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Blood, 13 August 2009, Vol. 114, No. 7, pp. 1405-1416. Prepublished online as a Blood First Edition Paper on May 8, 2009; DOI 10.1182/blood-2009-02-202614. This Article Full Text Full Text (PDF) Supplemental Methods, Tables, and Figures All Versions of this Article: blood-2009-02-202614v1 114/7/1405    most recent Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Rights and Permissions Citing Articles Citing Articles via HighWire Citing Articles via CrossRef Google Scholar Articles by Jones, C. I. Articles by Ouwehand, W. H. PubMed PubMed Citation Articles by Jones, C. I. Articles by Ouwehand, W. H. Related Collections Platelets and Thrombopoiesis Related Article in Blood Online Social Bookmarking                   What's this?  Previous Article  |  Table of Contents  |  Next Article  PLATELETS AND THROMBOPOIESIS A functional genomics approach reveals novel quantitative trait loci associated with platelet signaling pathways Chris I. Jones1,*, Sarah Bray2,*, Stephen F. Garner3,*, Jonathan Stephens3, Bernard de Bono4, Will G. J. Angenent5, David Bentley5, Philippa Burns3, Alison Coffey5, Panos Deloukas5, Mark Earthrowl5, Richard W. Farndale6, Marc F. Hoylaerts7, Kerstin Koch3, Angela Rankin3, Catherine M. Rice5, Jane Rogers5, Nilesh J. Samani1, Michael Steward8, Adam Walker8, Nicholas A. Watkins3, Jan-Willem Akkerman9, Frank Dudbridge2, Alison H. Goodall1, Willem H. Ouwehand3,5, on behalf of the Bloodomics Consortium 1 Department of Cardiovascular Science, University of Leicester, Clinical Sciences Wing, Glenfield Hospital, Leicester, United Kingdom; 2 Medical Research Council Biostatistics Unit, Cambridge, United Kingdom; 3 Department of Haematology, University of Cambridge and National Health Service Blood and Transplant, Cambridge, United Kingdom; 4 European Bioinformatics Institute, and 5 The Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, United Kingdom; 6 Department of Biochemistry, University of Cambridge, Cambridge, United Kingdom; 7 Center for Molecular and Vascular Biology, University of Leuven, Leuven, Belgium; 8 Domantis Limited, Cambridge, United Kingdom; and 9 Department of Clinical Chemistry and Haematology, University Medical Center Utrecht, Utrecht, The Netherlands Platelet response to activation varies widely between individuals but shows interindividual consistency and strong heritability. The genetic basis of this variation has not been properly explored. We therefore systematically measured the effect on function of sequence variation in 97 candidate genes in the collagen and adenosine-diphosphate (ADP) signaling pathways. Resequencing of the genes in 48 European DNA samples nearly doubled the number of known single nucleotide polymorphisms (SNPs) and informed the selection of 1327 SNPs for genotyping in 500 healthy Northern European subjects with known platelet responses to collagen-related peptide (CRP-XL) and ADP. This identified 17 novel associations with platelet function (P < .005) accounting for approximately 46% of the variation in response. Further investigations with platelets of known genotype explored the mechanisms behind some of the associations. SNPs in PEAR1 associated with increased platelet response to CRP-XL and increased PEAR1 protein expression after platelet degranulation. The minor allele of a 3' untranslated region (UTR) SNP (rs2769668) in VAV3 was associated with higher protein expression (P = .03) and increased P-selectin exposure after ADP activation (P = .004). Furthermore the minor allele of the intronic SNP rs17786144 in ITPR1 modified Ca2+ levels after activation with ADP (P < .004). These data provide novel insights into key hubs within platelet signaling networks. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? Related Article in Blood Online: Platelet genomics beats the catch-22 Paul F. Bray Blood 2009 114: 1286-1287. [Full Text] [PDF] This article has been cited by other articles: P. F. Bray Platelet genomics beats the catch-22 Blood, August 13, 2009; 114(7): 1286 - 1287. [Full Text] [PDF]

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