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

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, cross-linked 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 hypo thesis for LRRFIP1 [leucine-rich 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.

• Authors: Alison H Goodall, Philippa Burns, Isabelle Salles, Iain C Macaulay, Chris I Jones, Diego Ardissino, Bernard de Bono, Sarah L Bray, Hans Deckmyn, Frank Dudbridge, Desmond J Fitzgerald, Stephen F Garner, Arief Gusnanto, Kerstin Koch, Cordelia Langford, Marie N O'Connor, Catherine M Rice, Derek Stemple, Jonathan Stephens, Mieke D Trip, Jaap-Jan Zwaginga, Nilesh J Samani, Nicholas A Watkins, Patricia B Maguire, Willem H Ouwehand, Bloodomics Consortium
• Journal: Blood (Blood) Vol. 116 Issue 22 Pg. 4646-56 (Nov 25 2010) ISSN: 1528-0020 [Electronic] United States
• PMID: 20833976 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Commd7 protein, zebrafish
• LRRFIP1 protein, human
• Proteome
• RNA-Binding Proteins
• Repressor Proteins
• Zebrafish Proteins

Topics

• Animals
• Blood Platelets (metabolism)
• Gene Expression Profiling
• Gene Silencing
• Genotype
• Humans
• Platelet Activation
• Proteome (metabolism)
• RNA-Binding Proteins (genetics, metabolism)
• Repressor Proteins (genetics, metabolism)
• Thrombosis
• Zebrafish
• Zebrafish Proteins (genetics, metabolism)