BACKGROUND: Genome-wide association studies are currently identifying new loci with potential roles in thrombosis and hemostasis: these loci include novel polymorphisms associated with platelet function traits and count. However, no genome-wide study performed on children has been reported to date, in spite of the potential that these subjects have in genetic studies, when compared to adults, given the minimal degree of confounders, i.e., acquired and environmental factors, such as smoking, physical activity, diet, and drug or hormone intake, which are particularly important in platelet function. DESIGN AND METHODS: To identify new genetic variants involved in platelet reactivity and count, we performed a genome-wide association study on 75 children (8.5±1.8 years) using the Illumina Sentrix Human CNV370-Quad BeadChip containing 320,610 single nucleotide polymorphisms. Functional analyses included assessment of platelet aggregation and granule secretion triggered by different agonists (arachidonic acid, collagen, epinephrine, ADP), as well as platelet count. Associations were selected based on statistical significance and physiological relevance for a subsequent replication study in a similar sample of 286 children. RESULTS: We confirmed previously established associations with plasma levels of factors XII, VII and VIII as well as associations with platelet responses to ADP. Additionally, we identified 82 associations with platelet reactivity and count with a P value less than 10(-5). From the associations selected for further replication, we validated two single nucleotide polymorphisms with mildly increased platelet reactivity (rs4366150 and rs1787566) on the LPAR1 and MYO5B genes, encoding lisophosphatidic acid receptor-1 and myosin VB, respectively; and rs1937970, located on the NRG3 gene coding neuroregulin-3, associated with platelet count. CONCLUSIONS: Our genome-wide association study performed in children, followed by a validation analysis, led us to the identification of new genes potentially relevant in platelet function and biogenesis.
BACKGROUND: Genome-wide association studies are currently identifying new loci with potential roles in thrombosis and hemostasis: these loci include novel polymorphisms associated with platelet function traits and count. However, no genome-wide study performed on children has been reported to date, in spite of the potential that these subjects have in genetic studies, when compared to adults, given the minimal degree of confounders, i.e., acquired and environmental factors, such as smoking, physical activity, diet, and drug or hormone intake, which are particularly important in platelet function. DESIGN AND METHODS: To identify new genetic variants involved in platelet reactivity and count, we performed a genome-wide association study on 75 children (8.5±1.8 years) using the Illumina Sentrix Human CNV370-Quad BeadChip containing 320,610 single nucleotide polymorphisms. Functional analyses included assessment of platelet aggregation and granule secretion triggered by different agonists (arachidonic acid, collagen, epinephrine, ADP), as well as platelet count. Associations were selected based on statistical significance and physiological relevance for a subsequent replication study in a similar sample of 286 children. RESULTS: We confirmed previously established associations with plasma levels of factors XII, VII and VIII as well as associations with platelet responses to ADP. Additionally, we identified 82 associations with platelet reactivity and count with a P value less than 10(-5). From the associations selected for further replication, we validated two single nucleotide polymorphisms with mildly increased platelet reactivity (rs4366150 and rs1787566) on the LPAR1 and MYO5B genes, encoding lisophosphatidic acid receptor-1 and myosin VB, respectively; and rs1937970, located on the NRG3 gene coding neuroregulin-3, associated with platelet count. CONCLUSIONS: Our genome-wide association study performed in children, followed by a validation analysis, led us to the identification of new genes potentially relevant in platelet function and biogenesis.
Authors: D Zhang; M X Sliwkowski; M Mark; G Frantz; R Akita; Y Sun; K Hillan; C Crowley; J Brush; P J Godowski Journal: Proc Natl Acad Sci U S A Date: 1997-09-02 Impact factor: 11.205
Authors: Marek Postula; Piotr K Janicki; Marek Rosiak; Agnieszka Kaplon-Cieslicka; Ewa Trzepla; Krzysztof J Filipiak; Dariusz A Kosior; Andrzej Czlonkowski; Grzegorz Opolski Journal: J Thromb Thrombolysis Date: 2013-07 Impact factor: 2.300
Authors: Emilie Montenont; Seema Bhatlekar; Shancy Jacob; Yasuhiro Kosaka; Bhanu K Manne; Olivia Lee; Ivan Parra-Izquierdo; Emilia Tugolukova; Neal D Tolley; Matthew T Rondina; Paul F Bray; Jesse W Rowley Journal: Blood Adv Date: 2021-05-11
Authors: María Eugenia de la Morena-Barrio; Alfonso Buil; Ana Isabel Antón; Irene Martínez-Martínez; Antonia Miñano; Ricardo Gutiérrez-Gallego; José Navarro-Fernández; Sonia Aguila; Juan Carlos Souto; Vicente Vicente; José Manuel Soria; Javier Corral Journal: PLoS One Date: 2013-05-21 Impact factor: 3.240
Authors: John D Eicher; Nathalie Chami; Tim Kacprowski; Akihiro Nomura; Ming-Huei Chen; Lisa R Yanek; Salman M Tajuddin; Ursula M Schick; Andrew J Slater; Nathan Pankratz; Linda Polfus; Claudia Schurmann; Ayush Giri; Jennifer A Brody; Leslie A Lange; Ani Manichaikul; W David Hill; Raha Pazoki; Paul Elliot; Evangelos Evangelou; Ioanna Tzoulaki; He Gao; Anne-Claire Vergnaud; Rasika A Mathias; Diane M Becker; Lewis C Becker; Amber Burt; David R Crosslin; Leo-Pekka Lyytikäinen; Kjell Nikus; Jussi Hernesniemi; Mika Kähönen; Emma Raitoharju; Nina Mononen; Olli T Raitakari; Terho Lehtimäki; Mary Cushman; Neil A Zakai; Deborah A Nickerson; Laura M Raffield; Rakale Quarells; Cristen J Willer; Gina M Peloso; Goncalo R Abecasis; Dajiang J Liu; Panos Deloukas; Nilesh J Samani; Heribert Schunkert; Jeanette Erdmann; Myriam Fornage; Melissa Richard; Jean-Claude Tardif; John D Rioux; Marie-Pierre Dube; Simon de Denus; Yingchang Lu; Erwin P Bottinger; Ruth J F Loos; Albert Vernon Smith; Tamara B Harris; Lenore J Launer; Vilmundur Gudnason; Digna R Velez Edwards; Eric S Torstenson; Yongmei Liu; Russell P Tracy; Jerome I Rotter; Stephen S Rich; Heather M Highland; Eric Boerwinkle; Jin Li; Ethan Lange; James G Wilson; Evelin Mihailov; Reedik Mägi; Joel Hirschhorn; Andres Metspalu; Tõnu Esko; Caterina Vacchi-Suzzi; Mike A Nalls; Alan B Zonderman; Michele K Evans; Gunnar Engström; Marju Orho-Melander; Olle Melander; Michelle L O'Donoghue; Dawn M Waterworth; Lars Wallentin; Harvey D White; James S Floyd; Traci M Bartz; Kenneth M Rice; Bruce M Psaty; J M Starr; David C M Liewald; Caroline Hayward; Ian J Deary; Andreas Greinacher; Uwe Völker; Thomas Thiele; Henry Völzke; Frank J A van Rooij; André G Uitterlinden; Oscar H Franco; Abbas Dehghan; Todd L Edwards; Santhi K Ganesh; Sekar Kathiresan; Nauder Faraday; Paul L Auer; Alex P Reiner; Guillaume Lettre; Andrew D Johnson Journal: Am J Hum Genet Date: 2016-06-23 Impact factor: 11.043