Current Pharmacogenomics and Personalized Medicine (Formerly Current Pharmacogenomics) - Volume 12, Issue 4, 2014

In the last few decades, popularity of coronary interventions has risen rapidly. Widespread use of coronary stents and high number of patients with atherosclerosis made the stents the focus of attention by the industry. This has led the stent technology to evolve rapidly. The aim of this review is to outline the evolution of coronary stents and the stent components in the timeline. Pharmacogenomics, personalized medicine and computational fluid dynamics can help us to design individualized stents.

Pancreatic cancer is the fourth leading cause of death from cancer. Maximizing therapeutic benefit relies on careful review of inter-individual characteristics. Current and future pharmacogenomics principles may assist in this personal approach and may eventually become widespread. Until then, providers must rely on the available data that might be considered most applicable at the current time. Systemic treatment of unresectable or metastatic pancreatic cancer has been based on gemcitabine and gemcitabine containing combinations for nearly fifteen years. Recently, clinical studies have substantiated two effective combination regimens, FOLFIRINOX, and gemcitabine plus nab-paclitaxel. These regimens have become standard of care for many patients. However, interindividual differences including clinical and physiological parameters can have significant implications for treatment planning. Baseline clinical characteristics such as age, performance status, and comorbidities remain a vital consideration in choosing therapy. Pharmacogenomic data are also shedding new light on the disease management. Genes such as BRCA1/2 and ERCC1 are helping to quantify the risk of developing pancreatic cancer and also guiding treatment in the context of efficacy to platinum agents and PARPi. Genetic polymorphisms in nucleoside transporters such as hCNT3 and hENT1 and the enzymes DCK, CDA, and DCTD can help explain the toxicity and efficacy of gemcitabine. Additionally, DPD and UGT1A1 have been useful in rationalizing adverse effects and managing patients who develop severe toxicity to 5-fluorouracil and irinotecan, respectively. Finally, a number of parameters including sequencing of therapy, dose-limiting toxicities, and other practical considerations can all guide the provider in developing an individual, personalized approach to the systemic treatment of unresectable or metastatic pancreatic cancer.

Methadone, a synthetic opioid, is mainly used as an analgesic and a maintenance antiaddictive and reductive preparation in the treatment of opioid dependence. A better understanding of the factors underlying individual responses to methadone is required in order to improve treatment individualization, thereby potentially leading to better clinical efficacy. Evidence now suggests that pharmacogenetics has a role in the effects of methadone medications, and the efficacy of methadone results from the combined effects of a number of genetic variants, such as single nucleotide polymorphisms (SNPs). Although there are not enough data currently available to prove this hypothesis, more and more genetic variants associated with methadone response are being discovered. In this review, we focus on the most recent developments in pharmacogenetics of methadone. Firstly, we survey the SNPs and genes identified as genetic markers that are correlated and associated with methadone treatment responses in various association studies. Secondly, we investigate candidate genes that have been suggested as contributing to pharmacokinetic properties during the course of methadone treatment in the various studies. For example, cytochrome P450 (CYP) 3A4 and 2B6 have been identified as the main candidate genes involved in methadone metabolism. Furthermore, we summarize the limitations with respect to the mentioned pharmacogenetics studies. Finally, we address a discussion of future directions and challenges. Future research with independent replication in light of large sample sizes and gene-gene interactions is needed to confirm the role of the candidate genes identified in these studies in methadone treatment response and will probably have major contributions for personalized medicine.

The identification of genetic factors that influence drug responses often focuses on genes whose variants are predicted to alter pharmacokinetic and/or pharmacodynamic parameters—leading to an increased risk of drug toxicity or therapeutic failure. In this study, we selected 48 genes identified as “Very Important Pharmacogenes (VIPs)” by the PharmGKB database, and developed a fivefeature Structural Disturbance Score (SDS) for their amino acid variants. “SDS Pharmacogenes” is a score that categorizes distinguishable characteristic profiles that annotate VIP variants as functional rather than neutral mutations. Unlike most existing conservation-based measures, SDS Pharmacogenes can be used to evaluate unknown variants of currently 45/48 VIPs and predict the degree to which each one will have strong impacts towards pharmacogenomics, potentially aiding optimization of drug therapy. SDS Pharmacogenes is built upon a systematic screening for structural disturbance of amino acid mutations within the 45/48 VIPs in the context of their 3-dimensional (3D) protein structures. Our variant evaluation pipeline focuses on the changes in inter-residue bonding, protein stability, protein flexibility, drug binding capability, protein-protein interactions, and amino acid dissimilarity, in addition to the localization of the variants and the amino acid secondary structure preference. While expertise in 3D-protein analysis is beneficial, our implementation does not require that an individual with experience in protein structures be engaged in the personalized genome evaluation, nor expect the users must have bioinformatic backgrounds. In addition, the analysis pipeline is systematic and scalable, thus expected to keep pace with the rapid accumulation of pharmacogenomic data. The SDS Pharmacogenes web application is publicly available at http://sdsp. cig.biology.gatech.edu.

The renin-angiotensin system (RAS) genes polymorphism have been associated with blood pressure (BP) response to antihypertensives drugs and may also influence the variability in visit-tovisit BP. Here we have investigated the association of RAS gene polymorphism with response to three classes of antihypertensive drugs (atenolol, amlodipine and enalapril) and also with genetic factor which may influence the variability in visit-to-visit BP. Total of 230 participants of south Indian ethnicity under the medication of any of these three classes of drugs were enrolled. The four polymorphisms analyzed were AGT M235T (rs699), ACE I/D (rs4340) and G2350A (rs4343) and AT1R A1166C (rs5186) were genotyped in all patients and were analyzed for association. Significant association with visit-to-visit variance in BP was found in ACE G2350A variant with the diastolic blood pressure (DBP) and a high significance was observed in AT1R A1166C variant with both systolic blood pressure (SBP) (p < 0.001) and DBP (p < 0.001). Further, we did not observe any significant association between drug response and RAS gene polymorphisms. The present study revealed significant association of visit-to-visit BP variability with ACE G2350A and AT1R A1166C polymorphisms in essential hypertensive subjects. However, results need to be replicated in larger population.

The present study is part of the genetic mapping of Indonesia focusing on drug metabolizing enzymes, which started with the Buginese population of Makassar, South Sulawesi. The two CYP450 gene subfamilies, i.e. CYP2C9 and CYP2C19 are of interest as they exhibit wide inter-individual variation in expression, which influence the drug metabolism capacity. The CYP2C9 alleles of interest in this study were CYP2C9*2 and *3, and of CYP2C19 was CYP2C19. The study aimed to determine the frequencies of the CYP2C9 genotype, which contains *1, *2 and *3 alleles, and the CYP2C19 genotype, which comprises the *1 and *17 alleles in the Buginese. Ninety six Buginese subjects, comprising 48 males and 48 females were studied. CYP2C9 and CYP2C19 alleles were detected by a PCR-RFLP assay method. Results showed that there was no CYP2C9*2 allele present, while the frequencies of CYP2C9*3 and CYP2C19 overall were 1.56 % and 4.68 %, respectively. The frequency of the CYP2C9*3 allele in females was 2.08%, and not statistically different from that in males (1.05%). The frequency of the CYP2C19 allele in females (8.33%), was significantly different (P<0.05) from that in males (1.05%). No subject carried the CYP2C9*2/*2, CYP2C9*3/*3, CYP2C19*17/*17, or CYP2C9*3/CYP2C19 genotype. The study is the first to describe the drug metabolizing enzyme polymorphisms, CYP2C9 and CYP2C19, in the Indonesian Buginese population.

Tyrosine kinase inhibitors (TKI) have significantly improved the prognosis for chronic myelogenous leukemia (CML) patients. Several mechanisms of resistance have been identified, however. BCR-ABL-dependent resistance is the most frequently occurring, usually as mutations preventing therapeutic drug interaction. This study addresses a mechanism of resistance observed in the absence of mutations. During TKI challenge, of downstream dephosphorylators such as Protein-Tyrosine Phosphatase, Nonreceptor-Type 6 (PTPN6 or SHP1) may supplement oncogenic activation. We retrospectively examined expression and control of SHP1 in TKI sensitive and resistant cases of CML in 122 North American patients of European and African ancestry employing mutation detection, methylation analysis and gene expression. Mean SHP1 gene expression was lower in CML cases (SHP1/beta2 microglobulin% = 399.4) than in nonleukemic samples (SHP1/beta2 microglobulin% = 704.5). Mutations were detected in 16/28, 26/47 and 5/18 of TKIresistant cases by standard PCR, quantitative PCR and sequencing, respectively. Expression of SHP1 was slightly lower in cases of drug-resistant CML than in drug sensitive CML (SHP1/beta 2 microglobulin% = 382 vs 422). Methylation of the SHP1 promoter at CpG site at -456 was significantly higher in cells from CML patients than in cells from normal patients (p=0.023). Depressed expression and increased methylation of SHP1 in CML cells are consistent with a role of tumor suppressor of SHP1, with its loss contributing to malignant cellular phenotypes. Although no significant differences were observed in SHP1 expression and methylation in TKI-resistant and TKI sensitive CML, expression was consistently lower and methylation higher in cases of TKI-resistant CML without detectable ABL kinase mutations. Methylation as the cause of SHP1 (or other tumor suppressor gene) suppression would offer new therapeutic strategies for treating CML.