Within the healthy population, there is substantial, heritable, and interindividual variability in the platelet response. We explored whether a proportion of this variability could be accounted for by interindividual variation in gene expression. Through a correlative analysis of genome-wide platelet RNA expression data from 37 subjects representing the normal range of platelet responsiveness within a cohort of 500 subjects, we identified 63 genes in which transcript levels correlated with variation in the platelet response to adenosine diphosphate and/or the collagen-mimetic peptide, crosslinked collagen-related peptide. Many of these encode proteins with no reported function in platelets. An association study of 6 of the 63 genes in 4235 cases and 6379 controls showed a putative association with myocardial infarction for COMMD7 (COMM domain-containing protein 7) and a major deviation from the null hypothesis for LRRFIP1 [leucinerich repeat (in FLII) interacting protein 1]. Morpholino-based silencing in Danio rerio identified a modest role for commd7 and a significant effect for lrrfip1 as positive regulators of thrombus formation. Proteomic analysis of human platelet LRRFIP1-interacting proteins indicated that LRRFIP1 functions as a component of the platelet cytoskeleton, where it interacts with the actin-remodeling proteins Flightless-1 and Drebrin. Taken together, these data reveal novel proteins regulating the platelet response. (Blood. 2010; 116(22): 4646-4656

Transcription profiling in human platelets reveals LRRFIP1 as a novel protein regulating platelet function / Goodall Alison, H.; Burns, Philippa; Salles, Isabelle; Macaulay Iain, C.; Jones Chris, I.; Ardissino, D; de Bono, Bernard; Bray Sarah, L.; Deckmyn, Hans; Dudbridge, Frank; Fitzgerald Desmond, J.; Garner Stephen, F.; Gusnanto, Arief; Koch, Kerstin; Langford, Cordelia; O'Connor Marie, N.; Rice Catherine, M.; Stemple, Derek; Stephens, Jonathan; Trip Mieke, D.; Zwaginga, Jaap-Jan; Samani Nilesh, J.; Watkins Nicholas, A.; Maguire Patricia, B.; Ouwehand Willem, H.. - In: BLOOD. - ISSN 0006-4971. - 116:22(2010), pp. 4646-4656. [10.1182/blood-2010-04-280925]

Transcription profiling in human platelets reveals LRRFIP1 as a novel protein regulating platelet function

Ardissino D;
2010

Abstract

Within the healthy population, there is substantial, heritable, and interindividual variability in the platelet response. We explored whether a proportion of this variability could be accounted for by interindividual variation in gene expression. Through a correlative analysis of genome-wide platelet RNA expression data from 37 subjects representing the normal range of platelet responsiveness within a cohort of 500 subjects, we identified 63 genes in which transcript levels correlated with variation in the platelet response to adenosine diphosphate and/or the collagen-mimetic peptide, crosslinked collagen-related peptide. Many of these encode proteins with no reported function in platelets. An association study of 6 of the 63 genes in 4235 cases and 6379 controls showed a putative association with myocardial infarction for COMMD7 (COMM domain-containing protein 7) and a major deviation from the null hypothesis for LRRFIP1 [leucinerich repeat (in FLII) interacting protein 1]. Morpholino-based silencing in Danio rerio identified a modest role for commd7 and a significant effect for lrrfip1 as positive regulators of thrombus formation. Proteomic analysis of human platelet LRRFIP1-interacting proteins indicated that LRRFIP1 functions as a component of the platelet cytoskeleton, where it interacts with the actin-remodeling proteins Flightless-1 and Drebrin. Taken together, these data reveal novel proteins regulating the platelet response. (Blood. 2010; 116(22): 4646-4656
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Utilizza questo identificativo per citare o creare un link a questo documento: http://hdl.handle.net/11381/2883724
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