title: 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.affiliation: Department of Cardiovascular Science, University of Leicester, Clinical Sciences Wing, Glenfield Hospital, Leicester, UK. ahg5@le.ac.uk
authors.forename: Alison H
authors.initials: AH
authors.lastname: Goodall
authors.forename: Philippa
authors.initials: P
authors.lastname: Burns
authors.forename: Isabelle
authors.initials: I
authors.lastname: Salles
authors.forename: Iain C
authors.initials: IC
authors.lastname: Macaulay
authors.forename: Chris I
authors.initials: CI
authors.lastname: Jones
authors.forename: Diego
authors.initials: D
authors.lastname: Ardissino
authors.forename: Bernard
authors.initials: B
authors.lastname: de Bono
authors.forename: Sarah L
authors.initials: SL
authors.lastname: Bray
authors.forename: Hans
authors.initials: H
authors.lastname: Deckmyn
authors.forename: Frank
authors.initials: F
authors.lastname: Dudbridge
authors.forename: Desmond J
authors.initials: DJ
authors.lastname: Fitzgerald
authors.forename: Stephen F
authors.initials: SF
authors.lastname: Garner
authors.forename: Arief
authors.initials: A
authors.lastname: Gusnanto
authors.forename: Kerstin
authors.initials: K
authors.lastname: Koch
authors.forename: Cordelia
authors.initials: C
authors.lastname: Langford
authors.forename: Marie N
authors.initials: MN
authors.lastname: O'Connor
authors.forename: Catherine M
authors.initials: CM
authors.lastname: Rice
authors.forename: Derek
authors.initials: D
authors.lastname: Stemple
authors.forename: Jonathan
authors.initials: J
authors.lastname: Stephens
authors.forename: Mieke D
authors.initials: MD
authors.lastname: Trip
authors.forename: Jaap-Jan
authors.initials: JJ
authors.lastname: Zwaginga
authors.forename: Nilesh J
authors.initials: NJ
authors.lastname: Samani
authors.forename: Nicholas A
authors.initials: NA
authors.lastname: Watkins
authors.forename: Patricia B
authors.initials: PB
authors.lastname: Maguire
authors.forename: Willem H
authors.initials: WH
authors.lastname: Ouwehand
mesh_terms: D000818:Animals; D001792:Blood Platelets / Q000378:metabolism*; D020869:Gene Expression Profiling; D020868:Gene Silencing; D005838:Genotype; D006801:Humans; D015539:Platelet Activation; D020543:Proteome / Q000378:metabolism; D016601:RNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D012097:Repressor Proteins / Q000235:genetics / Q000378:metabolism; D013927:Thrombosis; D015027:Zebrafish; D029961:Zebrafish Proteins / Q000235:genetics / Q000378:metabolism
chemical_list: C554946:Commd7 protein, zebrafish; C114370:LRRFIP1 protein, human; D020543:Proteome; D016601:RNA-Binding Proteins; D012097:Repressor Proteins; D029961:Zebrafish Proteins