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Pharmacogenetic analysis of the cardiovascular response in mice

English title Pharmacogenetic analysis of the cardiovascular response in mice
Applicant Beckmann Jacques
Number 112552
Funding scheme Project funding
Research institution Département de génétique médicale Faculté de biologie et de médecine CHUV & Université de Lausanne
Institution of higher education University of Lausanne - LA
Main discipline Genetics
Start/End 01.05.2006 - 30.04.2012
Approved amount 425'000.00
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All Disciplines (3)

Discipline
Genetics
Cardiovascular Research
Physiology : other topics

Keywords (4)

pharmacogenetics; cardiovascular genetics; mouse genetics; genetic mapping

Lay Summary (English)

Lead
Lay summary
Poorly predictable response variability to many commonly-used drugs may impose important clinical and economical constraints, sometimes leading to unwanted side-effects or showing at best little relief. Amid critical factors that contribute to such drawbacks, common genetic variants may modulate not only disease but also drug action and response. Yet, the identification of pharmacogenetic determinants in humans is complicated by limitations (genetic heterogeneity, sample size, compliance to drug prescription, poly-medication, placebo effect) that can be more easily addressed in controlled animal models. To date, most murine cardiovascular-associated quantitative trait loci (QTL) map concordant human QTLs. Besides, genetic determinants for both mono- and multigenic traits have been successfully characterised in such models. Thus, we reasoned that identifying pharmacogenetic variants in mice may advantageously contribute to the understanding of drug response variability in humans. As most inbred laboratory mice descend from a very limited number of progenitors, each strain can be considered as an individual member of a rather close family of mice. Moreover, the sequencing of the mouse genome, together with the availability of ever denser single nucleotide polymorphism (SNP) maps for diverse inbred strains provide major tools to enhance and accelerate mouse genetic trait mapping by correlating in vivo phenotypes with SNP alleles.
Here, we propose to develop a systemic and unbiased genome-wide screening model for cardiovascular pharmacogenetic variants in mice. Specifically, we will phenotype age- and sex-matched inbred mice of at least 20 strains for parameters like systolic blood pressure, heart rate and electrocardiogram, under basal conditions and in response to isoproterenol (a Beta-adrenergic agonist) or atenolol (a Beta-blocker). At the end of the 2-week treatment, complementary phenotypes such as cardiac mass, as well as lipids, electrolytes and drug metabolites in urine and plasma will be measured. Mice will then be sacrificed and several biological samples will be collected and stored for later studies (functional genomics, transcription profiling, proteomics). To map the genetic loci that modulate the cardiovascular response in untreated and drug-exposed mice by bio-statistical correlation methods, we will use publicly available multi-strain SNP information to identify SNP alleles that co-segregate with the divergent phenotypes.
Apart from providing information on the genetic architecture of the trait studied, these studies will allow the identification of the etiologic variants underlying these differences, some of which will map in previously unsuspected genes. Also, they may shed new light on the normal and patho-physiological mechanisms of cardiac diseases. In the long term, these results may open up onto a whole new field of functional, physiological or pharmacological projects, eventually allowing the testing of orthologous human loci for their involvement in differential drug responses. Once validated, these could be introduced into clinical practice as prognostic biomarkers.
Direct link to Lay Summary Last update: 21.02.2013

Responsible applicant and co-applicants

Employees

Publications

Publication
RNAseq analysis of heart tissue from mice treated with atenolol and isoproterenol reveals a reciprocal transcriptional response
Prunotto Andrea, Stevenson Brian J., Berthonneche Corinne, Schüpfer Fanny, Beckmann Jacques S., Maurer Fabienne, Bergmann Sven (2016), RNAseq analysis of heart tissue from mice treated with atenolol and isoproterenol reveals a reciprocal transcriptional response, in BMC Genomics, 17, 717.
Mapping genetic variants associated with beta-adrenergic responses in inbred mice
Hersch Micha, Peter Bastian, Kang Hyun Min, Schüpfer Fanny, Abriel Hugues, Pedrazzini Thierry, Eskin Eleazar, Beckmann Jacques S., Bergmann Sven, Maurer Fabienne (2012), Mapping genetic variants associated with beta-adrenergic responses in inbred mice, in PLoS ONE, 7(7), e41032.
Cardiovascular response to beta-adrenergic blockade or activation in 23 inbred mouse strains.
Berthonneche Corinne, Peter Bastian, Schüpfer Fanny, Hayoz Pamela, Kutalik Zoltán, Abriel Hugues, Pedrazzini Thierry, Beckmann Jacques S, Bergmann Sven, Maurer Fabienne (2009), Cardiovascular response to beta-adrenergic blockade or activation in 23 inbred mouse strains., in PLoS ONE, 4(8), 6610-6610.

Collaboration

Group / person Country
Types of collaboration
Université de Lausanne, Prof. S. Bergmann Switzerland (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
- Research Infrastructure
- Exchange of personnel
SIB, Prof. S. Bergmann Switzerland (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
- Research Infrastructure
- Exchange of personnel
Université de Berne, Prof. H. Abriel Switzerland (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
CHUV, Prof. T. Pedrazzini Switzerland (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
- Research Infrastructure
UCLA, Prof. E. Eskin United States of America (North America)
- in-depth/constructive exchanges on approaches, methods or results
- Publication

Scientific events

Active participation

Title Type of contribution Title of article or contribution Date Place Persons involved
CHUV Reseach Day 2011 Talk given at a conference Mapping genetic variants associated to beta-adrenergic responses in inbred mice 27.01.2011 Lausanne, Switzerland Beckmann Jacques; Abriel Hugues; Pedrazzini Thierry; Berthonneche Corinne; Maurer Fabienne;
CHUV Research Day 2009 Poster Βeta-adrenergic response in 23 inbred mouse strains 29.01.2009 Lausanne, Switzerland Pedrazzini Thierry; Beckmann Jacques; Maurer Fabienne; Berthonneche Corinne; Abriel Hugues;
USGEB 2008 Poster Large scale pharmacogenetics in laboratory mice 06.02.2008 Lausanne, Switzerland Abriel Hugues; Berthonneche Corinne; Maurer Fabienne; Beckmann Jacques; Pedrazzini Thierry;
CHUV Research Day 2007 Poster Pharmacogenetic anaylsis of the cardiovascular response in mice 01.02.2007 Lausanne, Switzerland Pedrazzini Thierry; Berthonneche Corinne; Beckmann Jacques; Abriel Hugues; Maurer Fabienne;


Associated projects

Number Title Start Funding scheme
135693 In vivo relevance of the PY and PDZ-domain binding motifs of the cardiac sodium channel Nav1.5 01.04.2011 Project funding

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