Interindividual Variability In Drug Response Research Articles

Awareness and attitude of the public toward personalized medicine in Korea.

ObjectivesAs personalized medicine (PM) is expected to greatly improve health outcomes, efforts have recently been made for its clinical implementation in Korea. We aimed to evaluate public awareness and attitude regarding PM.MethodsWe performed a self-administered questionnaire survey to 703 adults, who participated in the survey on a voluntary basis. The primary outcome measures included public knowledge, attitude, and acceptance of PM. We conducted multinomial multivariate logistic analysis for outcome variables with three response categories and performed multivariate logistic regression analyses for dichotomous outcome variables.ResultsOnly 28% of participants had knowledge that genetic factors can contribute to inter-individual variations in drug response and the definition of PM (199 out of 702). Higher family income was correlated with greater knowledge concerning PM (OR = 3.76, p = 0.034). A majority of respondents preferred integrated pharmacogenomic testing over drug-specific testing and agreed to inclusion of pharmacogenomic testing in the national health examination (64% and 77%, respectively), but only 51% were willing to pay for it.DiscussionOur results identify the urgent need for public education as well as the potential health disparities in access to PM. This study helps to frame policies for implementing PM in clinical practice.

Pharmacogenetics and Genetic Polymorphism of CYP Enzymes in Indian Population: A Clinical Review

Pharmacogenetic polymorphism results from the mutations in a Cytochrome P450 (CYP) gene leading to functional alterations, such as increased or decreased activity and occurs at a frequency of at least one percent in a population. At present clinical situation drug clearance and inter-individual variation in drug response is a usual and complex problem. In this clinical review there is a fast update on pharmacogenetics and genetic polymorphism of CYP enzymes in Indian population.

Differential connectivity of gene regulatory networks distinguishes corticosteroid response in asthma

Variations in drug response between individuals have prevented us from achieving high drug efficacy in treating many complex diseases, including asthma. Genetics plays an important role in accounting for such interindividual variations in drug response. However, systematic approaches for addressing how genetic factors and their regulators determine variations in drug response in asthma treatment are lacking. We sought to identify key transcriptional regulators of corticosteroid response in asthma using a novel systems biology approach. We used Passing Attributes between Networks for Data Assimilations (PANDA) to construct the gene regulatory networks associated with good responders and poor responders to inhaled corticosteroids based on a subset of 145 white children with asthma who participated in the Childhood Asthma Management Cohort. PANDA uses gene expression profiles and published relationships among genes, transcription factors (TFs), and proteins to construct the directed networks of TFs and genes. We assessed the differential connectivity between the gene regulatory network of good responders versus that of poor responders. When compared with poor responders, the network of good responders has differential connectivity and distinct ontologies (eg, proapoptosis enriched in network of good responders and antiapoptosis enriched in network of poor responders). Many of the key hubs identified in conjunction with clinical response are also cellular response hubs. Functional validation demonstrated abrogation of differences in corticosteroid-treated cell viability following siRNA knockdown of 2TFs and differential downstream expression between good responders and poor responders. We have identified and validated multiple TFs influencing asthma treatment response. Our results show that differential connectivity analysis can provide new insights into the heterogeneity of drug treatment effects.

Novel Applications of Metabolomics in Personalized Medicine: A Mini-Review

Interindividual variability in drug responses and disease susceptibility is common in the clinic. Currently, personalized medicine is highly valued, the idea being to prescribe the right medicine to the right patient. Metabolomics has been increasingly applied in evaluating the therapeutic outcomes of clinical drugs by correlating the baseline metabolic profiles of patients with their responses, i.e., pharmacometabonomics, as well as prediction of disease susceptibility among population in advance, i.e., patient stratification. The accelerated advance in metabolomics technology pinpoints the huge potential of its application in personalized medicine. In current review, we discussed the novel applications of metabolomics with typical examples in evaluating drug therapy and patient stratification, and underlined the potential of metabolomics in personalized medicine in the future.

The emerging science of precision medicine and pharmacogenomics for Parkinson's disease.

Current therapies for Parkinson's disease are problematic because they are symptomatic and have adverse effects. New drugs have failed in clinical trials because of inadequate efficacy. At the core of the problem is trying to make one drug work for all Parkinson's disease patients, when we know this premise is wrong because (1) Parkinson's disease is not a single disease, and (2) no two individuals have the same biological makeup. Precision medicine is the goal to strive for, but we are only at the beginning stages of building the infrastructure for one of the most complex projects in the history of science, and it will be a long time before Parkinson's disease reaps the benefits. Pharmacogenomics, a cornerstone of precision medicine, has already proven successful for many conditions and could also propel drug discovery and improve treatment for Parkinson's disease. To make progress in the pharmacogenomics of Parkinson's disease, we need to change course from small inconclusive candidate gene studies to large-scale rigorously planned genome-wide studies that capture the nuclear genome and the microbiome. Pharmacogenomic studies must use homogenous subtypes of Parkinson's disease or apply the brute force of statistical power to overcome heterogeneity, which will require large sample sizes achievable only via internet-based methods and electronic databases. Large-scale pharmacogenomic studies, together with biomarker discovery efforts, will yield the knowledge necessary to design clinical trials with precision to alleviate confounding by disease heterogeneity and interindividual variability in drug response, two of the major impediments to successful drug discovery and effective treatment. © 2017 International Parkinson and Movement Disorder Society.

Personalized Medicine in the Paediatric Population: The Balance Between Pharmacogenetic Progress and Bioethics.

Personalized medicine (PM) is becoming increasingly important in contemporary clinical and research scenarios. In the context of PM, pharmacogenomics and pharmacogenetics are aimed at the genetic personalization of drug response. Extrinsic and intrinsic factors may explain interindividual variability in drug response. Among such factors, age seems to specifically intervene to modulate drug response since normal developmental changes may influence the exposure-response relation. Consequently, the potential benefit of pharmacogenomics (PGx) in the paediatric population is considerable. However, many challenges still exist in incorporating PGx into clinical practice. In fact, drug prescribing in the paediatric population is often based on extrapolation from clinical trials conducted on adults as there is often a lack of paediatric data. Children are not just 'small adults', as they have their own pharmacological characteristics in terms of drug metabolism and efficacy, adverse drug reactions and toxicity. Although children might potentially benefit from such research, many ethical concerns arise at the intersection of the spheres of drug development and genetic testing. Children require particular attention because of their vulnerability both in research and the clinical applications of PGx; furthermore, children range from preterm newborns and neonates to infants and toddlers and to adolescents, thus forming a further heterogeneous target group. In this paper, we focus on some ethically relevant concerns (i.e., informed consent, stigmatization, ancillary information) that might arise as a result of the possible application of PGx tests in both paediatric practice and research.

Determination of inosine 5'-monophosphate dehydrogenase activity in red blood cells of thiopurine-treated patients using HPLC.

Thiopurine drugs are commonly used in immune diseases and to a lesser extent, in transplant rejection prophylaxis: however interindividual variability in drug response and in the occurrence of adverse events is observed. Genetic variation in thiopurine S-methyltransferase (TPMT) doesn't completely explain the occurrence of all adverse events and drug response variability. The potential implication of other enzymes involved in thiopurine metabolism, such as ITPA, has been investigated over the last decade but little data is available on inosine 5'-monophosphate dehydrogenase (IMPDH) in patients treated with thiopurine drugs. The authors reported a HPLC method to determine IMPDH activity in the red blood cells (RBCs) of thiopurine-treated patients. IMPDH activity was evaluated by enzymatic conversion of inosine 5'-monophosphate (IMP) to xanthosine 5'-monophosphate (XMP). The XMP formed was analyzed on a Luna® NH2 stationary phase, a weak anion exchange phase that exhibits both ionic and hydrophobic properties. XMP was eluted below 15min. Intra-assay and inter-assay precisions were below 9% for RBCs supplemented with 2, 40 and 80μmol/L of XMP. IMPDH activity was measured in adults without thiopurine treatment as well as in adult and paediatric patients treated with thiopurines. A wide interindividual variability in IMPDH activity in RBCs was observed. No difference in IMPDH activity was found between untreated subjects and adult and paediatric patients on thiopurine therapy (median value 11.8, 7.9 and 7.7nmol XPM/g Hb/h respectively). The method described is useful in the determination of IMPDH phenotype from patients on thiopurine therapy and in the investigation of the potential relationship between IMPDH activity in RBCs and the occurrence of adverse events and drug response variability.

Genetic Polymorphisms of ABCB1 Gene in Patients Having Resistance to Clopidogrel

Objectives: We sought to study the genetic polymorphisms of ABCB1 gene in post percutaneous coronary intervention (PCI) patients with clopidogrel resistance. Background: Dual antiplatelet therapy (DAPT) is a guideline mandated therapy for patients who undergo PCI. However there exists interindividual variability in drug response to the antiplatelet agents leading to recurrent thrombotic events. Genetic polymorphisms of ABCB1 gene are one among the causes of this interindividual variability. Methods: It is a single center prospective trial and includes221 patients who underwent PCI and were given clopidogrel as a part of DAPT. Platelet reactivity was assessed by grading of platelet activity index (PAI) and considered as high on treatment platelet reactivity (HTPR), i.e., clopidogrel resistance if PAI > 5. Genetic analysis for ABCB1 C-T polymorphism was done by polymerase chain reaction (PCR) and single strand confirmation polymorphism (SSCP) analysis. Results: Amongst 221 patients, 37 (16.7%) patients had ABCB1 C-T polymorphisms. The mean PAI value in these patients was 5.1 ± 3.0, while it was 3.5 ± 2.5 in those patients without ABCB1 C-T polymorphisms (p = 0.004). Compared to patients without HTPR, the occurrence of primary endpoints was not significantly increased in patients with HTPR except for stent thrombosis which was significantly high in patients with HTPR. HTPR was also associated with ABCB1 C-T polymorphisms (p = 0.04), but these polymorphisms did not predict the clinical outcome. Conclusions: There was significant prevalence of ABCB1 C-T polymorphisms in patients with HTPR. However it was not an independent risk factor for clopidogrel resistance and also it did not influence adverse cardiovascular outcomes.

M54 - Pharmaco-Epigenomic Response of Antipsychotic Drugs In Theranostics of Schizophrenia

Background Antipsychotic drugs are considered as the first line treatment for psychotic disorders including Schizophrenia. The patients receiving antipsychotic medications show a wide variability in drug response and drug induced side effects which could be attributed to genetic or non-genetic components influencing drug response. Epigenetic mechanisms can offer an alternate mechanism for interindividual drug variability which cannot be explained by genetic polymorphisms. The present study involves evaluating the epigenetic modifications induced by antipsychotic drugs, first in an in-vitro system and then follows it up, to understand its implication in therapeutic response in schizophrenia patients. Methods In the in-vitro study, HepG2, a liver cell line was treated with various antipsychotic drugs including haloperidol, clozapine and olanzapine in varying concentrations for different time interval, either individually or in combination. Various epigenetic parameters were measured at global as well as gene specific level post antipsychotic treatment. Assessment of global DNA methylation and global histone modifications were carried out. The gene expression status of various epigenetic genes and pharmacologically relevant genes and their target miRNA profiles were also evaluated. The conclusions from in-vitro data were extrapolated to a clinical setting by validating the observations between schizophrenia and healthy subjects and between drug responsive and non-responsive schizophrenia patients. Results Our in-vitro data showed that antipsychotic drugs induced increase in global DNA methylation at 5-methylcytosine and 5-hydroxymethylcytosine level in a dosage and time dependent manner. These alterations in methylation were attributed to the increase in gene expression of various epigenetic genes including DNA methyltransferases, methyl CpG binding proteins and DNA demethylases which in turn was regulated by their target microRNAs. The gene expression of various pharmacologically relevant genes including multi drug transporter and drug metabolizing enzymes were upregulated by antipsychotic drugs and this was mediated by altered expression of miRNAs that regulate these genes. Validation of in-vitro observations in a clinical setting have shown that global DNA methylation, epigenetic as well as pharmacologically relevant gene expression and their target microRNA expression was significantly different between drug responders, non responders and controls. Also the epigenetic alterations were markedly associated with drug response rather than disease pathogenesis. Discussion Our in-vitro data followed up with clinical data suggest that antipsychotic drugs can modulate the epigenome. The responsiveness to antipsychotic drugs shown by Schizophrenia patients is due to various epigenetic events induced by antipsychotic drugs, clearly suggesting the epigenetic mode of action of antipsychotic drugs. The study also highlights that the reported epigenetic alteration in schizophrenia may be influenced by antipsychotic drugs and not precisely for pathogenesis. The outcome of the study would help us to understand the role of epigenetic mechanisms in the pharmacological effects of antipsychotic medications and address the issue of interindividual variability in drug response.

Integration of pharmacometabolomics with pharmacokinetics and pharmacodynamics: towards personalized drug therapy

Personalized medicine, in modern drug therapy, aims at a tailored drug treatment accounting for inter-individual variations in drug pharmacology to treat individuals effectively and safely. The inter-individual variability in drug response upon drug administration is caused by the interplay between drug pharmacology and the patients’ (patho)physiological status. Individual variations in (patho)physiological status may result from genetic polymorphisms, environmental factors (including current/past treatments), demographic characteristics, and disease related factors. Identification and quantification of predictors of inter-individual variability in drug pharmacology is necessary to achieve personalized medicine. Here, we highlight the potential of pharmacometabolomics in prospectively informing on the inter-individual differences in drug pharmacology, including both pharmacokinetic (PK) and pharmacodynamic (PD) processes, and thereby guiding drug selection and drug dosing. This review focusses on the pharmacometabolomics studies that have additional value on top of the conventional covariates in predicting drug PK. Additionally, employing pharmacometabolomics to predict drug PD is highlighted, and we suggest not only considering the endogenous metabolites as static variables but to include also drug dose and temporal changes in drug concentration in these studies. Although there are many endogenous metabolite biomarkers identified to predict PK and more often to predict PD, validation of these biomarkers in terms of specificity, sensitivity, reproducibility and clinical relevance is highly important. Furthermore, the application of these identified biomarkers in routine clinical practice deserves notable attention to truly personalize drug treatment in the near future.

Pharmacokinetics in Children with Sickle Cell Anemia Following Single Dose Versus Chronic Treatment with Hydroxyurea

Introduction: Hydroxyurea (HU) reduces vaso-occlusive complications, hospitalizations and transfusion requirements in children with sickle cell anemia (SCA; HbSS and HbSβ0thalassemia). Despite linear pharmacokinetics (PK) and apparent dose dependency for HU effect, there remains unexplained large inter-individual variability in drug response. To better understand this variability, we conducted a PK study of HU to assess: 1) effect of multiple dosing on PK of HU, and 2) explore the utility of using a single post-dose HU plasma concentration as a basis for therapeutic drug monitoring.Methods: Data from two prospective trials, "Pharmacokinetics of Liquid Hydroxyurea in Pediatric Patients with Sickle Cell Anemia" (NCT01506544) and "Single-Dose (SD) and Steady-State (SS) Pharmacokinetics of Hydroxyurea in Children and Adolescents with Sickle Cell Disease", were utilized for this analysis. Participants were children (≤18 years) with HgbSS and HbSβ0 thalassemia from 8 medical centers in the U.S. One cohort of patients had never been treated with HU and the second cohort had been treated with HU for at least ≥3 months at a stable dose. All participants received a single oral dose of HU and plasma PK samples were collected pre-dose, then at 15, 30, 45, and 60 minutes, and 1.5, 2, 4, 6, and 8 hours after study drug was administered under direct supervision. HU was quantitated from plasma and urine using a validated HPLC method. PK parameters for HU were determined from each patient using a standard model-independent approach (apparent Cmax observed from plasma concentration vs time data; AUC determined via a log-linear approach). PK parameters were compared using parametric (two-sample t-test) or nonparametric (Wilcoxon Rank Sum test) as appropriate based on normality of distribution. The coefficient of determination was used to determine the most predictive relationship between post-peak HU plasma concentrations and systemic exposure (AUC). The significance limit accepted for all statistical analyses was a = 0.05.Results: A complete plasma HU PK profile was obtained for 59 children. Participants with PK after the first dose (n=7, HUfirst) group received an average dose of 17.9 ±2.6 mg/Kg of HU whereas those with PK after multiple doses (n=52, HUchronic group) received an average dose of 23.8 ±5.1 mg/Kg (p < 0.01). Absorption of HU was rapid in both groups with a time to maximal plasma concentration (Tmax) of 0.9 ±0.58 hours in the HUfirst group and 0.8 ±0.47 hours in the HUchronic group (p=0.68). The mean dose/weight- normalized Cmax in the HUfirst group (2.0 mg/L per 1 mg/kg dose) was 1.4 fold higher than in the HUchronic (1.4 mg/L per 1 mg/kg) (p=0.03). A similar relationship was observed in mean dose/weight-normalized AUCinf, where the HUfirst group was 1.3 fold higher than in the HUchronic group (5.9 vs 4.6 mg/L*hr per 1 mg/kg; p=0.002). Weight-normalized mean apparent oral clearance (Cl/F) was significantly lower in the HUfirst cohort (0.17 L/hr/kg) as compared to the HUchronic (0.23 L/hr/kg) (p<0.001). The mean apparent volume of distribution (Vz/F) for the HUfirst cohort (0.52 L/kg) was not significantly different than that in the HUchronic cohort (0.61 L/kg) (Table 1). As suggested by data in Figure 1a, the apparent mean elimination half-life did not vary between the groups (e.g., 2.1 hr in HUfirst vs. 2.3 hr in HUchronic). Finally, between 45 minutes post-dose and through the last blood sampling point, the 4 hour post-dose concentration most accurately predicted the AUC of HU (r2= 0.78) (Figure 1b).Conclusion: Weight and dose-normalized PK parameters for HU suggest potential differences in the bioavailability of the drug with multiple dosing. This finding may contribute to the known wide variability in HU response. Finally, a single 4 hour post-dose HU plasma concentration adequately predicts systemic exposure (AUC) to HU and thus, could provide an approach to facilitate dose individualization / optimization. [Display omitted] [Display omitted] [Display omitted] DisclosuresLiem:National Institute of Health: Research Funding; Ann & Robert H. Lurie Children’s Hospital of Chicago: Research Funding; Ann & Robert H. Lurie Children’s Hospital of Chicago: Employment. Estepp:Daiichi Sankyo: Membership on an entity’s Board of Directors or advisory committees, Research Funding; Global Blood Therapeutics: Membership on an entity’s Board of Directors or advisory committees, Research Funding; Pfizer: Research Funding; National Institute of Health: Research Funding.

Pharmacogenomic approaches to lipid-regulating trials.

Randomized clinical outcome trials are costly, long, and often yield neutral or modestly positive results, and these issues have impeded cardiovascular drug development in the past decade. Despite the significant reduction of cardiovascular morbidity and mortality with statins, substantial residual risk of major cardiovascular events remains. This could be because of the difficulty of demonstrating benefits of new drugs in addition to the current standard of care in unselected populations as well as the interindividual variability in drug response. Pharmacogenomics is a promising avenue for the development of novel or failed drugs and for the repurposing of other medications. Several variants were identified in genes that were associated with the effects of statins on plasma lipids. Genomic studies of mutations in genes that encode drug targets have the potential to inform on the link between drug therapy acting on those targets and clinical outcomes. Recently, ADCY9 gene variants were shown to be significantly associated with responses to dalcetrapib in terms of clinical outcomes, atherosclerosis imaging, cholesterol efflux, and inflammation, which provided support for the conduct of a new prospective clinical trial in a genetically determined population. Pharmacogenomics hold great potential in future lipid trials to decrease failure rates in drug development and to identify patients who will respond with greater benefits and smaller risk.

Simultaneous Determination of Cytochrome P450 Oxidation Capacity in Humans: A Review on the Phenotyping Cocktail Approach.

Intra- and/or inter-individual variability in drug response is mainly a result of either subtherapeutic or supratherapeutic plasma levels of the active drugs and their metabolites, with this variability mainly being influenced by differences in the rate of drug metabolism. Indeed, drug metabolism is largely determined by genetic polymorphism in the CYP enzymes, which are responsible for approximately 85% of the drug metabolism process. However, this genetic heterogeneity can accurately predict actual drug metabolizing capacity (oxidation phenotype) for some individuals: poor metabolizers (PMs), who cannot produce the drug metabolizing enzymes, and 20% of ultra-rapid metabolizers. According to EMA recommendations, phenotyping procedures for drug interaction studies and clinical research are therefore required to obtain actual data on the main CYP enzymes. With this purpose, cocktail phenotyping approaches give information on the activity of different CYPs in just one experiment. In this review, the issues related to the phenotyping of the main CYP enzymes are reviewed, and the current in vivo phenotyping cocktails are analysed: the sampling procedures, probe drugs utilized, analytical techniques and main applications are also discussed. Based on this analysis, a fully validated cocktail approach to measure the metabolic activity of the main CYP enzymes and drug transporters is still required. This novel approach should fulfil certain conditions: a faster and simpler analytical methodology to obtain information on several CYPs in one experiment, minimal sample amounts, and minimal doses of optimal probe drugs.

Nonalcoholic Steatohepatitis Modulates Membrane Protein Retrieval and Insertion Processes.

Interindividual variability in drug response in nonalcoholic steatohepatitis (NASH) can be mediated by altered regulation of drug metabolizing enzymes and transporters. Among these is the mislocalization of multidrug resistance-associated protein (MRP2)/Mrp2 away from the canalicular membrane, which results in decreased transport of MRP2/Mrp2 substrates. The exact mechanism of this mislocalization is unknown, although increased activation of membrane retrieval processes may be one possibility. The current study measures the activation status of various mediators implicated in the active membrane retrieval or insertion of membrane proteins to identify which processes may be important in rodent methionine and choline deficient diet-induced NASH. The mediators currently known to be associated with transporter mislocalization are stimulated by oxidative stressors and choleretic stimuli, which play a role in the pathogenesis of NASH. The activation of protein kinases PKA, PKCα, PKCδ, and PKCε and substrates radixin, myristoylated alanine-rich C-kinase substrate, and Rab11 were measured by comparing the expression, phosphorylation, and membrane translocation between control and NASH. Many of the mediators exhibited altered activation in NASH rats. Consistent with membrane retrieval of Mrp2, NASH rats exhibited a decreased phosphorylation of radixin and increased membrane localization of PKCδ and PKCε, thought to be mediators of radixin dephosphorylation. Altered activation of PKCδ, PKA, and PKCα may impair the Rab11-mediated active insertion of Mrp2. Overall, these data suggest alterations in membrane retrieval and insertion processes that may contribute to altered localization of membrane proteins in NASH.

Association of the DRD2 CAn-STR and DRD3 Ser9Gly polymorphisms with Parkinson's disease and response to dopamine agonists

Dopamine agonists (DAs) play important roles in the treatment of Parkinson's disease (PD). Currently, it is thought that genetic variations in the genes encoding dopamine receptors (DR) are important factors in determining inter-individual variability in drug responses. To investigate the association between Dopamine receptor D type 2 (DRD2) dinucleotide short tandem repeat (CAn-STR) and Dopamine receptor D type 3 (DRD3) Ser9Gly polymorphisms and the risk of PD, as well as the possible reasons for PD patients using different doses of DAs, we recruited 168 idiopathic PD patients and 182 controls. There were no significant differences in DRD2 CAn-STR and DRD3 Ser9Gly genotypes (p=0.184, p=0.196) or in allele frequencies (p=0.239, p=0.290) between PD patients and controls. There was no association between DRD2 CAn-STR polymorphism and doses of DAs. Among three different DRD3 Ser9Gly genotypes (Ser/Ser, Ser/Gly, Gly/Gly), patients carrying Gly/Gly genotype used higher doses of DAs than patients with Ser/Gly and Ser/Ser genotypes (p=0.001). In pramipexole subgroup, the Gly/Gly group took more pramipexole than the other genotype groups (p<0.001), whereas the doses of piribedil were not significantly different among three genotypes (p=0.735). Our results suggest that genotype in DRD3 Ser9Gly was the main factor determining different doses of DAs and PD patients carrying Gly/Gly genotype require higher doses of pramipexole for effective treatment. This study may provide insights into understanding possible reasons for different responses to DAs in Chinese PD patients.

RP1-13D10.2 Is a Novel Modulator of Statin-Induced Changes in Cholesterol.

Numerous genetic contributors to cardiovascular disease risk have been identified through genome-wide association studies; however, identifying the molecular mechanism underlying these associations is not straightforward. The Justification for the Use of Statins in Primary Prevention: An Intervention Trial Evaluating Rosuvastatin (JUPITER) trial of rosuvastatin users identified a sub-genome-wide association of rs6924995, a single-nucleotide polymorphism ≈10 kb downstream of myosin regulatory light chain interacting protein (MYLIP, aka IDOL and inducible degrader of low-density lipoprotein receptor [LDLR]), with LDL cholesterol statin response. Interestingly, although this signal was initially attributed to MYLIP, rs6924995 lies within RP1-13D10.2, an uncharacterized long noncoding RNA. Using simvastatin and sham incubated lymphoblastoid cell lines from participants of the Cholesterol and Pharmacogenetics (CAP) simvastatin clinical trial, we found that statin-induced change in RP1-13D10.2 levels differed between cell lines from the tails of the white and black low-density lipoprotein cholesterol response distributions, whereas no difference in MYLIP was observed. RP1-13D10.2 overexpression in Huh7 and HepG2 increased LDLR transcript levels, increased LDL uptake, and decreased media levels of apolipoprotein B. In addition, we found a trend of slight differences in the effects of RP1-13D10.2 overexpression on LDLR transcript levels between hepatoma cells transfected with the rs6924995 A versus G allele and a suggestion of an association between rs6924995 and RP1-10D13.2 expression levels in the CAP lymphoblastoid cell lines. Finally, RP1-13D10.2 expression levels seem to be sterol regulated, consistent with its potential role as a novel lipid regulator. RP1-13D10.2 is a long noncoding RNA that regulates LDLR and may contribute to low-density lipoprotein cholesterol response to statin treatment. These findings highlight the potential role of noncoding RNAs as determinants of interindividual variation in drug response.

Pharmacogenetic analysis of advanced non-small-cell lung cancer patients treated with first-line paclitaxel and carboplatin chemotherapy.

Genetic polymorphisms contribute toward interindividual variations in drug response. We investigated the effects of genetic polymorphisms on the clinical outcome of advanced non-small-cell lung cancer patients with first-line paclitaxel and carboplatin. A total of 194 non-small-cell lung cancer patients were prospectively enrolled from January 2010 to January 2013. We genotyped 11 polymorphisms in seven genes involved in the glycolysis pathway and the related pharmacokinetic/pharmacodynamic pathway. Genetic associations with PET-SUV, survival outcome, and toxicity were analyzed, and in-vitro drug transport activity was measured in the oocyte system. Patients with the c.334 T>G and c.699 G>A homozygous variant in SLCO1B3 showed a higher incidence of grade 3/4 anemia (P=0.002). Transport activities of oocyte that overexpress the SLCO1B3 c.699 G>A variant showed a significantly decreased uptake of paclitaxel compared with the wild-type expressing oocytes. In addition, patients with GG/GA/AA genotypes of ABCB1, c.2677 T>G/A locus showed inferior progression-free survival (hazard ratio=1.49, P=0.017) compared with other genotypes. The GA genotype of HIF1A, c.1834 G>A locus was associated with inferior progression-free survival compared with the GG genotype (hazard ratio=2.47, P=0.008). This study showed that the SLCO1B3 c.699 G>A polymorphism may predict anemia and ABCB1, HIF1A polymorphism are highly predictive for worse survival in advanced NSCLC with first-line paclitaxel and carboplatin.

DNA Methylation of ADME Genes.

The epigenetic regulation of expression of genes involved in the absorption, distribution, metabolism, and excretion (ADME) of drugs contributes to interindividual variability in drug response. Epigenetic mechanisms include DNA methylation, histone modifications, and miRNAs. This review systematically outlines the influence of DNA methylation on ADME gene expression and highlights the consequences for interindividual variability in drug response or drug-induced toxicity and the implications for personalized medicine.

The Frequency of UGT2B7*2 (802C&gt;T) Allele among Healthy Unrelated Jordanian Volunteers

The UDP-Glucuronesyl Transferase (UGT) 2B7*2 802C>T is the most common functional genetic variant on UGT2B7 gene with reported influence on drug response. Objective: To determine the frequency of UGT2B7*2 (802C>T) genetic variant among Jordanian population. Methods: The DNA samples from 90 healthy Jordanian volunteers were analyzed by polymerase chain reaction followed by restriction fragment length polymorphism assays (PCR-RFLP) to determine the UGT2B7*2 allele. Results: The frequency (95% confidence interval) of UGT2B7*2 802C allele was 0.59 (0.52 to 0.66) and for UGT2B7*2 802T was 0.41 (0.34 to 0.48), which was similar to the Caucasian but different than African ethnic populations. The UGT2B7 genotype frequency among Jordanians was 0.31 (0.22 to 0.4) for wild, 0.57(0.47 to 0.67) for heterozygote and 0.12 (0.06 to 0.18) for homozygote UGT2B7*2 genotype. Conclusion: This study reported for the first time the UGT2B7*2 frequency and genotype profile among Jordanians. The findings of this study will increase our understanding in explaining the inter-individual variation in drug response among Jordanian population.

Genetics of resistant hypertension: a novel pharmacogenomics phenotype.

Resistant hypertension (RHTN), defined as an uncontrolled blood pressure despite the use of multiple antihypertensive medications, is an increasing clinical problem associated with increased cardiovascular (CV) risk, including stroke and target organ damage. Genetic variability in blood pressure (BP)-regulating genes and pathways may, in part, account for the variability in BP response to antihypertensive agents, when taken alone or in combination, and may contribute to the RHTN phenotype. Pharmacogenomics focuses on the identification of genetic factors responsible for inter-individual variability in drug response. Expanding pharmacogenomics research to include patients with RHTN taking multiple BP-lowering medications may identify genetic markers associated with RHTN. To date, the available evidence surrounding pharmacogenomics in RHTN is limited and primarily focused on candidate genes. In this review, we summarize the most current data in RHTN pharmacogenomics and offer some recommendations on how to advance the field.