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

Goodall, A. H., Burns, P., Salles, I., Macaulay, I. C., Jones, C. I. ORCID: https://orcid.org/0000-0001-7537-1509, Ardissino, D., de Bono, B., Bray, S. L., Deckmyn, H., Dudbridge, F., Fitzgerald, D. J., Garner, S. F., Gusnanto, A., Koch, K., Langford, C., O'Connor, M. N., Rice, C. M., Stemple, D., Stephens, J., Trip, M. D., Zwaginga, J. J., Samani, N. J., Watkins, N. A., Maguire, P. B. and Ouwehand, W. H. (2010) Transcription profiling in human platelets reveals LRRFIP1 as a novel protein regulating platelet function. Blood, 116 (22). pp. 4646-4656. ISSN 0006-4971 doi: 10.1182/blood-2010-04-280925

Abstract/Summary

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.