Journal of pharmacogenomics & pharmacoproteomics最新文献

{"title":"Respiratory Viral Infections and Subversion of Cellular Antioxidant Defenses.","authors":"Narayana Komaravelli,&nbsp;Antonella Casola","doi":"10.4172/2153-0645.1000141","DOIUrl":"https://doi.org/10.4172/2153-0645.1000141","url":null,"abstract":"<p><p>Reactive oxygen species (ROS) formation is part of normal cellular aerobic metabolism, due to respiration and oxidation of nutrients in order to generate energy. Low levels of ROS are involved in cellular signaling and are well controlled by the cellular antioxidant defense system. Elevated levels of ROS generation due to pollutants, toxins and radiation exposure, as well as infections, are associated with oxidative stress causing cellular damage. Several respiratory viruses, including respiratory syncytial virus (RSV), human metapneumovirus (hMPV) and influenza, induce increased ROS formation, both intracellularly and as a result of increased inflammatory cell recruitment at the site of infection. They also reduce antioxidant enzyme (AOE) levels and/or activity, leading to unbalanced oxidative-antioxidant status and subsequent oxidative cell damage. Expression of several AOE is controlled by the activation of the nuclear transcription factor NF-E2-related factor 2 (Nrf2), through binding to the antioxidant responsive element (ARE) present in the AOE gene promoters. While exposure to several pro-oxidant stimuli usually leads to Nrf2 activation and upregulation of AOE expression, respiratory viral infections are associated with inhibition of AOE expression/activity, which in the case of RSV and hMPV is associated with reduced Nrf2 nuclear localization, decreased cellular levels and reduced ARE-dependent gene transcription. Therefore, administration of antioxidant mimetics or Nrf2 inducers represents potential viable therapeutic approaches to viral-induced diseases, such as respiratory infections and other infections associated with decreased cellular antioxidant capacity.</p>","PeriodicalId":89693,"journal":{"name":"Journal of pharmacogenomics & pharmacoproteomics","volume":"5 4","pages":""},"PeriodicalIF":0.0,"publicationDate":"2014-09-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4288774/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"32970815","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Pharmacogenetics of Statin-Induced Myopathy: A Focused Review of the Clinical Translation of Pharmacokinetic Genetic Variants.","authors":"Jasmine A Talameh,&nbsp;Joseph P Kitzmiller","doi":"10.4172/2153-0645.1000128","DOIUrl":"https://doi.org/10.4172/2153-0645.1000128","url":null,"abstract":"<p><p>Statins are the most commonly prescribed drugs in the United States and are extremely effective in reducing major cardiovascular events in the millions of Americans with hyperlipidemia. However, many patients (up to 25%) cannot tolerate or discontinue statin therapy due to statin-induced myopathy (SIM). Patients will continue to experience SIM at unacceptably high rates or experience unnecessary cardiovascular events (as a result of discontinuing or decreasing their statin therapy) until strategies for predicting or mitigating SIM are identified. A promising strategy for predicting or mitigating SIM is pharmacogenetic testing, particularly of pharmacokinetic genetic variants as SIM is related to statin exposure. Data is emerging on the association between pharmacokinetic genetic variants and SIM. A current, critical evaluation of the literature on pharmacokinetic genetic variants and SIM for potential translation to clinical practice is lacking. This review focuses specifically on pharmacokinetic genetic variants and their association with SIM clinical outcomes. We also discuss future directions, specific to the research on pharmacokinetic genetic variants, which could speed the translation into clinical practice. For simvastatin, we did not find sufficient evidence to support the clinical translation of pharmacokinetic genetic variants other than <i>SLCO1B1</i>. However, <i>SLCO1B1</i> may also be clinically relevant for pravastatin- and pitavastatin-induced myopathy, but additional studies assessing SIM clinical outcome are needed. <i>CYP2D6*4</i> may be clinically relevant for atorvastatin-induced myopathy, but mechanistic studies are needed. Future research efforts need to incorporate statin-specific analyses, multi-variant analyses, and a standard definition of SIM. As the use of statins is extremely common and SIM continues to occur in a significant number of patients, future research investments in pharmacokinetic genetic variants have the potential to make a profound impact on public health.</p>","PeriodicalId":89693,"journal":{"name":"Journal of pharmacogenomics & pharmacoproteomics","volume":"5 2","pages":""},"PeriodicalIF":0.0,"publicationDate":"2014-04-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.4172/2153-0645.1000128","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"32668659","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Beyond IC₅₀<i>s</i>: Towards Robust Statistical Methods for <i>in vitro</i> Association Studies.","authors":"Andrew Beam,&nbsp;Alison Motsinger-Reif","doi":"10.4172/2153-0645.1000121","DOIUrl":"https://doi.org/10.4172/2153-0645.1000121","url":null,"abstract":"<p><p>Cell line cytotoxicity assays have become increasingly popular approaches for genetic and genomic studies of differential cytotoxic response. There are an increasing number of success stories, but relatively little evaluation of the statistical approaches used in such studies. In the vast majority of these studies, concentration response is summarized using curve-fitting approaches, and then summary measure(s) are used as the phenotype in subsequent genetic association studies. The curve is usually summarized by a single parameter such as the curve's inflection point (e.g. the EC/IC₅₀). Such modeling makes major assumptions and has statistical limitations that should be considered. In the current review, we discuss the limitations of the EC/IC₅₀ as a phenotype in association studies, and highlight some potential limitations with a simulation experiment. Finally, we discuss some alternative analysis approaches that have been shown to be more robust.</p>","PeriodicalId":89693,"journal":{"name":"Journal of pharmacogenomics & pharmacoproteomics","volume":"5 1","pages":"1000121"},"PeriodicalIF":0.0,"publicationDate":"2014-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.4172/2153-0645.1000121","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"32574716","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"A Proposal for an Individualized Pharmacogenetic-Guided Warfarin Dosage Regimen for Puerto Rican Patients Commencing Anticoagulation Therapy.","authors":"Luis Ángel Bermúdez Bosch","doi":"10.4172/2153-0645.T-001","DOIUrl":"10.4172/2153-0645.T-001","url":null,"abstract":"<p><p>Warfarin is the current standard of care in oral anticoagulation therapy. It is commonly prescribed to treat venous thromboembolism, pulmonary embolism, acute myocardial infarction, and to decrease the risk of stroke in atrial fibrillation. Warfarin therapy is challenging because of marked and often unpredictable inter-individual dosing variations that effectively reach and maintain adequate anticoagulation. Several researchers have developed pharmacogenetic-guided maintenance dose algorithms that incorporate genetics and individual patient characteristics. However, there is limited information available concerning dosing during warfarin initiation. This is considered the most clinically challenging therapeutic phase. In such, the risk of recurrent thromboembolism and hemorrhage are elevated. The objective of this retrospective study is to predict the individual initial doses for Puerto Rican patients (n=175) commencing anticoagulation therapy at Veterans Affairs Caribbean Healthcare System (VACHS) using pharmacogenetic/pharmacokinetic-driven model. A pharmacogenetic driven model (R2=0.4809) was developed in Puerto Rican patients and combined with pharmacokinetic formulas that enabled us to predict the individual initial doses for patients (n=121) commencing anticoagulation therapy. WinNonlin® pharmacokinetic-pharmacodynamic simulations were carried out to determine the predictability of this model. This model demonstrated promising results with few (n=10) simulations outside of their respective therapy range. A customized pharmacogenetic-based warfarin maintenance dose algorithm (R2=0.7659) was developed in a derivation cohort of 131 patients. The predictability of this developed pharmacogenetic algorithm was compared with the International Warfarin Pharmacogenomics Consortium (IWPC) algorithm and it demonstrated superior predictability within our study population.</p>","PeriodicalId":89693,"journal":{"name":"Journal of pharmacogenomics & pharmacoproteomics","volume":"5 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2014-01-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4181534/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"32722309","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Frequencies of Functional Polymorphisms in Three Pharmacokinetic Genes of Clinical Interest within the Admixed Puerto Rican Population.","authors":"Carmelo Orengo-Mercado, Bianca Nieves, Lizbeth López, Nabila Vallés-Ortiz, Jessicca Y Renta, Pedro J Santiago-Borrero, Carmen L Cadilla, Jorge Duconge","doi":"10.4172/2153-0645.1000113","DOIUrl":"10.4172/2153-0645.1000113","url":null,"abstract":"<p><strong>Objective: </strong>This cross-sectional study was aimed at determining the allele frequencies for the <i>CYP2C19*2, CYP2C19*3, CYP2D6*10</i> and <i>PON1</i> (rs662) polymorphisms in the Puerto Rican population. The <i>CYP2C19, CYP2D6</i> and <i>PON1</i> genes are known to be associated with functional changes in drug metabolism and activation. Individuals carrying the aforementioned polymorphisms are at a higher risk of suffering from drug-induced adverse events and/ or unresponsiveness from a variety of drugs that includes antidepressants, atypical antipsychotics and antiplatelet compounds. Information on the frequency of these polymorphisms is more commonly found on homogeneous populations, but is scarce in highly heterogeneous populations like Hispanics, as in the case of Puerto Ricans.</p><p><strong>Method: </strong>Genotyping was carried out in 100 genomic DNA samples from dried blood spots supplied by the Puerto Rican Newborn Screening program using Taqman® Genotyping Assays.</p><p><strong>Results: </strong>The Minor Allele Frequencies (MAF) obtained were 9% for <i>CYP2C19*2</i> and <i>CYP2D6*10,</i> 50% for <i>PON1</i> (rs662), while the <i>CYP2C19*3</i> variant was not detected in our study. Furthermore, Hardy Weinberg equilibrium analysis was assessed as well as a comparison between Puerto Rico and other reference populations using a Z-test for proportions.</p><p><strong>Conclusion: </strong>The observed allele and genotype frequencies on these relevant pharmacogenes in Puerto Ricans were more closely related to those early reported in two other reference populations of Americans (Mexicans and Colombians).</p>","PeriodicalId":89693,"journal":{"name":"Journal of pharmacogenomics & pharmacoproteomics","volume":"4 113","pages":""},"PeriodicalIF":0.0,"publicationDate":"2013-03-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3769800/pdf/nihms-499933.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"31736457","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Omics Screening for Pharmaceutical Efficacy and Safety in Clinical Practice.","authors":"Andrew A Monte,&nbsp;Vasilis Vasiliou,&nbsp;Kennon J Heard","doi":"10.4172/2153-0645.s5-001","DOIUrl":"10.4172/2153-0645.s5-001","url":null,"abstract":"<p><p>As molecular techniques have improved, investigators have attempted to improve pharmaceutical efficacy and safety by making trait associations with genomic, epigenomic, transcriptomic, proteomic, and metabolomic polymorphisms. The 'omics era has seen screening assays for pharmaceutical efficacy and safety translated into clinical practice. This manuscript will discuss each 'omic field and the screening assays available to the clinician. While success has been demonstrated in each 'omic field, many challenges remain. Assays need wider availability, predictive values remain low, and costs remain high. In order for clinicians to realize improved efficacy and safety due 'omic screens, development of improved techniques, combining of 'omic assays, and increased clinical utilization is necessary. This is an exciting time for investigators and clinicians that desire improved pharmaceutical therapy.</p>","PeriodicalId":89693,"journal":{"name":"Journal of pharmacogenomics & pharmacoproteomics","volume":"S5 ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2012-03-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3526192/pdf/nihms421602.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"31140947","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Epigenomics: Pioneering a New Frontier in Cancer Research.","authors":"Yana Chervona,&nbsp;Max Costa,&nbsp;Wei Dai","doi":"10.4172/2153-0645.1000e109","DOIUrl":"https://doi.org/10.4172/2153-0645.1000e109","url":null,"abstract":"Cancer typically occurs as the consequence of mutations or deregulated expression of genes that control cell survival, proliferation and/or death. Given its remarkable intricacy and complexity, the concept of cancer as a disease that can be greatly impacted by alterations in epigenetic regulation (and thus gene expression) has gained considerable momentum within the scientific community. In the 1990s, one focal point of epigenetic cancer research was ascertaining the extent of DNA methylation abnormalities and defining how DNA methylation influences expression of oncogenes and tumor suppressor genes in transformed cells [1]. However, during the past decade, this focus has been significantly broadened by the upsurge of research identifying and studying the role of molecules that affect chromatin dynamics (i.e. global DNA methylation and post-translational modifications of histones) in cancer cells. This new wave of research has given way to an emerging view of what may now be called “the cancer epigenome,” which consists of heritable abnormalities that occur in the absence of DNA sequence alterations in the genome [2].","PeriodicalId":89693,"journal":{"name":"Journal of pharmacogenomics & pharmacoproteomics","volume":"3 ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2012-01-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4118684/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"32556831","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Acceptance of Asthma Pharmacogenetic Study by Children and Adults.","authors":"Ann Chen Wu,&nbsp;Robert Davis,&nbsp;Kelan Tantisira,&nbsp;M Maya Dutta-Linn,&nbsp;Mia Hemmes,&nbsp;Scott T Weiss","doi":"10.4172/2153-0645.1000103","DOIUrl":"https://doi.org/10.4172/2153-0645.1000103","url":null,"abstract":"<p><strong>Background: </strong>Pharmacogenetic testing may change clinical medicine by allowing clinicians to tailor medications based on a patient's genetic makeup, however, these tests must first be validated in large, real-life populations of subjects that include children. A dearth of knowledge exists for whether pediatric populations are as willing as adult populations to provide samples for such studies.</p><p><strong>Objective: </strong>(1) To assess whether pediatric and adult patients with persistent asthma are willing to provide specimens for DNA extraction and genetic studies. (2) To assess whether patients' willingness to provide blood as compared to buccal smear specimens differ.</p><p><strong>Methods: </strong>Of 644 patients ages 4-38 years who had three or more prescription fills for inhaled corticosteroids in one year, 60% (385) were randomized to the blood specimen group and 40% (259) were randomized to the buccal smear group in order to study acceptance of different biospecimen collection methods. Research assistants contacted subjects to obtain consent, perform a phone survey, and request a specimen.</p><p><strong>Results: </strong>There were no baseline differences between subjects randomized to the blood specimen group versus buccal smear group with respect to age, gender, or number of dispensings of inhaled corticosteroids. Of 259 subjects in the buccal smear group, 30% (78) provided samples, and of 385 subjects in the blood specimen group, 16% (60) provided samples. Subjects randomized to the buccal smear group were more likely to provide specimens for genetic study compared to subjects randomized to the blood specimen group (RR 1.21; 95% CI 1.10 - 1.32), even after adjusting for age. Pediatric subjects were more likely to provide specimens for genetic study than adult subjects with 23% (113) of pediatric subjects providing samples and 15% (25) of adult subjects providing samples (p=0.03).</p><p><strong>Conclusion: </strong>Children with asthma are as likely to participate in genetic studies as adults. Both children and adult subjects are more likely to provide buccal smear specimens rather than blood specimens for genetic study.</p>","PeriodicalId":89693,"journal":{"name":"Journal of pharmacogenomics & pharmacoproteomics","volume":"2 103","pages":""},"PeriodicalIF":0.0,"publicationDate":"2011-04-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3614400/pdf/nihms388969.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"40247319","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The Emerging Role of Admixture in the Pharmacogenetics of Puerto Rican Hispanics.","authors":"Jorge Duconge, Gualberto Ruaño","doi":"10.4172/2153-0645.1000101","DOIUrl":"10.4172/2153-0645.1000101","url":null,"abstract":"<p><p>Admixture is of great relevance to the clinical application of pharmacogenetics and personalized medicine. Preliminary findings in Puerto Ricans further substantiate the argument for admixture as a critical covariate in a customized DNA-guided warfarin dosing algorithm. To this purpose, a genome-wide approach that incorporates admixture as an independent predictor of dose variability in DNA-guided algorithms has been postulated. Admixture is expected to be able to reveal some relevant associations in the genetic epidemiology of Hispanics and will be indispensable to assure that pharmacogenomic research can be pursued in such mixed populations. Consequently, the clinical utility of knowing an individual's genotype before initiating drug treatment in Puerto Ricans, and Hispanics in general, will finally be untangled by developing a \"Genetic Prescription Model\" that takes admixture into consideration. This approach will help lead physicians and patients to their desired treatment goal, resulting in more effective healthcare in admixed people.</p>","PeriodicalId":89693,"journal":{"name":"Journal of pharmacogenomics & pharmacoproteomics","volume":"1 101","pages":""},"PeriodicalIF":0.0,"publicationDate":"2010-10-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3515058/pdf/nihms276155.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"31111922","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}