A haplotype ABCB1 T-G-T-A is reported that is associated with significantly increased plasma efavirenz levels. This is the first report on 61A>G, 2677G>T/A, and 4036A>G SNPs in the South African population. ABCB1 plays a role in determining the plasma concentrations of efavirenz and should be taken into account in future design of assays for genotype-based dosing of efavirenz-containing regimens.
    Frontiers in Genetics 11/2012; 3:236. DOI:10.3389/fgene.2012.00236
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    • "The significance of the final model was determined by comparing the prediction error and cross validation consistency of the final model with the distribution. A p value was extracted for the model by its theoretical location in the permutation distribution (Motsinger et al., 2006). In considering the possible unbalanced ratio of cases to controls in the data set, a balanced accuracy approach was used to evaluate the performance of the models (Velez et al., 2007). "
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    ABSTRACT: A broad region of chromosome 10 (chr10) has engendered continued interest in the etiology of late-onset Alzheimer Disease (LOAD) from both linkage and candidate gene studies. However, there is a very extensive heterogeneity on chr10. We converged linkage analysis and gene expression data using the concept of genomic convergence that suggests that genes showing positive results across multiple different data types are more likely to be involved in AD. We identified and examined 28 genes on chr10 for association with AD in a Caucasian case-control dataset of 506 cases and 558 controls with substantial clinical information. The cases were all LOAD (minimum age at onset > or = 60 years). Both single marker and haplotypic associations were tested in the overall dataset and 8 subsets defined by age, gender, ApoE and clinical status. PTPLA showed allelic, genotypic and haplotypic association in the overall dataset. SORCS1 was significant in the overall data sets (p=0.0025) and most significant in the female subset (allelic association p=0.00002, a 3-locus haplotype had p=0.0005). Odds Ratio of SORCS1 in the female subset was 1.7 (p<0.0001). SORCS1 is an interesting candidate gene involved in the Abeta pathway. Therefore, genetic variations in PTPLA and SORCS1 may be associated and have modest effect to the risk of AD by affecting Abeta pathway. The replication of the effect of these genes in different study populations and search for susceptible variants and functional studies of these genes are necessary to get a better understanding of the roles of the genes in Alzheimer disease.
    Human Mutation 03/2009; 30(3):463-71. DOI:10.1002/humu.20953 · 5.14 Impact Factor
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    • "This finding led authors to speculate that the mutation may alter the risk of the development of drug resistance in patients discontinuing efavirenz containing therapy (Ribaudo et al 2006). Others have demonstrated that response to efavirenz treatment is due to a complex phenotype that is influenced by multiple genes, of which the G516T polymorphism is only one component of the haplotype (Motsinger et al 2006). Additional studies are needed to clarify the genetic influences on efavirenz pharmacokinetics in order to improve the ability to individualize therapy and provide enhanced treatment strategies for HIV infected persons (Gatanaga et al 2007). "
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    Therapeutics and Clinical Risk Management 05/2008; 4(2):291-302. · 1.47 Impact Factor
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