12 new pubmed citations were retrieved for your search. Click on the search hyperlink below to display the complete search results:

pharmacogenomics

These pubmed results were generated on 2018/10/02

PubMed comprises more than millions of citations for biomedical literature from MEDLINE, life science journals, and online books. Citations may include links to full-text content from PubMed Central and publisher web sites.

Pharmacogenomics and variations in the risk of toxicity during the consolidation/maintenance phases of the treatment of pediatric B-cell leukemia patients from an admixed population in the Brazilian Amazon.

Leuk Res. 2018 Sep 15;74:10-13

Authors: de Carvalho DC, Wanderley AV, Dos Santos AMR, Fernandes MR, Cohen Lima de Castro AN, Leitão LPC, de Carvalho JAN, de Souza TP, Khayat AS, Dos Santos SEB, de Assumpção PP, Dos Santos NPC

Abstract
The treatment of Acute Lymphoblastic Leukemia (ALL) in children has a high clinical success rate, although toxicological complications are frequent, and often result in the interruption of the treatment. Various studies have shown that toxicities resulting from the treatment are influenced by pharmacogenetic variants. Most of this research has focused on relatively homogeneous populations, and the influence of these variants in highly admixed populations, such as that of Brazil, is still poorly understood. The present study investigated the association between pharmacogenetic variants and severe toxicities in pediatric B-cell ALL patients from an admixed population of the Brazilian Amazon. The rs2306283 (of SLCO1B1) mutant allele increased the risk of neurotoxicity threefold, and the homozygous mutant rs9895420 (of ABCC3) genotype was associated with a fivefold increase in protection against severe gastrointestinal toxicity. This indicates that the rs2306283 and rs9895420 polymorphisms may be relevant to the prediction of severe toxicity in pediatric ALL patients.

PMID: 30269037 [PubMed - as supplied by publisher]

Endothelial Colony-Forming Cells Do Not Participate to Fibrogenesis in a Bleomycin-Induced Pulmonary Fibrosis Model in Nude Mice.

Stem Cell Rev. 2018 Sep 28;:

Authors: Blandinières A, Gille T, Sadoine J, Bièche I, Slimani L, Dizier B, Gaussem P, Chaussain C, Planes C, Dorfmüller P, Israël-Biet D, Smadja DM

Abstract
Idiopathic pulmonary fibrosis (IPF) is a devastating lung disease characterized by fibroblast proliferation, extracellular matrix deposition, destruction of pulmonary alveolar architecture and vascular remodeling. Apart pirfenidone or nintendanib that only slow down the fibrotic process, there is no curative treatment other than lung transplantation. Because cell therapy approaches have been proposed in IPF, we hypothesized that injection of endothelial colony-forming cells (ECFCs), the vasculogenic subtype of endothelial progenitor cells, could modulate fibrosis in a Nude mouse model of bleomycin induced-pulmonary fibrosis. Mice were injected with ECFCs isolated from cord blood and from peripheral blood of adult IPF patients at two time-points: during the development of the fibrosis or once the fibrosis was constituted. We assessed morbidity, weight variation, collagen deposition, lung imaging by microCT, Fulton score and microvascular density. Neither ECFCs isolated from cord blood nor from IPF patients were able to modulate fibrosis or vascular density during fibrogenesis or when fibrosis was constituted. These findings indicate that human ECFCs do not promote an adaptive regenerative response in the lung upon fibrosis or angiogenic process in the setting of bleomycin-induced pulmonary fibrosis in Nude mice.

PMID: 30267203 [PubMed - as supplied by publisher]

Ustekinumab in psoriatic arthritis and related phenotypes.

Ther Adv Chronic Dis. 2018 Oct;9(10):191-198

Authors: Dobbin-Sears I, Roberts J, O'Rielly DD, Rahman P

Abstract
Psoriatic arthritis (PsA) is an inflammatory arthritis that commonly occurs with psoriasis and is attributed to genetic, immunologic and environmental factors. The T-helper (Th)-17 pathway and the interleukin (IL)-23/IL-17 axis have become prominent players in PsA and considerably increased our understanding of disease pathogenesis. In this review article, we will focus on the emerging role of IL-12/23 and its blockade, in the pathogenesis and management of PsA as well as of psoriasis and inflammatory bowel disease. Ustekinumab, is a fully human monoclonal immunoglobulin (Ig)G1 antibody that binds specifically to the p40 subunit of IL-12 and IL-23, primarily inhibiting downstream Th-17 signalling pathways. Ustekinumab produced consistent and sustained clinical efficacy in two phase III clinical trials in PsA, PSUMMIT-1 and PSUMMIT-2, with data out to 52 weeks, and no new safety signals. PSUMMIT-1 included patients with active PsA despite conventional therapy who were all naïve to anti-tumour necrosis factor (TNF) agents, whereas PSUMMIT-2 also included anti-TNF experienced patients. Similarly, ustekinumab produced consistent clinical efficacy in two phase III clinical trials in psoriasis, PHOENIX-1 and PHOENIX-2, and in both induction and maintenance of moderate-to-severe Crohn's disease, UNITI-1, UNITI-2 and IM-UNITI, without an increased safety signal. Currently, ustekinumab is used in the treatment of PsA following the failure of nonsteroidal anti-inflammatory drugs (NSAIDs) and conventional disease-modifying antirheumatic drugs (DMARDs), and as an alternative to, or after failure of an anti-TNF agent.

PMID: 30263103 [PubMed]

Homozygosity disequilibrium associated with treatment response and its methylation regulation.

BMC Proc. 2018;12(Suppl 9):45

Authors: Yang HC, Chen CW

Abstract
Homozygosity disequilibrium (HD), indicating a nonrandom pattern of sizable runs of homozygosity that deviates from a random allocation of homozygous and heterozygous genotypes in the genome, is an important phenomenon in population genomics and medical genomics. We performed the first genome-wide study investigating the roles of HD in pharmacogenomics and pharmacoepigenomics by analyzing GAW20 data. We inferred whole-genome profiles of homozygosity intensities and performed genome-wide homozygosity association analyses to identify regions of HD associated with triglyceride (TG) response to fenofibrate by using LOHAS (Loss-of-Heterozygosity Analysis Suite) software. The analysis identified a region of HD contained in MACROD2 at 20p12 to be significantly associated with TG response to fenofibrate. We also examined the common genetic component in TG and methylation responses to fenofibrate. The methylation response to fenofibrate was regarded as a methylation quantitative trait, and our methylation quantitative trait locus analysis identified a cis-acting regulation association with marginal significance between the homozygosity intensity of MACROD2 and the methylation response to fenofibrate. These findings may help delineate the genetic basis of pharmacogenomic and pharmacoepigenomic responses to fenofibrate intervention.

PMID: 30263048 [PubMed]

GAW20: methods and strategies for the new frontiers of epigenetics and pharmacogenomics.

BMC Proc. 2018;12(Suppl 9):26

Authors: Tintle NL, Fardo DW, de Andrade M, Aslibekyan S, Bailey JN, Bermejo JL, Cantor RM, Ghosh S, Melton P, Wang X, MacCluer JW, Almasy L

Abstract
GAW20 provided a platform for developing and evaluating statistical methods to analyze human lipid-related phenotypes, DNA methylation, and single-nucleotide markers in a study involving a pharmaceutical intervention. In this article, we present an overview of the data sets and the contributions analyzing these data. The data, donated by the Genetics of Lipid Lowering Drugs and Diet Network (GOLDN) investigators, included data from 188 families (N = 1105) which included genome-wide DNA methylation data before and after a 3-week treatment with fenofibrate, single-nucleotide polymorphisms, metabolic syndrome components before and after treatment, and a variety of covariates. The contributions from individual research groups were extensively discussed prior, during, and after the Workshop in groups based on discussion themes, before being submitted for publication.

PMID: 30263042 [PubMed]

Genome-wide enrichment of m6A-associated single-nucleotide polymorphisms in the lipid loci.

Pharmacogenomics J. 2018 Sep 27;:

Authors: Mo X, Lei S, Zhang Y, Zhang H

Abstract
N6-methyladenosine (m6A) plays critical roles in many fundamental biological processes and a variety of diseases. The aim of this study was to investigate the effect of m6A-SNPs on lipid levels. We examined the association of m6A-SNPs with lipid levels in a genome-wide association studies (GWAS) of 188,578 individuals. Furthermore, we performed expression quantitative trait loci and differential expression analyses to add additional information for the identified m6A-SNPs. We found 1,655 m6A-SNPs in the GWAS dataset. Among them, 395 (23.9%) were nominally (P < 0.05) associated with lipid levels, and 22 reached the genome-wide significance level (P < 5.0 × 10-8). Using the fgwas method we found that SNPs, which influence high-density lipoprotein cholesterol (log2 enrichment of 3.35, 95% CI: (0.92, 4.48)) and TG (log enrichment of 3.22, 95% CI: (1.18, 4.44)), were enriched in m6A methylation. The high confidence (determined by miCLIP experiment) m6A-SNP rs6859 at the 3'-untranslated region of PVRL2 was associated with high-density lipoprotein cholesterol (P = 1.21 × 10-15), low-density lipoprotein cholesterol (P = 1.77 × 10-106), total cholesterol (P = 4.82 × 10-82), and triglycerides (P = 8.10 × 10-5) levels, coronary artery disease (P = 0.01), as well as PVRL2 mRNA expression in artery tibial (P = 2.38 × 10-6) and whole blood (P = 5.59 × 10-19). Moreover, PVRL2 was differentially expressed in adipose tissue of familial combined hyperlipidemia (P = 9.27 × 10-4). The present study found plenty of lipid-associated m6A-SNPs and demonstrated that m6A-SNPs may play important roles in lipid metabolisms. Further studies were needed to elucidate the mechanisms.

PMID: 30262821 [PubMed - as supplied by publisher]

Genetic Tools for Coronary Risk Assessment in Type 2 Diabetes: A Cohort Study From the ACCORD Clinical Trial.

Diabetes Care. 2018 Sep 27;:

Authors: Morieri ML, Gao H, Pigeyre M, Shah HS, Sjaarda J, Mendonca C, Hastings T, Buranasupkajorn P, Motsinger-Reif AA, Rotroff DM, Sigal RJ, Marcovina SM, Kraft P, Buse JB, Wagner MJ, Gerstein HC, Mychaleckyj JC, Parè G, Doria A

Abstract
OBJECTIVE: We evaluated whether the increasing number of genetic loci for coronary artery disease (CAD) identified in the general population could be used to predict the risk of major CAD events (MCE) among participants with type 2 diabetes at high cardiovascular risk.
RESEARCH DESIGN AND METHODS: A weighted genetic risk score (GRS) derived from 204 variants representative of all the 160 CAD loci identified in the general population as of December 2017 was calculated in 5,360 and 1,931 white participants in the Action to Control Cardiovascular Risk in Diabetes (ACCORD) and Outcome Reduction With Initial Glargine Intervention (ORIGIN) studies, respectively. The association between GRS and MCE (combining fatal CAD events, nonfatal myocardial infarction, and unstable angina) was assessed by Cox proportional hazards regression.
RESULTS: The GRS was associated with MCE risk in both ACCORD and ORIGIN (hazard ratio [HR] per SD 1.27, 95% CI 1.18-1.37, P = 4 × 10-10, and HR per SD 1.35, 95% CI 1.16-1.58, P = 2 × 10-4, respectively). This association was independent from interventions tested in the trials and persisted, though attenuated, after adjustment for classic cardiovascular risk predictors. Adding the GRS to clinical predictors improved incident MCE risk classification (relative integrated discrimination improvement +8%, P = 7 × 10-4). The performance of this GRS was superior to that of GRS based on the smaller number of CAD loci available in previous years.
CONCLUSIONS: When combined into a GRS, CAD loci identified in the general population are associated with CAD also in type 2 diabetes. This GRS provides a significant improvement in the ability to correctly predict future MCE, which may increase further with the discovery of new CAD loci.

PMID: 30262460 [PubMed - as supplied by publisher]

Differential Expression Profile of MicroRNAs During Prolonged Storage of Platelet Concentrates As a Quality Measurement Tool in Blood Banks.

OMICS. 2018 Sep 27;:

Authors: Maués JHDS, Moreira-Nunes CFA, Pontes TB, Vieira PCM, Montenegro RC, Lamarão LM, Lima EM, Burbano RMR

Abstract
Platelet concentrate (PC) is a key blood component, which even in good storage conditions, susceptible to cellular damage over time. Hence, blood banks discard unused PC bags after 5 days of storage. Biomarkers of PC quality are therefore highly sought after in blood bank governance. We used the data (Gene Expression Omnibus: GSE61856) generated with next-generation sequencing to examine the expression profiles of microRNAs (miRNAs) from PCs that were stored for 6 days in a blood bank, that is, 1 day longer than is normally stored PC. We identified the 14 most differentially expressed miRNAs by comparing a control PC on the first day of storage with the PCs on each of the subsequent 5 days of storage from day 1 to 6. In all, we identified nine miRNAs with the downregulated profile (miR-145-5p, miR-150-5p, miR-183-5p, miR-26a-5p, miR-331-3p, miR-338-5p, miR-451a, miR-501-3p, and miR-99b-5p) and five upregulated miRNAs (miR-1304-3p, miR-411-5p, miR-432-5p, miR-668-3p, and miR-939-5p). These miRNAs were validated by real-time quantitative PCR in 100 PC units. As each PC unit is composed of platelets of five individuals, the validation was thus performed in 500 individuals (250 men and 250 women, comprised 18-40 years old adults). The data were analyzed with hierarchical clustering and principal component analysis, which revealed the variation of mean relative expression and the instability of miRNAs half-life on the fourth day of PC storage, which coincides with time of onset of platelet storage lesions. These new observations can usefully inform future decision-making and governance in blood banks concerning PC quality.

PMID: 30260743 [PubMed - as supplied by publisher]

A Pharmacogenetic Prediction Model of Progression-Free Survival in Breast Cancer using Genome-Wide Genotyping Data from CALGB 40502 (Alliance).

Clin Pharmacol Ther. 2018 Sep 27;:

Authors: Rashkin SR, Chua KC, Ho C, Mulkey F, Jiang C, Mushiroda T, Kubo M, Friedman PN, Rugo HS, McLeod HL, Ratain MJ, Castillos F, Naughton M, Overmoyer B, Toppmeyer D, Witte JS, Owzar K, Kroetz DL

Abstract
Genome-wide genotyping data are increasingly available for pharmacogenetic association studies, but application of these data for development of prediction models is limited. Prediction methods such as elastic net regularization have recently been applied to genetic studies but only limitedly to pharmacogenetic outcomes. An elastic net was applied to a pharmacogenetic study of progression-free survival of 468 advanced breast cancer patients in a clinical trial of paclitaxel, nab-paclitaxel, and ixabepilone. A final model included 13 SNPs in addition to clinical covariates (prior taxane status, hormone receptor status, disease-free interval, and presence of visceral metastases) with an AUC integrated over time of 0.81, an increase compared to an AUC of 0.64 for a model with clinical covariates alone. This model may be of value in predicting progression-free survival with microtubule targeting agents and may inform reverse translational studies to understand differential response to these drugs. This article is protected by copyright. All rights reserved.

PMID: 30260474 [PubMed - as supplied by publisher]

Precision medicine in oncology: what is it exactly and where are we?

Per Med. 2018 Sep 27;:

Authors: Le Tourneau C, Kamal M, Bièche I

PMID: 30260312 [PubMed - as supplied by publisher]

Dosing Recommendations based on Population Pharmacokinetics of Tacrolimus in Mexican Adult Patients with Kidney Transplant.

Basic Clin Pharmacol Toxicol. 2018 Sep 27;:

Authors: Eduardo RJ, Edith MS, Del Carmen MR, Del Carmen NP, Javier IS, Silvia RM

Abstract
The aim of this study was to perform a population pharmacokinetic analysis of tacrolimus in adult Mexican kidney transplant to analyse the influence of clinical and genetic covariates to propose a dosage regimen. Kidney transplant patients (>18 years old) receiving oral tacrolimus treatment were included in the current study. The population pharmacokinetic model was built using a one-compartment model and the First-Order Conditional method with Interaction (FOCEI via NONMEM (v.7.3). A total of 600 tacrolimus trough blood concentrations from 52 kidney transplant patients were analysed. Tacrolimus clearances were 26, 18.8 and 12.3 L/h, for patients with genetic polymorphisms CYP3A5*1*1, *1*3 and *3*3, respectively. The influence of hematocrit was inversely related to tacrolimus clearance, following an allometric power function. Total volume of distribution was 604 L. Inter-individual variability associated to tacrolimus clearance and distribution volume for the final model was 33 and 63%, respectively, with a residual error of 2.5 ng/mL. Relative bioavailability was calculated between generic formulations A (0.53) and B (1) of tacrolimus. Internal validation was performed through bootstrap analysis to evaluate stability of the final model; external validation was performed in a new group of patients (n=13) to estimate residual errors on basic (57.8%) and final (34.8%) models. Finally, stochastic simulations were performed to propose a dosage regimen based on hematocrit, CYP3A5 genotype and generic formulation of tacrolimus. A stable and predictive population pharmacokinetic model of tacrolimus was developed for Mexican adult kidney transplant patients; additionally, the proposed dosage regimen of tacrolimus should be prospectively validated. This article is protected by copyright. All rights reserved.

PMID: 30260084 [PubMed - as supplied by publisher]

Combining Homologous Recombination and Phosphopeptide-binding Data to Predict the Impact of BRCA1 BRCT Variants on Cancer Risk.

Mol Cancer Res. 2018 Sep 26;:

Authors: Petitalot A, Dardillac E, Jacquet E, Nhiri N, Guirouilh-Barbat J, Julien P, Bouazzaoui I, Bonte D, Feunteun J, Schnell JA, Lafitte P, Aude JC, Nogues C, Rouleau E, Lidereau R, Lopez BS, Zinn-Justin S, Caputo SM

Abstract
BRCA1 mutations have been identified that increase the risk of developing hereditary breast and ovarian cancers. Genetic screening is now offered to patients with a family history of cancer, in order to adapt their treatment and the management of their relatives. However, a large number of BRCA1 variants of uncertain significance (VUS) are detected. To better understand the significance of these variants, a high-throughput structural and functional analysis was performed on a large set of BRCA1-VUS. Information on both cellular localization and homology-directed DNA-repair (HR) capacity was obtained for 78 BRCT-missense variants in the UMD-BRCA1 database and measurement of the structural stability and phosphopeptide-binding capacities was performed for 42 mutated BRCT-domains. This extensive and systematic analysis revealed that most characterized causal variants affect BRCT-domain solubility in bacteria and all impair BRCA1 HR activity in cells. Furthermore, binding to a set of 5 different phosphopeptides was tested: all causal variants showed phosphopeptide-binding defects and no neutral variant showed such defects. A classification is presented based on mutated BRCT-domain solubility, phosphopeptide-binding properties, and VUS HR-capacity. These data suggest that HR-defective variants, which present, in addition, BRCT-domains either insoluble in bacteria or defective for phosphopeptide-binding, lead to an increased cancer risk. Furthermore, the data suggest that variants with a WT HR-activity and whose BRCT-domains bind with a WT affinity to the 5 phosphopeptides are neutral. The case of variants with WT HR-activity and defective phosphopeptide-binding should be further characterized, as this last functional defect might be sufficient per se to lead to tumorigenesis.

PMID: 30257991 [PubMed - as supplied by publisher]

Impact of Genetic Variability on Physiological Responses to Caffeine in Humans: A Systematic Review.

Nutrients. 2018 Sep 25;10(10):

Authors: Fulton JL, Dinas PC, Carrillo AE, Edsall JR, Ryan EJ, Ryan EJ

Abstract
Emerging research has demonstrated that genetic variation may impact physiological responses to caffeine consumption. The purpose of the present review was to systematically recognize how select single nucleotide polymorphisms (SNPs) impact habitual use of caffeine as well as the ergogenic and anxiogenic consequences of caffeine. Two databases (PubMed and EBSCO) were independently searched using the same algorithm. Selected studies involved human participants and met at least one of the following inclusion criteria: (a) genetic analysis of individuals who habitually consume caffeine; (b) genetic analysis of individuals who underwent measurements of physical performance with the consumption of caffeine; (c) genetic analysis of individuals who underwent measurements of mood with the consumption of caffeine. We included 26 studies (10 randomized controlled trials, five controlled trials, seven cross-sectional studies, three single-group interventional studies and one case-control study). Single nucleotide polymorphisms in or near the cytochrome P450 (CYP1A2) and aryl hydrocarbon receptor (AHR) genes were consistently associated with caffeine consumption. Several studies demonstrated that the anxiogenic consequences of caffeine differed across adenosine 2a receptor (ADORA2A) genotypes, and the studies that investigated the effects of genetic variation on the ergogenic benefit of caffeine reported equivocal findings (CYP1A2) or warrant replication (ADORA2A).

PMID: 30257492 [PubMed - in process]

Gene isoforms as expression-based biomarkers predictive of drug response in vitro.

Nat Commun. 2017 10 24;8(1):1126

Authors: Safikhani Z, Smirnov P, Thu KL, Silvester J, El-Hachem N, Quevedo R, Lupien M, Mak TW, Cescon D, Haibe-Kains B

Abstract
Next-generation sequencing technologies have recently been used in pharmacogenomic studies to characterize large panels of cancer cell lines at the genomic and transcriptomic levels. Among these technologies, RNA-sequencing enable profiling of alternatively spliced transcripts. Given the high frequency of mRNA splicing in cancers, linking this feature to drug response will open new avenues of research in biomarker discovery. To identify robust transcriptomic biomarkers for drug response across studies, we develop a meta-analytical framework combining the pharmacological data from two large-scale drug screening datasets. We use an independent pan-cancer pharmacogenomic dataset to test the robustness of our candidate biomarkers across multiple cancer types. We further analyze two independent breast cancer datasets and find that specific isoforms of IGF2BP2, NECTIN4, ITGB6, and KLHDC9 are significantly associated with AZD6244, lapatinib, erlotinib, and paclitaxel, respectively. Our results support isoform expressions as a rich resource for biomarkers predictive of drug response.

PMID: 29066719 [PubMed - indexed for MEDLINE]

17 new pubmed citations were retrieved for your search. Click on the search hyperlink below to display the complete search results:

pharmacogenomics

These pubmed results were generated on 2018/09/27

PubMed comprises more than millions of citations for biomedical literature from MEDLINE, life science journals, and online books. Citations may include links to full-text content from PubMed Central and publisher web sites.

16 new pubmed citations were retrieved for your search. Click on the search hyperlink below to display the complete search results:

pharmacogenomics

These pubmed results were generated on 2018/09/27

PubMed comprises more than millions of citations for biomedical literature from MEDLINE, life science journals, and online books. Citations may include links to full-text content from PubMed Central and publisher web sites.

11 new pubmed citations were retrieved for your search. Click on the search hyperlink below to display the complete search results:

pharmacogenomics

These pubmed results were generated on 2018/09/26

PubMed comprises more than millions of citations for biomedical literature from MEDLINE, life science journals, and online books. Citations may include links to full-text content from PubMed Central and publisher web sites.

Combined Albendazole and Praziquantel Therapy in an Adult Female with Neurocysticercosis and Generalized Tonic-clonic Seizures.

Cureus. 2018 Jul 18;10(7):e2996

Authors: Petrov K, Ihongbe F, Chang M, Choudhary S, Bhatia D

Abstract
The use of albendazole monotherapy has been favored as the treatment option for neurocysticercosis. This case reports an incidence of neurocysticercosis in a 32-year-old woman who presented to the emergency department with a generalized tonic-clonic seizure. Neurocysticercosis was confirmed by magnetic resonance imaging (MRI) of the brain and a positive Taenia solium serologic test. The patient was treated with the combined dual therapy of albendazole and praziquantel at standard doses for a minimum effective duration of 14 days in the setting of scarce patient resources. She tolerated therapy without any adverse reactions and remained seizure free. A repeat MRI scan post-treatment revealed the complete eradication of cysticerci. Clinicians should be aware of and consider the efficacy and safety of combined albendazole and praziquantel therapy for the treatment of neurocysticercosis.

PMID: 30245950 [PubMed]

In silico Prioritization of Transporter-Drug Relationships From Drug Sensitivity Screens.

Front Pharmacol. 2018;9:1011

Authors: César-Razquin A, Girardi E, Yang M, Brehme M, Saez-Rodriguez J, Superti-Furga G

Abstract
The interplay between drugs and cell metabolism is a key factor in determining both compound potency and toxicity. In particular, how and to what extent transmembrane transporters affect drug uptake and disposition is currently only partially understood. Most transporter proteins belong to two protein families: the ATP-Binding Cassette (ABC) transporter family, whose members are often involved in xenobiotic efflux and drug resistance, and the large and heterogeneous family of solute carriers (SLCs). We recently argued that SLCs are collectively a rather neglected gene group, with most of its members still poorly characterized, and thus likely to include many yet-to-be-discovered associations with drugs. We searched publicly available resources and literature to define the currently known set of drugs transported by ABCs or SLCs, which involved ∼500 drugs and more than 100 transporters. In order to extend this set, we then mined the largest publicly available pharmacogenomics dataset, which involves approximately 1,000 molecularly annotated cancer cell lines and their response to 265 anti-cancer compounds, and used regularized linear regression models (Elastic Net, LASSO) to predict drug responses based on SLC and ABC data (expression levels, SNVs, CNVs). The most predictive models included both known and previously unidentified associations between drugs and transporters. To our knowledge, this represents the first application of regularized linear regression to this set of genes, providing an extensive prioritization of potentially pharmacologically interesting interactions.

PMID: 30245630 [PubMed]