JoVE Visualize What is visualize?
Stop Reading. Start Watching.
Advanced Search
Stop Reading. Start Watching.
Regular Search
Find video protocols related to scientific articles indexed in Pubmed.
Cost Effectiveness of New Oral Anticoagulants for Stroke Prevention in Patients with Atrial Fibrillation in Two Different European Healthcare Settings.
Am J Cardiovasc Drugs
PUBLISHED: 10-19-2014
Show Abstract
Hide Abstract
Our objectives were to investigate the cost effectiveness of apixaban, rivaroxaban, and dabigatran compared with coumarin derivatives for stroke prevention in patients with atrial fibrillation in a country with specialized anticoagulation clinics (the Netherlands) and in a country without these clinics (the UK).
Related JoVE Video
No association between CYP3A4*22 and statin effectiveness in reducing the risk for myocardial infarction.
Pharmacogenomics
PUBLISHED: 10-11-2014
Show Abstract
Hide Abstract
Genetic variation has been shown to influence statin response in terms of lowering LDL cholesterol. The recently discovered CYP3A4*22 allele (defined as rs35599367) has been shown to affect statin-induced LDL cholesterol lowering. Our objective was to investigate whether this polymorphism modifies the risk reduction for myocardial infarction (MI) by statins.
Related JoVE Video
The SLCO1B1 c.521T>C polymorphism is associated with dose decrease or switching during statin therapy in the Rotterdam Study.
Pharmacogenet. Genomics
PUBLISHED: 07-16-2014
Show Abstract
Hide Abstract
The SLCO1B1 c.521T>C polymorphism is associated with statin plasma levels and simvastatin-induced adverse drug reactions. We studied whether the c.521T>C polymorphism is associated with dose decreases or switches to other cholesterol-lowering drugs during simvastatin and atorvastatin therapy, because these events are indicators of adverse drug reactions.
Related JoVE Video
Pharmacogenetic analysis of GLCCI1 in three north European pediatric asthma populations with a reported use of inhaled corticosteroids.
Pharmacogenomics
PUBLISHED: 06-05-2014
Show Abstract
Hide Abstract
GLCCI1 rs37972 has previously been associated with decreased lung function improvement upon treatment with inhaled corticosteroids (ICS) in asthmatics.
Related JoVE Video
Beliefs about medicines in Dutch acenocoumarol and phenprocoumon users.
Br J Clin Pharmacol
PUBLISHED: 02-04-2014
Show Abstract
Hide Abstract
Adherence to the generally complex regimen of coumarin derivatives is vital in order to keep patients in the adequate International Normalized Ratio range. Patients' beliefs about medicines are associated with the level of therapy adherence. Our first aim was to assess beliefs about coumarins. Secondly, we compared the beliefs about coumarins with the beliefs about other cardiovascular drugs.
Related JoVE Video
Arg16 ADRB2 genotype increases the risk of asthma exacerbation in children with a reported use of long-acting ?2-agonists: results of the pacman cohort.
Pharmacogenomics
PUBLISHED: 11-28-2013
Show Abstract
Hide Abstract
Background: Current evidence suggests that asthma patients with the ADRB2 Arg16 genotype have a poorer response to long-acting ?2-agonists (LABA), but the results remain inconsistent. Aim: This study assessed the association between Arg16 variants and treatment outcome in children treated with inhaled corticosteroids (ICS) and LABA. Materials & methods: ADRB2 Arg16 was genotyped in 597 children (4-12 years of age) participating in the PACMAN cohort study. A questionnaire was used to assess asthma control, frequency of asthma-related emergency department visits and use of oral corticosteroids in the past year. Results: Arg/Arg carriers with a reported use of ICS and LABA had an increased risk of oral corticosteroid use (odds ratio: 14.9; 95% CI: 1.59-140.1) and emergency department visits in the past year (odds ratio: 11.9; 95% CI: 1.22-115.8) compared to Gly/Gly carriers. This effect was not observed in Arg/Arg genotype carriers reporting ICS use only. Conclusion: Children who are homozygous for ADRB2 Arg16 have an increased risk of exacerbations when treated with combined LABA and ICS. Original submitted 4 September 2013; Revision submitted 27 September 2013.
Related JoVE Video
Cost-effectiveness of pharmacogenetic-guided dosing of phenprocoumon in atrial fibrillation.
Pharmacogenomics
PUBLISHED: 06-11-2013
Show Abstract
Hide Abstract
To investigate the cost-effectiveness of pharmacogenetic-guided phenprocoumon dosing versus standard anticoagulation care in Dutch patients with atrial fibrillation.
Related JoVE Video
Inflammatory phenotypes underlying uncontrolled childhood asthma despite inhaled corticosteroid treatment: rationale and design of the PACMAN2 study.
BMC Pediatr
PUBLISHED: 06-10-2013
Show Abstract
Hide Abstract
BACKGROUND: The diagnosis of childhood asthma covers a broad spectrum of pathological mechanisms that can lead to similarly presenting clinical symptoms, but may nonetheless require different treatment approaches. Distinct underlying inflammatory patterns are thought to influence responsiveness to standard asthma medication.Methods/design: The purpose of the PACMAN2 study is to identify inflammatory phenotypes that can discriminate uncontrolled childhood asthma from controlled childhood asthma by measures in peripheral blood and exhaled air. PACMAN2 is a nested, case--control follow-up study to the ongoing pharmacy-based "Pharmacogenetics of Asthma medication in Children: Medication with Anti-inflammatory effects" (PACMAN) study. The original PACMAN cohort consists of children aged 4--12 years with reported use of asthma medication. The PACMAN2 study will be conducted within the larger PACMAN cohort, and will focus on detailed phenotyping of a subset of the PACMAN children. The selected participants will be invited to a follow-up visit in a clinical setting at least six months after their baseline visit based on their adherence to usage of inhaled corticosteroids, their asthma symptoms in the past year, and their age (>= 8 years). During the follow-up visit, current and long-term asthma symptoms, medication use, environmental factors, medication adherence and levels of exhaled nitric oxide will be reassessed. The following measures will also be examined: pulmonary function, exhaled volatile organic compounds, as well as inflammatory markers in peripheral blood and blood plasma. Comparative analysis and cluster-analyses will be used to identify markers that differentiate children with uncontrolled asthma despite their use of inhaled corticosteroids (ICS) (cases) from children whose asthma is controlled by the use of ICS (controls). DISCUSSION: Asthmatic children with distinct inflammatory phenotypes may respond differently to anti-inflammatory therapy. Therefore, by identifying inflammatory phenotypes in children with the PACMAN2 study, we may greatly impact future personalised treatment strategies, uncover new leads for therapeutic targets and improve the design of future clinical studies in the assessment of the efficacy of novel therapeutics.
Related JoVE Video
Clinical utility of asthma biomarkers: from bench to bedside.
Biologics
PUBLISHED: 01-01-2013
Show Abstract
Hide Abstract
Asthma is a chronic disease characterized by airway inflammation, bronchial hyperresponsiveness, and recurrent episodes of reversible airway obstruction. The disease is very heterogeneous in onset, course, and response to treatment, and seems to encompass a broad collection of heterogeneous disease subtypes with different underlying pathophysiological mechanisms. There is a strong need for easily interpreted clinical biomarkers to assess the nature and severity of the disease. Currently available biomarkers for clinical practice - for example markers in bronchial lavage, bronchial biopsies, sputum, or fraction of exhaled nitric oxide (FeNO) - are limited due to invasiveness or lack of specificity. The assessment of markers in peripheral blood might be a good alternative to study airway inflammation more specifically, compared to FeNO, and in a less invasive manner, compared to bronchoalveolar lavage, biopsies, or sputum induction. In addition, promising novel biomarkers are discovered in the field of breath metabolomics (eg, volatile organic compounds) and (pharmaco)genomics. Biomarker research in asthma is increasingly shifting from the assessment of the value of single biomarkers to multidimensional approaches in which the clinical value of a combination of various markers is studied. This could eventually lead to the development of a clinically applicable algorithm composed of various markers and clinical features to phenotype asthma and improve diagnosis and asthma management.
Related JoVE Video
Asthma symptoms in pediatric patients: differences throughout the seasons.
J Asthma
PUBLISHED: 08-02-2011
Show Abstract
Hide Abstract
Seasonal variation in asthma has been widely recognized. The aim of this study was to describe seasonal patterns of asthma symptoms and asthma medication use in a cohort of pediatric asthma medication users and to study determinants of seasonal childhood asthma.
Related JoVE Video
Limited agreement between current and long-term asthma control in children: the PACMAN cohort study.
Pediatr Allergy Immunol
PUBLISHED: 07-13-2011
Show Abstract
Hide Abstract
Several studies have shown that predictors of asthma treatment outcomes differ depending on the definition of the outcome chosen. This provides evidence that different outcomes studied may reflect distinct aspects of asthma control. To assess predictors of asthma control, we need firm outcome phenotypes. The aim of this study was to investigate the association between measurements of current and long-term asthma control.
Related JoVE Video
Genetic variability within the cholesterol lowering pathway and the effectiveness of statins in reducing the risk of MI.
Atherosclerosis
PUBLISHED: 06-10-2011
Show Abstract
Hide Abstract
Genetic variability has been shown to affect statin responsiveness. Participants from the Utrecht Cardiovascular Pharmacogenetics (UCP) studies were enrolled from a population-based registry of pharmacy records linked to hospital discharge records (PHARMO) to investigate tagging SNPs within candidate genes involved in the cholesterol lowering pathway for modification of the effectiveness of statins in reducing the risk of myocardial infarction (MI). Patients who received a prescription for an antihypertensive drug and/or had hypercholesterolemia were selected from the PHARMO database. We designed a nested case-control study in which cases were hospitalized for MI and controls were not. Patients were contacted through their community pharmacies. For this study, only hypercholesterolemic participants were selected. Logistic regression analysis was used to investigate pharmacogenetic interactions. The Heart and Vascular Health Study (HVH) was used to replicate findings from UCP. The study population included 668 cases and 1217 controls. We selected 231 SNPs of which 209 SNPs in 27 genes passed quality control. Ten SNPs in eight genes were found to influence the effectiveness of statins in UCP, of which the most significant interaction was found with SCARB1 rs4765615. Other genes that reached statistical significance (p<0.05) included two SNPs in PCSK9 (rs10888896 and rs505151 (E670G)), two SNPs in ABCG5 (rs4245786 and rs1864815), LIPC rs16940379, ABCA1 rs4149264, PPARG rs2972164, LRP1 rs715948, and SOAT1 rs2493121. None of the total of 5 SNPs that were available for replication in HVH reached statistical significance. In conclusion, ten SNPs were found to modify the effectiveness of statins in reducing the risk of MI in the UCP study. Five were also tested in the HVH study, but no interactions reached statistical significance.
Related JoVE Video
Genotyping for CYP2C9 and VKORC1 alleles by a novel point of care assay with HyBeacon® probes.
Clin. Chim. Acta
PUBLISHED: 06-09-2011
Show Abstract
Hide Abstract
Coumarin anticoagulants such as warfarin are used to treat and prevent thromboembolic events in patients. The required dosage is difficult to predict and the risk of over or under anticoagulation are dependent on several environmental and clinical factors, such as concurrent medication, diet, age and genotype for polymorphisms in two genes CYP2C9 and VKORC1.
Related JoVE Video
Loading and maintenance dose algorithms for phenprocoumon and acenocoumarol using patient characteristics and pharmacogenetic data.
Eur. Heart J.
PUBLISHED: 06-02-2011
Show Abstract
Hide Abstract
Polymorphisms in CYP2C9 and VKORC1 influence patients phenprocoumon (PHE) and acenocoumarol (ACE) dose requirements. To provide physicians with tools to estimate the patients individual dose, we aimed to develop algorithms for PHE and ACE.
Related JoVE Video
Practical recommendations for pharmacogenomics-based prescription: 2010 ESF-UB Conference on Pharmacogenetics and Pharmacogenomics.
Pharmacogenomics
PUBLISHED: 04-05-2011
Show Abstract
Hide Abstract
The present article summarizes the discussions of the 3rd European Science Foundation-University of Barcelona (ESF-UB) Conference in Biomedicine on Pharmacogenetics and Pharmacogenomics, which was held in June 2010 in Spain. It was focused on practical applications in routine medical practice. We provide practical recommendations for ten different clinical situations, that have either been approved or not approved by regulatory agencies. We propose some comments that might accompany the results of these tests, indicating the best drug and doses to be prescribed. The discussed examples include KRAS, cetuximab, panitumumab, EGFR-gefitinib, CYP2D6-tamoxifen, TPMT-azathioprine-6-mercaptopurine, VKORC1/CYP2C9-warfarin, CYP2C19-clopidogrel, HLA-B*5701-abacavir, HLA-B*5701-flucloxacillin, SLCO1B1-statins and CYP3A5-tacrolimus. We hope that these practical recommendations will help physicians, biologists, scientists and other healthcare professionals to prescribe, perform and interpret these genetic tests.
Related JoVE Video
Inhaled corticosteroid adherence in paediatric patients: the PACMAN cohort study.
Pharmacoepidemiol Drug Saf
PUBLISHED: 03-16-2011
Show Abstract
Hide Abstract
Poor adherence with inhaled corticosteroids (ICSs) has been reported frequently and may be associated with uncontrolled asthma. A better understanding of factors influencing adherence may help to achieve higher adherence rates for a larger part of the population, which will eventually lead to better asthma control. The aim of this study was to investigate factors associated with adherence in paediatric ICS users.
Related JoVE Video
Uncontrolled asthma at age 8: the importance of parental perception towards medication.
Pediatr Allergy Immunol
PUBLISHED: 02-20-2011
Show Abstract
Hide Abstract
Despite existing effective treatment options, asthma is uncontrolled in a considerable proportion of patients. The aim of this study was to identify determinants of uncontrolled asthma at age 8 in children participating in the PIAMA birth cohort study.
Related JoVE Video
From evidence based medicine to mechanism based medicine. Reviewing the role of pharmacogenetics.
Int J Clin Pharm
PUBLISHED: 02-11-2011
Show Abstract
Hide Abstract
The translation of evidence based medicine to a specific patient presents a considerable challenge. We present by means of the examples nortriptyline, tramadol, clopidogrel, coumarins, abacavir and antipsychotics the discrepancy between available pharmacogenetic information and its implementation in daily clinical practice.
Related JoVE Video
Asthma medication use in infancy: determinants related to prescription of drug therapy.
Fam Pract
PUBLISHED: 02-02-2011
Show Abstract
Hide Abstract
Little is known about factors that determine prescribing of asthma therapy in infancy.
Related JoVE Video
Genetic variation in the renin--angiotensin system, use of renin--angiotensin system inhibitors and the risk of myocardial infarction.
J Renin Angiotensin Aldosterone Syst
PUBLISHED: 12-16-2010
Show Abstract
Hide Abstract
This study investigated whether variation in the genes encoding for ACE, AGT and AGTR1 modifies the risk of myocardial infarction (MI) related to ACE inhibitors and AT II antagonists.
Related JoVE Video
Variants of ADAMTS1 modify the effectiveness of statins in reducing the risk of myocardial infarction.
Pharmacogenet. Genomics
PUBLISHED: 11-02-2010
Show Abstract
Hide Abstract
To investigate the influence of tagging single-nucleotide polymorphisms (SNPs) within candidate genes involved in the putative anti-inflammatory effects of statins on the effectiveness of statins in reducing the risk of myocardial infarction (MI).
Related JoVE Video
Pharmacogenetics and pharmacogenomics: practical applications in routine medical practice.
Genome Med
PUBLISHED: 09-21-2010
Show Abstract
Hide Abstract
A report of the 3rd joint European Science Foundation and University of Barcelona Conference in Biomedicine, San Feliu de Guixols, Catalonia, Spain, 6-11 June 2010.
Related JoVE Video
Meta-analysis of Dense Genecentric Association Studies Reveals Common and Uncommon Variants Associated with Height.
Matthew B Lanktree, Yiran Guo, Muhammed Murtaza, Joseph T Glessner, Swneke D Bailey, N Charlotte Onland-Moret, Guillaume Lettre, Halit Ongen, Ramakrishnan Rajagopalan, Toby Johnson, Haiqing Shen, Christopher P Nelson, Norman Klopp, Jens Baumert, Sandosh Padmanabhan, Nathan Pankratz, James S Pankow, Sonia Shah, Kira Taylor, John Barnard, Bas J Peters, Cliona M Maloney, Maximilian T Lobmeyer, Alice Stanton, M Hadi Zafarmand, Simon P R Romaine, Amar Mehta, Erik P A van Iperen, Yan Gong, Tom S Price, Erin N Smith, Cecilia E Kim, Yun R Li, Folkert W Asselbergs, Larry D Atwood, Kristian M Bailey, Deepak Bhatt, Florianne Bauer, Elijah R Behr, Tushar Bhangale, Jolanda M A Boer, Bernhard O Boehm, Jonathan P Bradfield, Morris Brown, Peter S Braund, Paul R Burton, Cara Carty, Hareesh R Chandrupatla, Wei Chen, John Connell, Chrysoula Dalgeorgou, Anthonius de Boer, Fotios Drenos, Clara C Elbers, James C Fang, Caroline S Fox, Edward C Frackelton, Barry Fuchs, Clement E Furlong, Quince Gibson, Christian Gieger, Anuj Goel, Diederik E Grobbee, Claire Hastie, Philip J Howard, Guan-Hua Huang, W Craig Johnson, Qing Li, Marcus E Kleber, Barbara E K Klein, Ronald Klein, Charles Kooperberg, Bonnie Ky, Andrea LaCroix, Paul Lanken, Mark Lathrop, Mingyao Li, Vanessa Marshall, Olle Melander, Frank D Mentch, Nuala J Meyer, Keri L Monda, Alexandre Montpetit, Gurunathan Murugesan, Karen Nakayama, Dave Nondahl, Abiodun Onipinla, Suzanne Rafelt, Stephen J Newhouse, F George Otieno, Sanjey R Patel, Mary E Putt, Santiago Rodriguez, Radwan N Safa, Douglas B Sawyer, Pamela J Schreiner, Claire Simpson, Suthesh Sivapalaratnam, Sathanur R Srinivasan, Christine Suver, Gary Swergold, Nancy K Sweitzer, Kelly A Thomas, Barbara Thorand, Nicholas J Timpson, Sam Tischfield, Martin Tobin, Maciej Tomaszewski, Maciej Tomaszweski, W M Monique Verschuren, Chris Wallace, Bernhard Winkelmann, Haitao Zhang, Dongling Zheng, Li Zhang, Joseph M Zmuda, Robert Clarke, Anthony J Balmforth, John Danesh, Ian N Day, Nicholas J Schork, Paul I W de Bakker, Christian Delles, David Duggan, Aroon D Hingorani, Joel N Hirschhorn, Marten H Hofker, Steve E Humphries, Mika Kivimäki, Debbie A Lawlor, Kandice Kottke-Marchant, Jessica L Mega, Braxton D Mitchell, David A Morrow, Jutta Palmen, Susan Redline, Denis C Shields, Alan R Shuldiner, Patrick M Sleiman, George Davey Smith, Martin Farrall, Yalda Jamshidi, David C Christiani, Juan P Casas, Alistair S Hall, Pieter A Doevendans, Jason D Christie, Gerald S Berenson, Sarah S Murray, Thomas Illig, Gerald W Dorn, Thomas P Cappola, Eric Boerwinkle, Peter Sever, Daniel J Rader, Muredach P Reilly, Mark Caulfield, Philippa J Talmud, Eric Topol, James C Engert, Kai Wang, Anna Dominiczak, Anders Hamsten, Sean P Curtis, Roy L Silverstein, Leslie A Lange, Marc S Sabatine, Mieke Trip, Danish Saleheen, John F Peden, Karen J Cruickshanks, Winfried März, Jeffrey R O'Connell, Olaf H Klungel, Cisca Wijmenga, Anke Hilse Maitland-van der Zee, Eric E Schadt, Julie A Johnson, Gail P Jarvik, George J Papanicolaou, , Struan F A Grant, Patricia B Munroe, Kari E North, Nilesh J Samani, Wolfgang Koenig, Tom R Gaunt, Sonia S Anand, Yvonne T van der Schouw, Nicole Soranzo, Garret A FitzGerald, Alex Reiner, Robert A Hegele, Hakon Hakonarson, Brendan J Keating.
Am. J. Hum. Genet.
PUBLISHED: 09-14-2010
Show Abstract
Hide Abstract
Height is a classic complex trait with common variants in a growing list of genes known to contribute to the phenotype. Using a genecentric genotyping array targeted toward cardiovascular-related loci, comprising 49,320 SNPs across approximately 2000 loci, we evaluated the association of common and uncommon SNPs with adult height in 114,223 individuals from 47 studies and six ethnicities. A total of 64 loci contained a SNP associated with height at array-wide significance (p < 2.4 × 10(-6)), with 42 loci surpassing the conventional genome-wide significance threshold (p < 5 × 10(-8)). Common variants with minor allele frequencies greater than 5% were observed to be associated with height in 37 previously reported loci. In individuals of European ancestry, uncommon SNPs in IL11 and SMAD3, which would not be genotyped with the use of standard genome-wide genotyping arrays, were strongly associated with height (p < 3 × 10(-11)). Conditional analysis within associated regions revealed five additional variants associated with height independent of lead SNPs within the locus, suggesting allelic heterogeneity. Although underpowered to replicate findings from individuals of European ancestry, the direction of effect of associated variants was largely consistent in African American, South Asian, and Hispanic populations. Overall, we show that dense coverage of genes for uncommon SNPs, coupled with large-scale meta-analysis, can successfully identify additional variants associated with a common complex trait.
Related JoVE Video
Clinical and economic consequences of pharmacogenetic-guided dosing of warfarin.
Expert Rev Pharmacoecon Outcomes Res
PUBLISHED: 08-19-2010
Show Abstract
Hide Abstract
Patients using warfarin for oral anticoagulant therapy need to be frequently monitored because of warfarins narrow therapeutic range and the large variation in dose requirements among patients. Patients receiving the wrong dose have an increased risk of bleeding or thromboembolic events. The required dose is influenced by environmental factors, such as gender, age, diet and concomitant medication, as well as genetic factors. Pharmacogenetic testing prior to warfarin initiation might improve dosing accuracy and, therefore, safety and efficacy of warfarin treatment. Meckley et al. studied the clinical consequences and costs of genotyping before warfarin treatment. The results of their study suggest that pharmacogenetic-guided dosing of patients initiating warfarin could improve health (quality-adjusted life-years) but at a high cost per quality-adjusted life-year gained. Owing to the inevitable assumptions that have to be made in all cost-effectiveness models, great uncertainty remains regarding the cost-effectiveness of pharmacogenetic-guided warfarin dosing.
Related JoVE Video
Pharmacogenetic interactions between ABCB1 and SLCO1B1 tagging SNPs and the effectiveness of statins in the prevention of myocardial infarction.
Pharmacogenomics
PUBLISHED: 08-18-2010
Show Abstract
Hide Abstract
Genetic variability within the SLCO1B1 and ABCB1 transporter genes has been associated with modification of statin effectiveness in cholesterol management.
Related JoVE Video
Patterns of asthma medication use: early asthma therapy initiation and asthma outcomes at age 8.
Pharmacoepidemiol Drug Saf
PUBLISHED: 08-17-2010
Show Abstract
Hide Abstract
Wheeze has many underlying pathophysiologies in childhood, but is the main reason for anti-asthma drugs prescription. This study was conducted to describe asthma medication use patterns among children in their first eight years of life. Longitudinal medication use data from 777 children participating in the PIAMA study were used. Medication patterns were described for four groups that started therapy before the third birthday, when the peak in prescriptions occurred in our cohort; short-acting ?-agonists (SABA), inhaled corticosteroids (ICS), SABA?+?ICS or none of these. One third (n?=?255) of the children received a first SABA or ICS prescription before age 8. Only three children (1.2%) used medication continuously during follow-up. Of the children who started SABA, 53.8% discontinued within 1-2 years. Of the children who started ICS before age 3, 42.1% discontinued within 1-2 years and 31.6% received additional SABA. 41.5% of the children who started SABA?+?ICS used this short-term (?1 -2 years) and 21.5% long-term (? 3 years). Fifteen percent of children who did not start asthma therapy in their first 3 years of life did receive prescriptions between age 3 and 8. Children prescribed SABA?+?ICS before age 3 had the highest prevalence of hyper responsiveness at age 8, and similar prevalence of atopy as the other groups. Asthma medication is prescribed frequently in the first 8 years of life, particularly before age 3, and only few children use it continuously. ICS and SABA prescription occurs especially in those who were more likely to develop signs of asthma at age 8.
Related JoVE Video
[Genetic variations affect drug safety and efficacy].
Ned Tijdschr Geneeskd
PUBLISHED: 08-12-2010
Show Abstract
Hide Abstract
Pharmacogenetics is a field that deals with the relationship between genetic variations and the effects and side-effects of drugs. Genetic variations in drug-metabolizing enzymes, transporters, receptors, and other drug targets have been linked to interindividual differences in the efficacy and safety of many drugs. Genotyping is performed increasingly in primary and secondary health care in patients with abnormal plasma drug levels, in insufficient efficacy or in the presence of side-effects. Trastuzumab and abacavir are examples of drugs where patients are tested before treatment is started, in order to ascertain whether they carry a particular genetic variant. Trastuzumab is effective only when a particular protein is expressed in breast cancer tissue and the AIDS inhibitor may cause serious hypersensitivity reactions in patients carrying a particular variant. It is expected that screening for genetic variants prior to drug treatment will occur more often. This depends on the intensity of the association between genotype and outcome, the severity or relevance of the clinical outcome and the availability of alternative treatment.
Related JoVE Video
High agreement between parental reported inhaled corticosteroid use and pharmacy prescription data.
Pharmacoepidemiol Drug Saf
PUBLISHED: 07-20-2010
Show Abstract
Hide Abstract
This study was conducted to assess the validity of parental reported use of inhaled corticosteroids (ICS) in children.
Related JoVE Video
From evidence based medicine to mechanism based medicine. Reviewing the role of pharmacogenetics.
Int J Clin Pharm
PUBLISHED: 07-16-2010
Show Abstract
Hide Abstract
The translation of evidence based medicine to a specific patient presents a considerable challenge. We present by means of the examples nortriptyline, tramadol, clopidogrel, coumarins, abacavir and antipsychotics the discrepancy between available pharmacogenetic information and its implementation in daily clinical practice.
Related JoVE Video
A systematic review of cost-effectiveness analyses of pharmacogenetic-guided dosing in treatment with coumarin derivatives.
Pharmacogenomics
PUBLISHED: 07-07-2010
Show Abstract
Hide Abstract
Anticoagulant therapy with coumarin derivatives is often sub- or supra-therapeutic, resulting in an increased risk of thromboembolic events or hemorrhage, respectively. Pharmacogenetic-guided dosing has been proposed as an effective way of reducing bleeding rates. Clinical trials to confirm the safety, efficacy and effectiveness of this strategy are ongoing, but in addition, it is also necessary to consider the cost-effectiveness of this strategy. This article describes the findings of a systematic review of published cost-effectiveness analyses of pharmacogenetic-guided dosing of coumarin derivatives. Similarities and differences in the approaches used were examined and the quality of the analyses was assessed. The results of the analyses are not sufficient to determine whether or not pharmacogenetic-guided dosing of coumarins is cost effective. More reliable cost-effectiveness estimates need to become available before it is possible to recommend whether or not this strategy should be applied in clinical practice.
Related JoVE Video
Statin prescribing in the elderly in the Netherlands: a pharmacy database time trend study.
Drugs Aging
PUBLISHED: 06-30-2010
Show Abstract
Hide Abstract
There is some evidence that the beneficial effects of HMG-CoA reductase inhibitors (statins) in the elderly are at least comparable to the effects in middle-aged people. However, several studies have shown prescription rates of statins to be significantly lower in the elderly than in younger populations.
Related JoVE Video
Methodological and statistical issues in pharmacogenomics.
J. Pharm. Pharmacol.
PUBLISHED: 05-22-2010
Show Abstract
Hide Abstract
Pharmacogenomics strives to explain the interindividual variability in response to drugs due to genetic variation. Although technological advances have provided us with relatively easy and cheap methods for genotyping, promises about personalised medicine have not yet met our high expectations. Successful results that have been achieved within the field of pharmacogenomics so far are, to name a few, HLA-B*5701 screening to avoid hypersensitivity to the antiretroviral abacavir, thiopurine S-methyltransferase (TPMT) genotyping to avoid thiopurine toxicity, and CYP2C9 and VKORC1 genotyping for better dosing of the anticoagulant warfarin. However, few pharmacogenetic examples have made it into clinical practice in the treatment of complex diseases. Unfortunately, lack of reproducibility of results from observational studies involving many genes and diseases seems to be a common pattern in pharmacogenomic studies. In this article we address some of the methodological and statistical issues within study design, gene and single nucleotide polymorphism (SNP) selection and data analysis that should be considered in future pharmacogenomic research. First, we discuss some of the issues related to the design of epidemiological studies, specific to pharmacogenomic research. Second, we describe some of the pros and cons of a candidate gene approach (including gene and SNP selection) and a genome-wide scan approach. Finally, conventional as well as several innovative approaches to the analysis of large pharmacogenomic datasets are proposed that deal with the issues of multiple testing and systems biology in different ways.
Related JoVE Video
Pharmacogenetics and the pharmaceutical industry.
Curr. Pharm. Des.
PUBLISHED: 03-09-2010
Show Abstract
Hide Abstract
The detailed knowledge of the human genome has not fulfilled its promise as yet. It seems fair to say that we are far from treating existing diseases by therapeutic interventions developed on the basis of genetic knowledge. However, pharmacogenetics has shown to be useful in improving our understanding of pharmacotherapy. Industry is starting to embed this knowledge in the design of innovative drugs and there are three important areas of interest: safety, efficacy and target identification. Application of pharmacogenetics e.g. in patient selection are leading to the direction of more personalised medicine. The future will bring more of such applications. However, current knowledge also leads to a more integrated approach of pharmacogenetics as part of systems biology, providing an even more complete image of reality surrounding disease and therapy, including for example environmental factors and behaviour. In addition, collaborative efforts with academic partners are very much welcomed by the pharmaceutical industry and are expected to have a synergistic effect on progression in this field.
Related JoVE Video
Asthma therapy during the first 8 years of life: a PIAMA cohort study.
J Asthma
PUBLISHED: 02-23-2010
Show Abstract
Hide Abstract
Many studies evaluated asthma medication use in children in a cross-sectional manner, yet little is known about longitudinal use patterns. This study describes the formation of a longitudinal data set on asthma medication use and shows first results regarding the prevalence and incidence of medication use.
Related JoVE Video
Pharmacogenomic insights into treatment and management of statin-induced myopathy.
Genome Med
PUBLISHED: 12-29-2009
Show Abstract
Hide Abstract
Although statins are generally well tolerated, the most common adverse drug reaction from statin therapy is myopathy. This article reviews the current pharmacogenomic knowledge of statin-induced myopathy. Furthermore, we will discuss the importance of recent pharmacogenetic advances for the treatment and management of statin-induced myopathy. Variation in the SLCO1B1 gene is associated with increased incidence of statin-induced myopathy, particularly with simvastatin and less so with other statins. If different pharmacokinetic enzymes and transporters are responsible for susceptibility to myopathy, this may explain differences in the occurrence of statin-induced myopathy in individual patients. Genotyping in patients suffering from statin-induced myopathy may help to personalize the choice of statin for the lowest chance of developing myopathy.
Related JoVE Video
Genotype-guided dosing of coumarin derivatives: the European pharmacogenetics of anticoagulant therapy (EU-PACT) trial design.
Pharmacogenomics
PUBLISHED: 10-22-2009
Show Abstract
Hide Abstract
The narrow therapeutic range and wide interpatient variability in dose requirement make anticoagulation response to coumarin derivatives unpredictable. As a result, patients require frequent monitoring to avert adverse effects and maintain therapeutic efficacy. Polymorphisms in VKORC1 and CYP2C9 jointly account for about 40% of the interindividual variability in dose requirements. To date, several pharmacogenetic-guided dosing algorithms for coumarin derivatives, predominately for warfarin, have been developed. However, the potential benefit of these dosing algorithms in terms of their safety and clinical utility has not been adequately investigated in randomized settings. The European Pharmacogenetics of Anticoagulant Therapy (EU-PACT) trial will assess, in a single-blinded and randomized controlled trial with a follow-up period of 3 months, the safety and clinical utility of genotype-guided dosing in daily practice for the three main coumarin derivatives used in Europe. The primary outcome measure is the percentage time in the therapeutic range for international normalized ratio. This report describes the design and protocol for the trial.
Related JoVE Video
Conference Scene: Pharmacogenomics at the second PharmSciFair 2009: adverse drug reactions and clinical implementation.
Pharmacogenomics
PUBLISHED: 09-19-2009
Show Abstract
Hide Abstract
From 8th to 12th June 2009, the second PharmSciFair took place in Nice, France. Sessions were organized on different types of pharmaceutical research. Two pharmacogenomics sessions were organized by the European Federation for Pharmaceutical Sciences Network on Research in Pharmacogenetics/Pharmacogenomics. The topics of the sessions were adverse drug reactions and clinical implementation. Important conclusions of the presentations were that there has been much progress in the field of pharmacogenomics and that implementation in clinical practice is not as easy as it was once thought. Large prospective trials might be necessary to prove clinical relevance.
Related JoVE Video
Genetic determinants of response to statins.
Expert Rev Cardiovasc Ther
PUBLISHED: 08-14-2009
Show Abstract
Hide Abstract
In developed countries, cardiovascular disease is one of the leading causes of death. Statins are abundantly prescribed to reduce the risk of coronary artery disease by lowering cholesterol. Genetic factors are thought to be partly responsible for the interindividual variation in the response to statins. This article reviews the most important studies conducted on pharmacogenetics of statins. Currently, there is no evidence to advocate pharmacogenetic testing before initiating therapy.
Related JoVE Video
Pharmacogenetics of anti-inflammatory treatment in children with asthma: rationale and design of the PACMAN cohort.
Pharmacogenomics
PUBLISHED: 08-12-2009
Show Abstract
Hide Abstract
To investigate the effects of genetic variation on treatment response to asthma medication in children and to identify (profiles of) SNPs that characterize response phenotypes.
Related JoVE Video
Recruitment of participants through community pharmacies for a pharmacogenetic study of antihypertensive drug treatment.
Pharm World Sci
PUBLISHED: 08-04-2009
Show Abstract
Hide Abstract
To describe the design, recruitment and baseline characteristics of participants in a community pharmacy based pharmacogenetic study of antihypertensive drug treatment.
Related JoVE Video
Conference scene: initiatives on future biobanking in pharmacogenomics.
Pharmacogenomics
PUBLISHED: 07-17-2009
Show Abstract
Hide Abstract
The conference Biobanking in Pharmacogenetics was held on the 23rd and 24th of April 2009 in London, UK. The conference was organized by the European Federation for Pharmaceutical Sciences European Research Network on Pharmacogenetics/Pharmacogenomics. The European Association for Clinical Pharmacology and Therapeutics, GlaxoSmithKline and the Dutch Top Institute Pharma provided financial sponsorship.
Related JoVE Video
Systems biology in pharmacogenomic research: the way to personalized prescribing?
Pharmacogenomics
PUBLISHED: 06-18-2009
Show Abstract
Hide Abstract
Response to pharmacotherapy can be highly variable amongst individuals. Pharmacogenomics may explain the interindividual variability in drug response due to genetic variation. However, besides genetics, many other factors can play a role in the response to pharmacotherapy, including disease severity, co-morbidity, environmental factors, therapy adherence and co-medication use. Better understanding of these factors and inter-relationships should bring about a much more effective approach to disease management. Systems biology that studies organisms as integrated and interacting networks of genes, proteins and biochemical reactions can contribute to this. Organisms are no longer studied part by part, but in a more integral manner. Integration of the genetic data with intermediate and end point phenotypic characterization may prove essential to define the inherent nature of drug effects. Therefore, in the future, a multidisciplinary systems-based approach will be necessary to deal with the bulk of the biological data that is available and, ultimately, to reach the goal of personalized prescribing.
Related JoVE Video
Reasons for non-response in observational pharmacogenetic research.
Pharmacoepidemiol Drug Saf
PUBLISHED: 05-23-2009
Show Abstract
Hide Abstract
In epidemiological studies, non-response may introduce bias and limit generalizability. In genetic pharmacoepidemiological research, collection of DNA might be a major reason for non-response. We determined reasons for non-response and compared characteristics of non-responders and responders in a pharmacogenetic case-control study.
Related JoVE Video
The effect of nine common polymorphisms in coagulation factor genes (F2, F5, F7, F12 and F13 ) on the effectiveness of statins: the GenHAT study.
Pharmacogenet. Genomics
PUBLISHED: 05-06-2009
Show Abstract
Hide Abstract
Pharmacogenetic research has shown that genetic variation may influence statin responsiveness. Statins exert a variety of beneficial effects beyond lipid lowering, including antithrombotic effects, which contribute to the risk reduction of cardiovascular disease. Statins have been shown to influence the expression of coagulation factors II, V, VII, XII and XIII.
Related JoVE Video
AAPS-FIP summary workshop report: Pharmacogenetics in individualized medicine: methods, regulatory, and clinical applications.
AAPS J
PUBLISHED: 01-23-2009
Show Abstract
Hide Abstract
The workshop "Pharmacogenetics in Individualized Medicine: Methods, Regulatory, and Clinical Applications" was held November 15-16, 2008 in Atlanta, Georgia, USA. This workshop provided an opportunity for pharmaceutical scientists, clinical practitioners, clinical laboratory scientists, and FDA to discuss methods, regulatory, and the application of pharmacogenetics in clinical practice and drug discovery. Key highlights of the workshop were: (a) the use of genetic information in individualized medicine has significant potential in advancing drug development and human health by optimizing drug response, drug efficacy, and preventing adverse drug reactions; (b) various barriers exist preventing the advance of the individualized medicine in the society, industry, and clinical practice; and (c) the barriers may be overcome by integrated approaches; the education of researchers, clinical practitioners, and patients and fostering interactive communication among stakeholders. By targeting the AAPS audience, this workshop was one step among many steps that AAPS-FIP is intending to take towards removing the barriers to widespread uptake of pharmacogenetics in drug discovery and clinical practice.
Related JoVE Video
Related JoVE Video
Pharmacogenetics of cardiovascular drug therapy.
Clin Cases Miner Bone Metab
PUBLISHED: 01-01-2009
Show Abstract
Hide Abstract
In developed countries cardiovascular disease is one of the leading causes of death. Cardiovascular drugs such as platelet aggregation inhibitors, oral anticoagulants, antihypertensives and cholesterol lowering drugs are abundantly prescribed to reduce risk of cardiovascular disease. Notable interindividual variation exists in the response to these pharmacotherapeutic interventions, which can be partially explained by factors such as gender, age, diet, concomitant drug use and environmental factors. Notwithstanding, a great part of this variability remains unknown. To a smaller or larger extent, genetic variability may contribute to the variability in response to these cardiovascular drugs. This review gives an overview of pharmacogenetic studies of genes that were reported to be associated with four commonly prescribed drugs/drug classes (platelet aggregation inhibitors, coumarins, antihypertensives and statins) and were studied at least 2 times with a similar outcome measure. In the field of cardiovascular drug therapy, polymorphisms in candidate genes such as the cycloxygenase-1, vitamin K reductase complex subunit 1, CYP2C9, alpha adducin and 3-hydroxy-3-methylglutaryl-CoA reductase have received a great amount of interest in the pharmacogenetics of aspirin, coumarins, antihypertensives and statins respectively. However, only variations in VKORC1 and CYP2C9 have consistently been associated with drug response (coumarins) and have clinical implications. Clinical trials should provide evidence for the effectiveness of genotyping before this procedure will be a part of every day anticoagulant therapy. In spite of the tremendous amount of publications in this field, there is no reason to advocate for genetic testing for any other drugs cardiovascular drug therapy yet. Current approaches in pharmacogenetic research do not seem to lead to results that meet our expectations of individualized medicine. Therefore, new approaches are needed addressing issues and challenges such as the number of SNPs studied, study power, study design and application of new statistical methods in (pharmaco-)genetic analysis.
Related JoVE Video
Related JoVE Video
Evaluation of the effect of statin use on the acenocoumarol and phenprocoumon maintenance dose.
Drug Metabol Drug Interact
Show Abstract
Hide Abstract
Statins and coumarins are prescribed in combination on a regular basis. Some case reports suggested that statins might affect the dose requirements of coumarins. The aim of the study was to investigate whether acenocoumarol and phenprocoumon maintenance doses are influenced by statin use.
Related JoVE Video
Cost-effectiveness of pharmacogenetics in anticoagulation: international differences in healthcare systems and costs.
Pharmacogenomics
Show Abstract
Hide Abstract
Genotyping patients for CYP2C9 and VKORC1 polymorphisms can improve the accuracy of dosing during the initiation of anticoagulation with vitamin K antagonists (coumarin derivatives). The anticipated degree of improvement in the safety of anticoagulation with coumarins through genotyping may vary depending on the quality of patient care, which varies both with and among countries. The management and the cost of anticoagulant care can therefore influence the cost-effectiveness of genotyping within any given country. In this article, we provide an overview of the cost-effectiveness of pharmacogenetics-guided dosing of coumarin derivatives. We describe the organization of anticoagulant care in the UK, Sweden, The Netherlands, Greece, Germany and Austria, where a genotype-guided dosing algorithm is currently being investigated as part of the EU-PACT trial. We also explore the costs of anticoagulant care for the treatment of atrial fibrillation in these countries.
Related JoVE Video
Validation of the acenocoumarol EU-PACT algorithms: similar performance in the Rotterdam Study cohort as in the original study.
Pharmacogenomics
Show Abstract
Hide Abstract
To evaluate the performance of the European Pharmacogenetics of Anticoagulant Therapy (EU-PACT) acenocoumarol dose algorithms in an independent data set. The EU-PACT trial investigates the added value of pretreatment genotyping for use of warfarin, phenprocoumon and acenocoumarol.
Related JoVE Video
Exhaled NO is a poor marker of asthma control in children with a reported use of asthma medication: a pharmacy-based study.
Pediatr Allergy Immunol
Show Abstract
Hide Abstract
A high fraction of nitric oxide in exhaled breath (FeNO) has been suggested to be a marker of ongoing airway inflammation and poorly controlled disease in asthma. The usefulness of FeNO to monitor asthma control is still debated today.
Related JoVE Video
Plasma HDL cholesterol and risk of myocardial infarction: a mendelian randomisation study.
Benjamin F Voight, Gina M Peloso, Marju Orho-Melander, Ruth Frikke-Schmidt, Maja Barbalic, Majken K Jensen, George Hindy, Hilma Holm, Eric L Ding, Toby Johnson, Heribert Schunkert, Nilesh J Samani, Robert Clarke, Jemma C Hopewell, John F Thompson, Mingyao Li, Gudmar Thorleifsson, Christopher Newton-Cheh, Kiran Musunuru, James P Pirruccello, Danish Saleheen, Li Chen, Alexandre F R Stewart, Arne Schillert, Unnur Thorsteinsdottir, Gudmundur Thorgeirsson, Sonia Anand, James C Engert, Thomas Morgan, John Spertus, Monika Stoll, Klaus Berger, Nicola Martinelli, Domenico Girelli, Pascal P McKeown, Christopher C Patterson, Stephen E Epstein, Joseph Devaney, Mary-Susan Burnett, Vincent Mooser, Samuli Ripatti, Ida Surakka, Markku S Nieminen, Juha Sinisalo, Marja-Liisa Lokki, Markus Perola, Aki Havulinna, Ulf de Faire, Bruna Gigante, Erik Ingelsson, Tanja Zeller, Philipp Wild, Paul I W de Bakker, Olaf H Klungel, Anke-Hilse Maitland-van der Zee, Bas J M Peters, Anthonius de Boer, Diederick E Grobbee, Pieter W Kamphuisen, Vera H M Deneer, Clara C Elbers, N Charlotte Onland-Moret, Marten H Hofker, Cisca Wijmenga, W M Monique Verschuren, Jolanda M A Boer, Yvonne T van der Schouw, Asif Rasheed, Philippe Frossard, Serkalem Demissie, Cristen Willer, Ron Do, José M Ordovás, Gonçalo R Abecasis, Michael Boehnke, Karen L Mohlke, Mark J Daly, Candace Guiducci, Noel P Burtt, Aarti Surti, Elena González, Shaun Purcell, Stacey Gabriel, Jaume Marrugat, John Peden, Jeanette Erdmann, Patrick Diemert, Christina Willenborg, Inke R König, Marcus Fischer, Christian Hengstenberg, Andreas Ziegler, Ian Buysschaert, Diether Lambrechts, Frans Van de Werf, Keith A Fox, Nour Eddine El Mokhtari, Diana Rubin, Jürgen Schrezenmeir, Stefan Schreiber, Arne Schäfer, John Danesh, Stefan Blankenberg, Robert Roberts, Ruth McPherson, Hugh Watkins, Alistair S Hall, Kim Overvad, Eric Rimm, Eric Boerwinkle, Anne Tybjaerg-Hansen, L Adrienne Cupples, Muredach P Reilly, Olle Melander, Pier M Mannucci, Diego Ardissino, David Siscovick, Roberto Elosua, Kari Stefansson, Christopher J O'Donnell, Veikko Salomaa, Daniel J Rader, Leena Peltonen, Stephen M Schwartz, David Altshuler, Sekar Kathiresan.
Lancet
Show Abstract
Hide Abstract
High plasma HDL cholesterol is associated with reduced risk of myocardial infarction, but whether this association is causal is unclear. Exploiting the fact that genotypes are randomly assigned at meiosis, are independent of non-genetic confounding, and are unmodified by disease processes, mendelian randomisation can be used to test the hypothesis that the association of a plasma biomarker with disease is causal.
Related JoVE Video
Large-scale gene-centric meta-analysis across 39 studies identifies type 2 diabetes loci.
Richa Saxena, Clara C Elbers, Yiran Guo, Inga Peter, Tom R Gaunt, Jessica L Mega, Matthew B Lanktree, Archana Tare, Berta Almoguera Castillo, Yun R Li, Toby Johnson, Marcel Bruinenberg, Diane Gilbert-Diamond, Ramakrishnan Rajagopalan, Benjamin F Voight, Ashok Balasubramanyam, John Barnard, Florianne Bauer, Jens Baumert, Tushar Bhangale, Bernhard O Böhm, Peter S Braund, Paul R Burton, Hareesh R Chandrupatla, Robert Clarke, Rhonda M Cooper-DeHoff, Errol D Crook, George Davey-Smith, Ian N Day, Anthonius de Boer, Mark C H de Groot, Fotios Drenos, Jane Ferguson, Caroline S Fox, Clement E Furlong, Quince Gibson, Christian Gieger, Lisa A Gilhuijs-Pederson, Joseph T Glessner, Anuj Goel, Yan Gong, Struan F A Grant, Diederick E Grobbee, Claire Hastie, Steve E Humphries, Cecilia E Kim, Mika Kivimäki, Marcus Kleber, Christa Meisinger, Meena Kumari, Taimour Y Langaee, Debbie A Lawlor, Mingyao Li, Maximilian T Lobmeyer, Anke-Hilse Maitland-van der Zee, Matthijs F L Meijs, Cliona M Molony, David A Morrow, Gurunathan Murugesan, Solomon K Musani, Christopher P Nelson, Stephen J Newhouse, Jeffery R O'Connell, Sandosh Padmanabhan, Jutta Palmen, Sanjey R Patel, Carl J Pepine, Mary Pettinger, Thomas S Price, Suzanne Rafelt, Jane Ranchalis, Asif Rasheed, Elisabeth Rosenthal, Ingo Ruczinski, Sonia Shah, Haiqing Shen, Günther Silbernagel, Erin N Smith, Annemieke W M Spijkerman, Alice Stanton, Michael W Steffes, Barbara Thorand, Mieke Trip, Pim van der Harst, Daphne L van der A, Erik P A van Iperen, Jessica van Setten, Jana V van Vliet-Ostaptchouk, Niek Verweij, Bruce H R Wolffenbuttel, Taylor Young, M Hadi Zafarmand, Joseph M Zmuda, , Michael Boehnke, David Altshuler, Mark McCarthy, W H Linda Kao, James S Pankow, Thomas P Cappola, Peter Sever, Neil Poulter, Mark Caulfield, Anna Dominiczak, Denis C Shields, Deepak L Bhatt, Deepak Bhatt, Li Zhang, Sean P Curtis, John Danesh, Juan P Casas, Yvonne T van der Schouw, N Charlotte Onland-Moret, Pieter A Doevendans, Gerald W Dorn, Martin Farrall, Garret A FitzGerald, Anders Hamsten, Robert Hegele, Aroon D Hingorani, Marten H Hofker, Gordon S Huggins, Thomas Illig, Gail P Jarvik, Julie A Johnson, Olaf H Klungel, William C Knowler, Wolfgang Koenig, Winfried März, James B Meigs, Olle Melander, Patricia B Munroe, Braxton D Mitchell, Susan J Bielinski, Daniel J Rader, Muredach P Reilly, Stephen S Rich, Jerome I Rotter, Danish Saleheen, Nilesh J Samani, Eric E Schadt, Alan R Shuldiner, Roy Silverstein, Kandice Kottke-Marchant, Philippa J Talmud, Hugh Watkins, Folkert W Asselbergs, Folkert Asselbergs, Paul I W de Bakker, Jeanne McCaffery, Cisca Wijmenga, Marc S Sabatine, James G Wilson, Alex Reiner, Donald W Bowden, Hakon Hakonarson, David S Siscovick, Brendan J Keating.
Am. J. Hum. Genet.
Show Abstract
Hide Abstract
To identify genetic factors contributing to type 2 diabetes (T2D), we performed large-scale meta-analyses by using a custom ?50,000 SNP genotyping array (the ITMAT-Broad-CARe array) with ?2000 candidate genes in 39 multiethnic population-based studies, case-control studies, and clinical trials totaling 17,418 cases and 70,298 controls. First, meta-analysis of 25 studies comprising 14,073 cases and 57,489 controls of European descent confirmed eight established T2D loci at genome-wide significance. In silico follow-up analysis of putative association signals found in independent genome-wide association studies (including 8,130 cases and 38,987 controls) performed by the DIAGRAM consortium identified a T2D locus at genome-wide significance (GATAD2A/CILP2/PBX4; p = 5.7 × 10(-9)) and two loci exceeding study-wide significance (SREBF1, and TH/INS; p < 2.4 × 10(-6)). Second, meta-analyses of 1,986 cases and 7,695 controls from eight African-American studies identified study-wide-significant (p = 2.4 × 10(-7)) variants in HMGA2 and replicated variants in TCF7L2 (p = 5.1 × 10(-15)). Third, conditional analysis revealed multiple known and novel independent signals within five T2D-associated genes in samples of European ancestry and within HMGA2 in African-American samples. Fourth, a multiethnic meta-analysis of all 39 studies identified T2D-associated variants in BCL2 (p = 2.1 × 10(-8)). Finally, a composite genetic score of SNPs from new and established T2D signals was significantly associated with increased risk of diabetes in African-American, Hispanic, and Asian populations. In summary, large-scale meta-analysis involving a dense gene-centric approach has uncovered additional loci and variants that contribute to T2D risk and suggests substantial overlap of T2D association signals across multiple ethnic groups.
Related JoVE Video
Pharmacogenetic-guided dosing of coumarin anticoagulants: algorithms for warfarin, acenocoumarol and phenprocoumon.
Br J Clin Pharmacol
Show Abstract
Hide Abstract
Coumarin derivatives, such as warfarin, acenocoumarol and phenprocoumon are frequently prescribed oral anticoagulants to treat and prevent thromboembolism. Because there is a large inter-individual and intra-individual variability in dose-response and a small therapeutic window, treatment with coumarin derivatives is challenging. Certain polymorphisms in CYP2C9 and VKORC1 are associated with lower dose requirements and a higher risk of bleeding. In this review we describe the use of different coumarin derivatives, pharmacokinetic characteristics of these drugs and differences amongst the coumarins. We also describe the current clinical challenges and the role of pharmacogenetic factors. These genetic factors are used to develop dosing algorithms, and can be used to predict the right coumarin dose. The effectiveness of this new dosing strategy is currently being investigated in clinical trials.
Related JoVE Video

What is Visualize?

JoVE Visualize is a tool created to match the last 5 years of PubMed publications to methods in JoVE's video library.

How does it work?

We use abstracts found on PubMed and match them to JoVE videos to create a list of 10 to 30 related methods videos.

Video X seems to be unrelated to Abstract Y...

In developing our video relationships, we compare around 5 million PubMed articles to our library of over 4,500 methods videos. In some cases the language used in the PubMed abstracts makes matching that content to a JoVE video difficult. In other cases, there happens not to be any content in our video library that is relevant to the topic of a given abstract. In these cases, our algorithms are trying their best to display videos with relevant content, which can sometimes result in matched videos with only a slight relation.