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Pharmacogenomics 03/2013; 14(4):337-9. · 3.97 Impact Factor
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Nature 02/2013; 494(7438):430. · 36.28 Impact Factor
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ABSTRACT: Aims: Human lymphoblastoid cell lines (LCLs) are a rich resource of information on human interindividual genomic, transcriptomic, proteomic and phenomic variations, and are therefore gaining popularity for pharmacogenomic studies. In the present study we demonstrate that genome-wide transcriptomic data from a small LCL panel from unrelated individuals is sufficient for detecting pairs of genes that exhibit highly correlated expression levels and may thus convey insights about coregulated genes. Materials & methods: RNA samples were prepared from LCLs representing 12 unrelated healthy adult female Caucasian donors. Transcript levels were determined with the Affymetrix Human Gene arrays. Expression-level correlations were searched using Partek(®) Genomics Suite™ and the R environment. Sequences of detected correlated gene pairs were compared for shared conserved 3´-UTR miRNA binding. Results: Most of the approximately 33,000 transcripts covered by the Affymetrix arrays showed closely similar expression levels in LCLs from unrelated donors. However, the expression levels of some transcripts showed large inter-individual variations. When comparing the expression levels of each of the top 1000 genes showing the largest interindividual expression variations against the others, two sets containing 156 and 4438 correlated gene pairs with false-discovery rates of 0.01 and 0.05 were detected, respectively. Similar analysis of another gene-expression data set from LCLs (GSE11582) indicated that 61 and 39% of identified pairs matched the pairs detected from our transcriptomic data, respectively. Shared conserved 3´-UTR miRNA binding sites were noted for 14-17% of the top 100 gene pairs, suggesting that regulation by miRNA may contribute to their coordinated expression. Conclusion: Probing genome-wide transcriptomic data sets of LCLs from unrelated individuals may detect coregulated genes, adding insights on cellular regulation by miRNAs. Original submitted 11 July 2012; Revision submitted 4 September 2012.
Pharmacogenomics 12/2012; 13(16):1893-1904. · 3.97 Impact Factor
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ABSTRACT: Adverse drug reactions (ADRs) are a major concern in pharmacotherapy and are more common among women. Immortalized human lymphoblastoid cell lines (LCLs) are emerging as a novel tool for studying interindividual variability in drug response, including ADRs. In the present study, we compared sensitivities of LCLs from unrelated healthy male and female donors to growth inhibition by a panel of common drugs. We observed large interindividual drug sensitivity variations with similar mean sensitivities recorded for LCLs from male and female donors for most tested drugs. A notable exception was observed for the typical antipsychotic haloperidol and the atypical antipsychotic risperidone, which exhibited, on average, more robust in vitro growth inhibition in male as compared with female LCLs. An opposite finding was observed for the antidepressant paroxetine, which was more potent for inhibiting the growth of female as compared with male LCLs. These observations are discussed in the context of the higher incidence of dystonia reported for male schizophrenia patients treated with haloperidol and the higher efficacy of paroxetine in female major depression patients.
Journal of Molecular Neuroscience 07/2012; · 2.50 Impact Factor
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ABSTRACT: Over 30% of patients with major depression do not respond well to first-line treatment with selective serotonin reuptake inhibitors (SSRIs). Using genome-wide expression profiling of human lymphoblastoid cell lines (LCLs) CHL1 was identified as a tentative SSRI sensitivity biomarker. This study reports on miRNAs implicated in SSRI sensitivity of LCLs.
Eighty LCLs were screened from healthy adult female individuals for growth inhibition by paroxetine. Eight LCLs exhibiting high or low sensitivities to paroxetine were chosen for genome-wide expression profiling with miRNA microarrays.
The miRNA miR-151-3p had 6.7-fold higher basal expression in paroxetine-sensitive LCLs. This corresponds with lower expression of CHL1, a target of miR-151-3p. The additional miRNAs miR-212, miR-132, miR-30b*, let-7b and let-7c also differed by >1.5-fold (p < 0.05) between the two LCL groups.
The potential value of these miRNAs as tentative SSRI response biomarkers awaits validation with lymphocyte samples of major depression patients.
Pharmacogenomics 07/2012; 13(10):1129-39. · 3.97 Impact Factor
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ABSTRACT: Chronic treatment with selective serotonin reuptake inhibitors (SSRIs) reduces the risk and severity of cardiovascular diseases. SSRIs block the serotonin transporter, thereby inhibiting serotonin (5-HT) uptake into presynaptic neurons as well as into platelets where 5-HT is stored in dense granules. When 5-HT is released in response to agonists it enhances platelet aggregation induced by injury-related signals. Chronic administration of SSRIs may thus reduce platelet aggregability secondary to depletion of platelets' serotonin stores.
The study included ten DSM-IV-TR major depression (MDD) and four obsessive compulsive disorder (OCD) patients and fourteen healthy untreated age- and sex-matched controls. The patients were chronically medicated (6-108 months) with various SSRIs. Platelet serotonin content was assessed in fresh samples of platelet rich plasma (PRP) using radioimmunoassay. ADP, collagen, arachidonic acid and epinephrine were used as inducers of platelet aggregation measured in PRP by turbometric method in a microplate reader.
Lower platelet serotonin content (66%; p<0.05) and lower ADP, collagen or epinephrine-induced platelet aggregation (10-52%; p<0.05) were detected in PRP of SSRI-medicated patients, while no such effect was obtained with arachidonic acid.
The small sample size and the co-treatment with non-SSRI drugs such as benzodiazepines.
Patients chronically medicated with SSRIs exhibit lower platelet 5-HT content and reduced platelet aggregation induced by ADP, collagen and epinephrine, but not by arachidonic acid. Our observations may explain the increased bleeding risk associated with chronic SSRI treatment as well as the reported beneficial effect of SSRIs in prevention of recurrent myocardial infarction.
Journal of affective disorders 09/2011; 136(1-2):99-103. · 3.76 Impact Factor
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The Lancet 05/2011; 377(9779):1745-6. · 38.28 Impact Factor
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New England Journal of Medicine 05/2011; 364(20):1972; author reply 1973. · 53.30 Impact Factor
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ABSTRACT: This article examines the challenges for health technology assessment (HTA) in the light of new developments of personalized health care, focusing on European HTA perspectives.
Using the example of the Integrated Genome Research Network - Mutanom (IG Mutanom) project, with focus on personalized cancer diagnostics and treatment, we assess the scope of current HTA and examine it prospectively in the context of the translation of basic and clinical research into public health genomics and personalized health care.
The approaches developed within the IG-Mutanom project are based on innovative technology potentially providing targeted therapies for cancer; making translation into clinical practice requires a novel course of action, however. New models of HTA are needed that can account for the unique types of evidence inherent to individualized targeted therapies. Using constructive health technology assessment (CTA) models is an option, but further suitable models should be developed.
Integrative, systems biology-based approaches toward personalized medicine call for novel assessment methods. The translation of their highly innovative technologies into the practice of health care requires the development of new HTA concepts.
International Journal of Technology Assessment in Health Care 03/2011; 27(2):118-26. · 1.37 Impact Factor
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ABSTRACT: Selective serotonin reuptake inhibitors (SSRIs) are the most commonly used class of antidepressants for treating major depression. However, approximately 30% of patients do not respond sufficiently to first-line antidepressant drug treatment and require alternative therapeutics. Genome-wide studies searching for SSRI response DNA biomarkers or studies of candidate serotonin-related genes so far have given inconclusive or contradictory results. Here, we present an alternative transcriptome-based genome-wide approach for searching antidepressant drug-response biomarkers by using drug-effect phenotypes in human lymphoblastoid cell lines (LCLs).
We screened 80 LCLs from healthy adult female individuals for growth inhibition by paroxetine. A total of 14 LCLs with reproducible high and low sensitivities to paroxetine (seven from each phenotypic group) were chosen for genome-wide expression profiling with commercial microarrays.
The most notable genome-wide transcriptome difference between LCLs displaying high versus low paroxetine sensitivities was a 6.3-fold lower (p = 0.0000256) basal expression of CHL1, a gene coding for a neuronal cell adhesion protein implicated in correct thalamocortical circuitry, schizophrenia and autism. The microarray findings were confirmed by real-time PCR (36-fold lower CHL1 expression levels in the high paroxetine sensitivity group). Several additional genes implicated in synaptogenesis or in psychiatric disorders, including ARRB1, CCL5, DDX60, DDX60L, ENDOD1, ENPP2, FLT1, GABRA4, GAP43, MCTP2 and SPRY2, also differed by more than 1.5-fold and a p-value of less than 0.005 between the two paroxetine sensitivity groups, as confirmed by real-time PCR experiments.
Genome-wide transcriptional profiling of in vitro phenotyped LCLs identified CHL1 and additional genes implicated in synaptogenesis and brain circuitry as putative SSRI response biomarkers. This method might be used as a preliminary tool for searching for potential depression treatment biomarkers.
Pharmacogenomics 02/2011; 12(2):171-84. · 3.97 Impact Factor
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ABSTRACT: Informing patients about risks and benefits of alternative treatment options and choosing between them is becoming a bigger challenge as knowledge about the relationship between the individual's genetic profile and the efficacy and safety of available medications accumulates. Putting personalized medicine into practice requires new modes of information sharing and decision making by patient and physician. This is illustrated by a case study on treatment choices of breast cancer patients following genotyping for CYP2D6, recently published in Genome Medicine.See research article: http://genomemedicine.com/content/3/10/64.
Genome Medicine 01/2011; 3(10):69.
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ABSTRACT: We describe the synthesis and the pharmacological characterization of a new quaternary selective serotonin reuptake inhibitor (SSRI) N-methyl-citalopram (NMC) with periphery restricted action due to its inability to cross the blood brain barrier. NMC recognized and blocked the human platelet serotonin transporter (SERT) with similar affinity to that of citalopram as was evident from competition binding studies with [(3)H]citalopram and uptake studies with [(3)H]5-HT. In contrast, the affinity of NMC to rat brain SERT was 10-fold lower than its parent compound citalopram. Similarly to citalopram, NMC did not inhibit dopamine and noradrenaline uptake in rat brain synaptosomes at 10(-7)M as well as [(3)H]ketanserin binding to rat brain membranes at 10(-5)M, demonstrating its SSRI profile. A comparison of radioactivity retained in perfused mice brain following in vivo intraperitoneal injections of tritium-labeled NMC or citalopram showed that unlike citalopram, NMC did not penetrate the brain. Taken together, our observations suggest that N-methyl-citalopram is a selective serotonin reuptake inhibitor that does not penetrate the mouse brain. Epidemiological studies have suggested that chronic use of SSRI drugs may confer a protective effect against myocardial infarction (MI) apparently reflecting reduced platelet aggregation secondary to reduced platelet serotonin levels. N-methyl-citalopram may therefore have a potential as a new anti-platelet drug that does not cross the blood brain barrier and is thus devoid of the adverse CNS effects of SSRI drugs.
Biochemical pharmacology 11/2010; 80(10):1546-52. · 4.25 Impact Factor
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David Gurwitz
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ABSTRACT: Lack of knowledge among clinicians regarding pharmacogenetics is often cited as one of the barriers delaying its clinical uptake, albeit there are many other, more crucial aspects that impede the implementation of pharmacogenetics into routine medical practice. Pharmacogenetics has been incorporated to the MD teaching curriculum at the Tel Aviv University Faculty of Medicine (Tel Aviv, Israel) since 2001 and offered as an elective class for graduate students since 2003. I share here my pharmacogenetics teaching experience over the past decade and look forward to 2020 when - hopefully - the use of pharmacogenetics tools will have become more established in routine clinical care.
Pharmacogenomics 05/2010; 11(5):647-9. · 3.97 Impact Factor
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ABSTRACT: Lack of knowledge regarding genotype-phenotype correlations is often cited as the major barrier delaying the uptake of pharmacogenomics into routine medical practice. When we look forward to genome-wide association studies as one of the most promising tools for overcoming the pharmacogenomics knowledge barrier, we must keep in mind that having large patient cohorts may not help improve our understanding of alleles implicated in drug-response phenotypes, unless we ensure that such phenotypes are precise and pertinent. It may be wiser, and far more cost effective, to invest scarce research funding in accurate patient drug-response phenotyping than to genotype (or fully sequence) hundreds to thousands of study participants. Biobanks created with personalized medicine research in mind should, when possible, have access to donors' clinical data, including detailed disease- and drug-response phenotypes.
Pharmacogenomics 04/2010; 11(4):469-70. · 3.97 Impact Factor
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ABSTRACT: While powerful in silico tools are emerging for predicting drug targets and pathways, general in vitro tools for assessing such predictions are lacking. We present a novel in vitro method for distinguishing shared versus distinct drug pathways based on comparative cell growth inhibition profiles across a small panel of human lymphoblastoid cell lines (LCLs) from individual donors.
LCLs from unrelated healthy donors were examined in parallel for growth inhibition profiles of various drugs, including antidepressants (paroxetine, fluoxetine, fluvoxamine, citalopram, amitriptyline and imipramine); anticancer drugs (5-fluorouracil, 6-mercaptopurine, azathioprine, methotrexate and resveratrol); steroid drugs (dexamethasone, beclomethasone and prednisolone); and antipsychotic drugs (haloperidol and clozapine). Cell growth was assessed by the colorimetric 2,3-bis(2-methoxy-4-nitro-5-sulfophenly)-5-[(phenylamino) carbonyl]-2H-tetrazolium hydroxide method following 72 h of drug exposure.
LCLs from unrelated individuals exhibited a wide range of sensitivities to growth inhibition by a given drug, which were independent of basal cell replication rates. Yet, each individual cell line demonstrated a consistent sensitivity to multiple drugs from the same family. High goodness-of-fit values (R(2) > 0.6) were consistently observed for plots comparing the growth-inhibition profiles for paired drugs sharing a similar pathway, for example antidepressants, steroid drugs, antipsychotics, or 6-mercaptopurine compared with azathioprine, but not for drugs with different pathways. The method's utility is demonstrated by the observation that chlorpheniramine, an antihistamine drug long suspected to also possess antidepressant-like properties, exhibits a growth-inhibition profile very similar to antidepressants.
Comparing the growth-inhibition profiles of drugs (or compounds) of interest with the profiles of drugs with known pathways may assist in drug pathway classification. The method is useful for in vitro assessment of in silico-generated drug pathway predictions and for distinguishing shared versus distinct pathways for compounds of interest. Comparative transcriptomics analysis of human lymphoblastoid cell lines exhibiting 'edge' sensitivities can subsequently be utilized in the search for drug response biomarkers for personalized pharmacotherapy. The limitations and advantages of the method are discussed.
Pharmacogenomics 03/2010; 11(3):327-40. · 3.97 Impact Factor
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Science 09/2009; 325(5942):818-9. · 31.20 Impact Factor
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ABSTRACT: Population biobanks, which store and distribute human DNA, cell lines, and tissue samples collected from large cohorts, are
being established and are growing in size (1). These population biobanks are often funded wholly or in part by governments and are envisaged as novel resources for national
and international biomedical research programs. Such programs include studies on associations between genotypes, environmental
exposure measures, socioeconomic parameters, and phenotypes of human health and disease.
Science 08/2009; 325(5942):818-819. · 31.20 Impact Factor
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ABSTRACT: Pharmacogenetic tests allow medications to be tailored to individual patients to improve efficacy and reduce drug toxicity. In 2005, the International Society of Pharmacogenomics (ISP) made recommendations for undergraduate medical teaching in pharmacogenetics. We aimed to establish the quantity and scope of this in British medical schools. An electronic survey was sent to all British medical schools. Nineteen out of 34 (56%) medical schools responded. Sixteen of the 19 (84%) respondents provided pharmacogenetics teaching, usually 1-2 h in total. Only four (21%) medical schools offered the four or more hours of teaching recommended by the ISP. However, 10 of 16 (63%) schools felt the amount of pharmacogenetic teaching offered was sufficient. The quantity of undergraduate teaching of pharmacogenetics is low. However, a majority of UK medical schools teach it, covering a broad scope of elements. It is encouraging that future clinicians are being provided with the knowledge to deliver pharmacogenetics into clinical practice.
Genomic Medicine 05/2009; 2(3-4):101-5.
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ABSTRACT: In order to ascertain data availability and feasibility for conducting cost-effectiveness studies in pharmacogenetics, and as part of a European Commission Joint Research Center, Institute for Prospective Technological Studies (JRC-IPTS) study, data concerning risperidone use and cytochrome P450 (CYP2D6) genotyping in medical care was collected in Germany, Spain and the USA, and are summarized in this perspective. The gene coding for CYP2D6 is highly polymorphic, resulting in a significant part of the population being poor metabolizers and ultrarapid metabolizers. Individuals who are CYP2D6 poor metabolizers, have an increased risk of adverse drug reactions (ADRs) when treated with CYP2D6-metabolized drugs, suggesting that CYP2D6 genotyping might be beneficial for patient care. This might be especially important in psychiatry, where approximately 50% of the patients use at least one drug primarily metabolized by CYP2D6. In particular, ADRs and poor response to treatment are major problems for some antipsychotics, including risperidone. However, there are no published cost-effectiveness studies on CYP2D6 genotyping, and the benefit that pharmacogenetic testing might represent by identifying problematic patients is still unclear. The present European Commission study found that current clinical and economical data concerning the frequency and direct healthcare costs of risperidone-related ADRs, the relation of such ADRs with the patients CYP2D6 genotypes, and costs for CYP2D6 genotyping, are not sufficient for determining if routine CYP2D6 genotyping might be cost beneficial for patients treated with risperidone. Therefore, efforts should be put on performing prospective cost-benefit studies with randomized treatment according to the CYP2D6 genotype to establish the utility of CYP2D6 genotyping for personalizing antipsychotic treatment.
Pharmacogenomics 05/2009; 10(4):685-99. · 3.97 Impact Factor
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ABSTRACT: New companies offering personal whole-genome information services over the internet are dynamic and highly visible players in the personal genomics field. For fees currently ranging from US$399 to US$2500 and a vial of saliva, individuals can now purchase online access to their individual genetic information regarding susceptibility to a range of chronic diseases and phenotypic traits based on a genome-wide SNP scan. Most of the companies offering such services are based in the United States, but their clients may come from nearly anywhere in the world. Although the scientific validity, clinical utility and potential future implications of such services are being hotly debated, several ethical and regulatory questions related to direct-to-consumer (DTC) marketing strategies of genetic tests have not yet received sufficient attention. For example, how can we minimize the risk of unauthorized third parties from submitting other people's DNA for testing? Another pressing question concerns the ownership of (genotypic and phenotypic) information, as well as the unclear legal status of customers regarding their own personal information. Current legislation in the US and Europe falls short of providing clear answers to these questions. Until the regulation of personal genomics services catches up with the technology, we call upon commercial providers to self-regulate and coordinate their activities to minimize potential risks to individual privacy. We also point out some specific steps, along the trustee model, that providers of DTC personal genomics services as well as regulators and policy makers could consider for addressing some of the concerns raised below.
European journal of human genetics: EJHG 04/2009; 17(7):883-9. · 3.56 Impact Factor
