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

Within the normal population there is substantial, heritable, inter-individual variability in the platelet response. We explored whether a proportion of this variability can be accounted for by inter-individual variation in gene expression. Through a correlative analysis of genome-wide platelet RNA expression data from 37 individuals representing the normal range of platelet responsiveness within a cohort of 500 individuals we identified 63 genes where transcript levels were correlated with variation in the platelet response to ADP and/or the collagen-mimetic peptide CRP-XL. Many of these encode proteins with no reported function in platelets. An association study of six of the 63 genes in 4,235 cases and 6,379 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 (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 remodelling proteins Flightless-1 and Drebrin. Taken together these data reveal novel proteins regulating the platelet response.