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Blood, 16 April 2009, Vol. 113, No. 16, pp. 3831-3837.
Prepublished online as a Blood First Edition Paper on February 12, 2009; DOI 10.1182/blood-2008-10-184234.
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Submitted October 23, 2008
Accepted December 24, 2008
A novel variant on chromosome 7Q22.3 associated with mean platelet volume, counts and function
Nicole Soranzo, Augusto Rendon, Christian Gieger, Chris I. Jones, Nicholas A. Watkins, Stephan Menzel, Angela Doring, Jonathan Stephens, Holger Prokisch, Wendy Erber, Simon C. Potter, Sarah L. Bray, Philippa Burns, Jennifer Jolley, Mario Falchi, Brigitte Kuhnel, Jeanette Erdmann, Heribert Schunkert, Nilesh Samani, Thomas Illig, Stephen F. Garner, Angela Rankin, Christa Meisinger, John R. Bradley, Swee Lay Thein, Alison H. Goodall, Tim D. Spector, Panos Deloukas, and Willem H. Ouwehand*
Human Genetics Department, Wellcome Trust Sanger Institute, Hinxton, Cambridge, United Kingdom
Department of Haematology, University of Cambridge & NHS Blood and Transplant (NHSBT), Cambridge, United Kingdom
Institute of Epidemiology, Helmholtz Zentrum Munchen, German Research Center for Environmental Health, Neuherberg, Germany
School of Biological Sciences, University of Reading, Reading, United Kingdom
Molecular Haematology, King's College London, London, United Kingdom
Institute of Human Genetics, Technical University Munich, Munich, Germany
Haematology Department, Cambridge University Hospitals NHS Foundation Trust, Cambridge, United Kingdom
MRC Biostatistics Unit, University Forvie Site, Cambridge, United Kingdom
Genomic Medicine, Imperial College London, London, United Kingdom
Medizinische Klinik II, Universitat zu Lubeck, Lubeck, Germany
Cardiovascular Sciences, University of Leicester, Leicester, United Kingdom
Department of Medicine, University of Cambridge School of Clinical Medicine, Addenbrooke's Hospital, Cambridge, United Kingdom
Department of Twin Research and Genetic Epidemiology, King's College London, London, United Kingdom
* Corresponding author; email: who1000{at}cam.ac.uk.
The volume (MPV) and count of platelets (PLT) are highly heritable and tightly regulated traits. We carried out a genome-wide association study for MPV and identified one SNP, rs342293, having highly significant and reproducible association with MPV (per-G allele effect 0.016±0.001 log fl, P = 1.08x10-24) and PLT (per-G effect -4.55±0.80 109/l, P = 7.19x10-8) in 8,586 healthy individuals. Whole-genome expression analysis in the 1-Mb region revealed a significant association with platelet transcript levels for PIK3CG (n=35, P = 0.047). The G allele at rs342293 was also associated with decreased binding of Annexin V to platelets activated with collagen-related peptide (n=84, P = 0.003). The region 7q22.3 identifies the first QTL influencing platelet volume, counts and function in healthy individuals. Notably, the association signal maps to a chromosome region implicated in myeloid malignancies, indicating this site as an important regulatory site for haematopoiesis. The identification of loci regulating MPV by this and other studies will increase our insight in the processes of megakaryopoiesis and proplatelet formation, and may aid the identification of genes that are somatically mutated in essential thrombocytosis.
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