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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 (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 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 Citing Articles via Google Scholar Google Scholar Articles by Jones, C. I Articles by Ouwehand, W. H Search for Related Content PubMed PubMed Citation Articles by Jones, C. I Articles by Ouwehand, W. H Related Collections Related Article in Blood Online Social Bookmarking                   What's this?  Previous Article  |  Next Article  Submitted February 4, 2009 Accepted April 25, 2009 A functional genomics approach reveals novel quantitative trait loci associated with platelet signalling pathways Chris I Jones, Sarah Bray, Stephen F Garner, Jonathan Stephens, Bernard de Bono, Will GJ Angenent, David Bentley, Philippa Burns, Alison Coffey, Panos Deloukas, Mark Earthrowl, Richard W Farndale, Marc F Hoylaerts, Kerstin Koch, Angela Rankin, Catherine M Rice, Jane Rogers, Nilesh J Samani, Michael Steward, Adam Walker, Nicholas A Watkins, Jan-Willem Akkerman, Frank Dudbridge, Alison H Goodall*, and Willem H Ouwehand Department of Cardiovascular Science, University of Leicester, Clinical Sciences Wing, Glenfield Hospital, Leicester, United Kingdom Medical Research Council Biostatistics Unit, Cambridge, United Kingdom Department of Haematology, Univeristy of Cambridge and National Health Service Blood and Transplant, Cambridge, United Kingdom European Bioinformatics Institute, Wellcome Trust Genome Campus, Hinxton, Cambridge, United Kingdom The Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, Cambridge, United Kingdom Department of Biochemistry, University of Cambridge, Cambridge, United Kingdom Center for Molecular and Vascular Biology, University of Leuven, Leuven, Belgium Domantis Limited, Cambridge, United Kingdom Department of Clinical Chemistry and Haematology University Medical Center Utrecht, Utrecht, Netherlands * Corresponding author; email: ahg5{at}le.ac.uk. Platelet response to activation varies widely between individuals but shows inter-individual 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 ADP signalling 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<0.005) accounting for ~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 following platelet degranulation. The minor allele of a 3'UTR SNP (rs2769668) in VAV3 was associated with higher protein expression (p=0.03) and increased P-selectin exposure following ADP activation (p=0.004). Furthermore the minor allele of the intronic SNP rs17786144 in ITPR1 modified Ca2+ levels after activation with ADP (p<0.004). These data provide novel insights into key hubs within platelet signalling 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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