Areas Of Pharmacogenetics Research Articles

Idiopathic Pulmonary Fibrosis: From Common Microscopy to Single-Cell Biology and Precision Medicine.

Idiopathic pulmonary fibrosis is a chronic, progressive, and usually fatal lung disease of unknown etiology and is included in the large, complex, and heterogeneous group of interstitial lung diseases (ILD). IPF is characterized by an aberrant activation of epithelial cells and fibroblasts and excessive accumulation of extracellular matrix, resulting in the progressive destruction of the lung architecture. Here we approach the fascinating historical evolution of our knowledge about this disorder from the past century, when most efforts were focused on ILD classification and terminology, until the current century, when the explosive progress in molecular genetics, epigenetics, and multiomics, as well as the development of complex computational tools, resulted in a huge advance in unveiling the pathogenic mechanisms of the disease. Recent advances in artificial intelligence, machine and deep learning, and artificial neural networks show promising results in identifying lung fibrotic patterns in high-resolution computed tomography or helping to create a tissue genomic classifier for specific diagnosis. Finally, incipient approaches to precision medicine are ongoing in the area of pharmacogenetics.

Standardizing terms for clinical pharmacogenetic test results: consensus terms from the Clinical Pharmacogenetics Implementation Consortium (CPIC)

Introduction:Reporting and sharing pharmacogenetic test results across clinical laboratories and electronic health records is a crucial step toward the implementation of clinical pharmacogenetics, but allele function and phenotype terms are not standardized. Our goal was to develop terms that can be broadly applied to characterize pharmacogenetic allele function and inferred phenotypes.Materials and methods:Terms currently used by genetic testing laboratories and in the literature were identified. The Clinical Pharmacogenetics Implementation Consortium (CPIC) used the Delphi method to obtain a consensus and agree on uniform terms among pharmacogenetic experts.Results:Experts with diverse involvement in at least one area of pharmacogenetics (clinicians, researchers, genetic testing laboratorians, pharmacogenetics implementers, and clinical informaticians; n = 58) participated. After completion of five surveys, a consensus (>70%) was reached with 90% of experts agreeing to the final sets of pharmacogenetic terms.Discussion:The proposed standardized pharmacogenetic terms will improve the understanding and interpretation of pharmacogenetic tests and reduce confusion by maintaining consistent nomenclature. These standard terms can also facilitate pharmacogenetic data sharing across diverse electronic health care record systems with clinical decision support.Genet Med19 2, 215–223.

Clinical Considerations of Heritable Factors in Common Heart Failure

Heart failure is a common condition responsible for at least 290 000 deaths each year in the United States alone.1 A small minority of heart failure cases are attributed to Mendelian or familial cardiomyopathies. The majority of systolic heart failure cases are not familial but represent the end result of 1 or many conditions that primarily injure the myocardium sufficiently to diminish cardiac output in the absence of compensatory mechanisms. Paradoxically, because they also injure the myocardium, it is the chronic actions of the compensatory mechanisms that in many instances contribute to the progression from simple cardiac injury to dilated cardiomyopathy and overt heart failure. Thus, the epidemiology of common heart failure appears to be just as sporadic as its major antecedent conditions (atherosclerosis, diabetes, hypertension, and viral myocarditis). Familial trends in preclinical cardiac remodeling2 and risk of developing heart failure3 reveal an important role for genetic modifiers in addition to clinical and environmental factors. Candidate gene studies performed over the past 10 years have identified a few polymorphic gene variants that modify risk or progression of common heart failure.4 Whole-genome sequencing will lead to the discovery of other genetic modifiers that were not candidates.5 The imminent availability of individual whole-genome sequences at a cost competitive with available genetic tests for familial cardiomyopathy will no doubt further expand the list of putative genetic heart failure modifiers. Heart failure risk alleles along with traditional clinical factors will need to be considered by clinical cardiologists in their design of optimal disease surveillance and prevention programs and in individually tailoring heart failure management. The use of individual genetic make-up is likely to have the earliest and greatest impact on managing patients with heart failure by tailoring available pharmacotherapeutics to optimize patient response and minimize adverse effects (ie, the …

Pharmacogenetic Approaches to Cognitive Enhancement in Schizophrenia

Research in the area of pharmacogenetics in psychiatry is aimed at identifying clinically relevant genetic variations that can predict treatment response. Ultimately, the goal is to individualize treatment in order to optimize outcome in disorders in which incomplete treatment response is common. Positive symptoms in patients with schizophrenia appear to be the most amenable to the currently available agents; however, negative symptoms and cognitive deficits frequently persist even when frank psychosis is well controlled. Given the relationship between these persistent traits and functional disability in schizophrenia, efforts are under way to directly target cognitive impairment and negative symptoms pharmacologically in order to improve quality of life. To date, most pharmacogenetic studies of schizophrenia have been focused on predicting clinical efficacy and side effects. In this review, we discuss the potential use of cognition as a primary outcome measure of interest in future pharmacogenetic trials of schizophrenia.

Databases in the area of pharmacogenetics

In the area of pharmacogenetics and personalized health care it is obvious that databases, providing important information of the occurrence and consequences of variant genes encoding drug metabolizing enzymes, drug transporters, drug targets, and other proteins of importance for drug response or toxicity, are of critical value for scientists, physicians, and industry. The primary outcome of the pharmacogenomic field is the identification of biomarkers that can predict drug toxicity and drug response, thereby individualizing and improving drug treatment of patients. The drug in question and the polymorphic gene exerting the impact are the main issues to be searched for in the databases. Here, we review the databases that provide useful information in this respect, of benefit for the development of the pharmacogenomic field.

The Human Cytochrome P450 (CYP) Allele Nomenclature website: a peer-reviewed database of CYP variants and their associated effects

Pharmacogenetics affects both pharmacokinetics and pharmacodynamics, thereby influencing an individual's response to drugs, both in terms of response and adverse reactions. Within the area of pharmacogenetics, findings of genetic variation influencing drug levels have been more prevalent, and variation in the cytochrome P450 (CYP) enzymes is one of the most common causes. Much of the work concerning sequence variations in CYPs aims at finding biomarkers of use for individualised treatment, thereby increasing the treatment response, lowering the number of side effects and decreasing the overall cost of treatment regimens. For over ten years, the Human Cytochrome P450 Allele Nomenclature (CYP-allele) website (http://www.cypalleles.ki.se/) has offered a database of genetic information on CYP variants, along with effects at the molecular as well as clinical level. Thus, this database serves as an assembly of past, current and soon-to-be published information on CYP alleles and their outcome effects. The website is used by academic researchers and companies (eg as a tool in drug development and for outlining new research projects). By providing peer-reviewed genetic information on CYP enzymes, the CYP-allele website has become increasingly popular and widely used. Recently, NADPH cytochrome P450 oxidoreductase (POR), the electron donor for CYP enzymes, was included on the website, which already contains 29 CYP genes, hence POR alleles are now also designated using the star allele (POR*) nomenclature. Although most CYPs on the CYP-allele website are involved in the metabolism of xenobiotics, polymorphic enzymes with endogenous functions are also included. Each gene on the CYP-allele website has its own webpage that lists the different alleles with their nucleotide changes, their functional consequences and links to publications in which the allele has been identified and/or characterised. Thus, the CYP-allele website offers a rapid online publication of new alleles, as well as providing an overview of peer-reviewed data.

The intersection of pharmacology, imaging, and genetics in the development of personalized medicine

We currently rely on large randomized controlled trials and meta-analyses to make clinical decisions; this places us at a risk of discarding subgroup or individually specific treatment options owing to their failure to prove efficacious across entire populations. There is a new era emerging in personalized medicine that will focus on individual differences that are not evident phenomenologically. Much research is directed towards identifying genes, endophenotypes, and biomarkers of disease that will facilitate diagnosis and predict treatment outcome. We are at the threshold of being able to predict treatment response, primarily through genetics and neuroimaging. In this review we discuss the most promising markers of treatment response and adverse effects emerging from the areas of pharmacogenetics and neuroimaging in depression and schizophrenia.

Small Molecule Inhibition of Cdc7, a Key Cell Cycle Regulator and Novel Therapeutic Target, Successfully Inhibits Leukemia Cell Growth in Vitro and in Vivo

Cdc7 is a heterodimeric serine/threonine protein kinase that is a key regulator in the process of initiation of DNA replication and the G1 to S phase transition. Both the kinase and its known substrates are over-expressed in the majority of human cancers. As a result of the recent progress in the areas of pharmacogenetics and high throughput screening technology, identifying specific small molecule inhibitors of cell cycle regulated protein kinases has provided a means not only to study these signal transduction pathways but also to identify potential novel therapeutic agents. To this end, we have developed an assay for Cdc7 kinase inhibitory activity using a highthroughput screening (HTS) approach, screening over 250,000 natural and synthetic small molecules. As a result, we have identified and confirmed seventeen compounds, representing nine different chemical scaffolds, with Cdc7 kinase inhibitory activity. Based on potency, we selected the lead compound (CKI-7) which was further characterized using kinase profiling, microarray experiments, and standard cell based cytotoxicity assays. These latter studies demonstrated that CKI-7 induced cytotoxicity of established leukemia and lymphoma cell lines in culture with inhibitory concentrations (IC50s) in the low nanomolar range. Significantly, CKI-7 likewise induced cytotoxicity of MDR1 overexpressing cell lines with similar IC50s, demonstrating that this novel compound can overcome a major mechanism of chemotherapy resistence in human tumor cells. We additonally demonstrate that CKI-7 induces cytotoxicity of patient-derived primary acute leukemia tumor cells (both chemotherapy naïve and relapsed/refractory samples) in vitro at similarly low nanomolar concentrations. In vivo dose-dependent anti-tumor activity of CKI-7 was subsequently demonstrated in a SCID-Beige mouse systemic tumor model utilzing a recently isolated Philadelphia chromosome positive acute lymphoblastic leukemia cell line (PhALL3.1). Standard cell cycle synchronization studies established that exposure to CKI-7 results in cell cycle dependent caspase 3 activation and apoptotic cell death. This cell death is the direct result of Cdc7 kinase inhibition by CKI-7 as demonstrated using a substrate biomarker assay. In conclusion, our data confirm that Cdc7 is a new promising target for cancer therapy, and that CKI-7, a selective small molecule inhibitor of this enzyme, is an equally promising novel cancer therapeutic agent.

The Marshfield Clinic Personalized Medicine Research Project: 2008 scientific update and lessons learned in the first 6years.

The Marshfield Clinic Personalized Medicine Research Project is the largest population-based biobank in the USA, with the ability to recontact subjects to obtain additional information to facilitate gene-environment studies. Nearly 20,000 adults have enrolled in the Personalized Medicine Research Project since 2001, after providing active written consent to access their Marshfield Clinic medical records to define phenotype and providing blood samples from which DNA, plasma and serum samples were stored. Numerous studies are underway in the area of pharmacogenetics and genetic epidemiology. In addition to the scientific discoveries being made, much has been learned regarding biobanking and the management of large amounts of data being generated. The purpose of this paper is to share the advice provided by the external Scientific Advisory Board and the scientific lessons learned along the way to build this research infrastructure and facilitate its use.

Pharmacogenetics and paediatric drug development: issues and consequences to labelling and dosing recommendations

The area of pharmacogenetics (PGt) is evolving rapidly. However, ongoing efforts in this field are not aligned with the requirements for the inclusion of clinically relevant findings into the label, especially with reference to paediatric indications. Clinical research in children poses unique issues from a practical and technical perspective, but many challenges can be overcome by applying advanced study design and data analysis methods. When investigating the role of PGt factors on treatment effect, all features that influence drug response must be taken into account. Yet, PGt often has a privileged status in research protocols, with PGt factors evaluated independently from other determinants of response, instead of being regarded as other demographic or clinical covariates (e.g., age, renal function). At present, guidelines to incorporate PGt findings into label statements are lacking in part because this is a new and incompletely understood area. This situation is no longer acceptable. To achieve the potential that PGt can offer to drug development and ultimately to drug prescription, academia, industry and regulatory agencies need to pool resources on the revision of study design and data analysis requisites, bringing in model-based methodologies to enable accurate interpretation of results and provide appropriate labelling recommendations.

Cytochrome P450 Protocols, 2nd edn

The pace of research on the cytochrome P450 superfamily of drug-metabolizing enzymes shows no signs of abating. This has been partly fuelled by renewed interest in the areas of pharmacogenetics and drug–drug interactions in relation to drug response. Much effort is being invested into the development and application of in vitro techniques to predict drug pharmacokinetics in vivo. In particular, cytochrome P450 in vitro inhibition data are a valuable aid in the design of clinical drug–drug interaction studies. The techniques used to study cytochrome P450 are varied, complex and subject to pitfalls. Detailed information on these methodologies tends to be scattered throughout the literature in very much a nonstandardized fashion. In this book, Ian Phillips and Elizabeth Shephard have brought much of this information ‘under one roof’ based on contributions from many individuals who have been involved in the development of these techniques. The two most impressive features of the book are (i) the step-by-step approach in the description of each method, which is generally straightforward and easy to understand, and (ii) the detailed notes at the end of each recipe. The latter give many extremely useful tips for optimizing experimental conditions, e.g. stating if a compound is light sensitive, or suggesting that fresh solutions of a compound should be prepared for each experiment, and for how results should be interpreted. In addition to the experimental detail, most chapters contain good, in-depth accounts of the background to each topic. There are 37 chapters, the book starting with a discussion of cytochrome P450 nomenclature. Although there is very thorough coverage of how individual enzymes are named, data are presented only up to September 2004 (out-of-date information is the bane of text books, particularly those that are multiauthored), at which time 3811 different forms had been identified. Looking at the author's website (http://drnelson.utmem.edu/P450.stats.2006.htm, accessed 2006 September 1), there has been a substantial increase to 6051 in the last 2 years. Fortunately for those of us studying them, only a small number of cytochromes P450 are involved in human drug metabolism. A further chapter on the Nomenclature Committee website appears rather oddly out of sequence in the middle of the book. This chapter focuses on human cytochromes P450, and rightly urges the interested reader to visit regularly the CYP allele website (http://www.imm.ki.se/CYPalleles) for updates. The topics covered include purification and detection techniques, use of liver microsomes and hepatocytes, enzyme assays, expression in heterologous systems, techniques for studying regulation and genetic polymorphisms of enzymes, and finally knockout mouse technology. The methods presented are mainly up to date, although it is surprising to see descriptions of probe substrate assays using the rather outdated techniques of spectrophotometry (for p-nitrophenol hydroxylase) and thin-layer chromatography (testosterone 6β-hydroxylase). My laboratory-based colleagues all praised this book, and I thank them for their input into this review. Although not cheap, I believe that it will be useful to everybody, from novices to experts, engaged in cytochrome P450 research.

Evaluation of an algorithm of tagging SNPs selection by linkage disequilibrium

Background: Single nucleotide polymorphisms (SNPs) are the most abundant kind of genetic polymorphism in the human genome. They are important in both genetic research and genetic testing in a clinical setting, such as in the area of pharmacogenetics. In order to improve efficiency, tagging SNPs (tagSNPs) are selected in genes of interest to represent other co-related SNPs in linkage disequilibrium (LD) with the tagSNPs. Various algorithms have been proposed to identify a subset of single nucleotide polymorphisms as tagSNPs. Most algorithms of tagSNPs selection are haplotype-based, in which the spatial relationship between SNPs is considered. Currently, a more efficient cluster-based algorithm is proposed which clusters SNPs solely by a LD parameter, such as r 2. Here, we evaluated the sample distribution of r 2 and its effect on the cluster-based tagSNPs selection. Design and methods: The genotype data of 198 individual within a 500-kb region on 5q31 was used to evaluate the sample distribution of r 2 and its effect on the cluster-based tagSNPs selection. Results: It was found that the degree of variation of LD depends on the LD structure of genes. Conclusion: As a cluster-based tagSNPs selection algorithm does not take into account the spatial position of SNPs, a more stringent r 2 threshold is required to achieve more reliable tagSNPs selection.

Metastatic Colorectal Cancer: First- and Second-Line Treatment in 2005

First-, second-, and third-line therapies for the treatment of metastatic colorectal cancer may influence choices for subsequent therapy. First-line treatment for metastatic colorectal cancer depends largely on combination chemotherapy regimens that have been proven to prolong survival, control disease progression, and improve quality of life, without excessive toxicity. Standard therapies include 5-fluorouracil, irinotecan, and oxaliplatin, but other combination therapies are currently under investigation. An upcoming area of study includes agents that target vascular endothelial growth factor and epidermal growth factor receptor. While doublet therapy is more active than 5-fluorouracil alone, triplet therapy is also emerging. Second-line therapy is dependent upon prior treatment, and second-line FOLFIRI or FOLFOX regimens that incorporate 5-fluorouracil, leucovorin, and either irinotecan or oxaliplatin, respectively, are still in question because of residual toxicities. After combination chemotherapy, a non-cross-resistant chemotherapy is the best choice. Second-line targeted therapy has been well-tolerated and active in several trials. Future developments will most likely occur in the areas of pharmacogenetics (eg, toxicity, age, comorbidities, patient choice, strategy of cure, palliation) and pharmacogenomics (eg, resistance/activity, gene expression) to produce individualized therapies for patients. The type of adjuvant treatment, genomic consideration, and genetic predisposition will be determining factors in the ideal protocol for first-line therapy.

Is There a Common Biological Basis for Reinforcement from Alcohol and Other Drugs?

Vulnerability to substance abuse is an important emerging issue. A critical aspect of this phenomenon is the degree to which individuals who abuse one substance are likely to abuse other substances, alone or in combination with each other. The extent to which several distinct drugs will come to serve as positive reinforcers within genetically defined subjects defines their commonality. Questions in this area are directed at determining whether reinforcement from and abuse of alcohol and other drugs define variations within a single behavioral phenomenon, or whether reinforcement and abuse must be individually defined for each substance involved. Findings related to this commonality issue are now emerging from the areas of pharmacogenetics and operant drug self-administration. Previous studies have shown that ethanol can be readily established as a positive reinforcer in LEWIS rats, as well as C57BL/6J mice. In low ethanol preferring F344 rats, ethanol maintains significant but low levels of responding. Ethanol does not maintain lever pressing behavior in BALB/cJ mice, and is avoided in DBA/2J mice. Initial findings reported in this paper show that these genotypic patterns of reinforcement from ethanol appear to correlate highly with patterns of reinforcement from cocaine and opiates. From these findings it is concluded that (1) there exist important genetic determinants of drug reinforced behavior; and (2) drug seeking behaviors maintained by ethanol, cocaine and opiates may have at least some common biological determinants.

Genetic approaches to studying drug abuse: Correlates of drug self-administration

Some important issues in substance abuse are the relationship between propensity to self-administer a drug and neurosensitivity to that drug; similarities and differences between various models of drug-seeking behavior; and the commonality of drug-seeking behavior across drugs and genotypes. Findings related to these issues are now emerging from the areas of pharmacogenetics and operant drug self-administration. Ethanol has been readily established as a positive reinforcer in AA (Alcohol Accepting), P (Preferring) and LEWIS rats, as well as C57BL/6J and LS/Ibg mice. In low ethanol preferring F344 and NP (Non-Preferring) rats, ethanol maintains significant but low levels of responding. Ethanol does not maintain lever-pressing behavior in BALB/cJ or SS/Ibg mice, and is avoided in DBA/2J mice. This pattern of reinforcement from ethanol is only moderately correlated with ethanol preference, and is not correlated with neurosensitivity to ethanol, at least as measured by duration of loss of the righting reflex (LORR). However, these genotypic patterns of reinforcement from ethanol do appear to correlate highly with patterns of reinforcement from cocaine and opiates. From these findings it is concluded that: 1) there exist important genetic determinants of drug reinforced behavior; 2) ethanol preference is not a highly accurate measure of reinforcement from ethanol; 3) sensitivity to ethanol as measured by LORR and self-administration of this drug are not highly genetically correlated; and 4) drug-seeking behaviors maintained by ethanol, cocaine and opiates may have at least some common biological determinants.

Genetic factors in relation to drugs.

In this review, recent developments in the area of pharmacogenetics will be emphasized that, according to the author's view, are especially important. References prior to 1964, the time covered by the previous review for this series by Kalow (79), have been excluded except where it seemed essential for clarity. Since the last general review appeared, numerous authors (38, 39, 80-82, 88, 89, 110, 112, 127, 128) have either surveyed the general field of pharmacogenetics or considered certain aspects of the area. Each has em­ phasized certain disciplines. In the following, consideration will be limited to those areas wherein there is a clear link between genetic factors and drug effects in man. Animal studies have been excluded except when they provide better understanding of studies in man. Also omitted from consideration here is the large area of resistance of microorganisms to the action of drugs, studies of which have provided so much basic information on the mechanisms of antibacterial chemotherapy. Similarly, the resistance of insects to in­ secticides has also been excluded. The history of hemolysis of erythrocytes by drugs began more than a century ago, and the number of hemolytic agents known today approxi­ mately parallels the development of pharmaceutical chemistry. Dausset & Contu (25) listed more than 50 drugs reported to have induced hemolysis of red blood cells under certain circumstances. These conditions include hemo­ lysis in normal erythrocytes, in red blood cells deficient in certain enzymes or co factors, in the newborn, and in individuals with various hemoglobinop­ athies. Although normal individuals may show hemolysis of red blood cells when exposed to a sufficiently high concentration of the hemolytic drugs, we are concerned here with those subjects in whom hemolysis occurs following a dose that ordinarily would have no effect in normal individuals. In sensitive individuals, the response, in numerous instances, results from some heredi­ tary deficiency or abnormality in metabolism of the red blood cell or in hemoglobin structure. The normal duration of active function and survival of the mature red cell is remarkahle since it has no nucleus, mitochondria, endoplastic reticulum,