title: New molecular insights into modulation of platelet reactivity in aspirin-treated patients using a network-based approach.
abstract: Platelet reactivity (PR) is variable between individuals and modulates clinical outcome in cardiovascular (CV) patients treated with antiplatelet drugs. Although several data point to a genetic control of platelet reactivity, the genes contributing to the modulation of this phenotype are not clearly identified. Integration of data derived from high-throughput technologies may yield novel insights into the molecular mechanisms that govern platelet reactivity. The aim of this study is to identify candidate genes modulating platelet reactivity in aspirin-treated CV patients using an integrative network-based approach. Patients with extreme high (n = 6) or low PR (n = 6) were selected and data derived from quantitative proteomic of platelets and platelet sub-cellular fractions, as well as from transcriptomic analysis were integrated with a network biology approach. Two modules within the network containing 123 and 182 genes were identified. We then specifically assessed the level of miRNAs in these two groups of patients. Among the 12 miRNAs differentially expressed, 2 (miR-135a-5p and miR-204-5p) correlated with PR. The predicted targets of these miRNAs were mapped onto the network, allowing the identification of seven overlapping genes (THBS1, CDC42, CORO1C, SPTBN1, TPM3, GTPBP2, and MAPRE2), suggesting a synergistic effect of these two miRNAs on these predicted targets. Integration of several omics data sets allowed the identification of 2 candidate miRNAs and 7 candidate genes regulating platelet reactivity in aspirin-treated CV patients.
authors.affiliation: Division of Angiology and Haemostasis, University Hospitals of Geneva, Rue Gabrielle-Perret-Gentil 4, 1205, Geneva, Switzerland.|Translational Biomarker Group, Human Protein Sciences Department, University of Geneva, Geneva, Switzerland.|Geneva Platelet Group, University of Geneva, Geneva, Switzerland.
authors.forename: Anne
authors.initials: A
authors.lastname: Zufferey
authors.affiliation: Vital-IT Group, SIB Swiss Institute of Bioinformatics, University of Lausanne, Lausanne, Switzerland.
authors.forename: Mark
authors.initials: M
authors.lastname: Ibberson
authors.affiliation: Geneva Platelet Group, University of Geneva, Geneva, Switzerland.|Division of Internal Medicine, and Rehabilitation, Trois-Chêne Hospital, University Hospitals of Geneva, Geneva, Switzerland.
authors.forename: Jean-Luc
authors.initials: JL
authors.lastname: Reny
authors.affiliation: Division of Angiology and Haemostasis, University Hospitals of Geneva, Rue Gabrielle-Perret-Gentil 4, 1205, Geneva, Switzerland.|Geneva Platelet Group, University of Geneva, Geneva, Switzerland.
authors.forename: Séverine
authors.initials: S
authors.lastname: Nolli
authors.affiliation: Translational Biomarker Group, Human Protein Sciences Department, University of Geneva, Geneva, Switzerland.
authors.forename: Domitille
authors.initials: D
authors.lastname: Schvartz
authors.affiliation: iGE3 Genomics Platform, University of Geneva, Geneva, Switzerland.
authors.forename: Mylène
authors.initials: M
authors.lastname: Docquier
authors.affiliation: Vital-IT Group, SIB Swiss Institute of Bioinformatics, University of Lausanne, Lausanne, Switzerland.|Swiss-Prot Group, SIB Swiss Institute of Bioinformatics, Geneva, Switzerland.
authors.forename: Ioannis
authors.initials: I
authors.lastname: Xenarios
authors.affiliation: Translational Biomarker Group, Human Protein Sciences Department, University of Geneva, Geneva, Switzerland.
authors.forename: Jean-Charles
authors.initials: JC
authors.lastname: Sanchez
authors.affiliation: Division of Angiology and Haemostasis, University Hospitals of Geneva, Rue Gabrielle-Perret-Gentil 4, 1205, Geneva, Switzerland. pierre.fontana@hcuge.ch.|Geneva Platelet Group, University of Geneva, Geneva, Switzerland. pierre.fontana@hcuge.ch.
authors.forename: Pierre
authors.identifier: http://orcid.org/0000-0003-1546-0774
authors.initials: P
authors.lastname: Fontana
mesh_terms: D001241:Aspirin / Q000494:pharmacology*; D001792:Blood Platelets / Q000187:drug effects*; D006801:Humans; D035683:MicroRNAs / Q000235:genetics; D040901:Proteomics; D012333:RNA, Messenger / Q000235:genetics
chemical_list: D035683:MicroRNAs; D012333:RNA, Messenger; D001241:Aspirin