Transcription profiling in human platelets reveals LRRFIP1 as a novel protein regulating platelet function.
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.
Goodall
Alison H
AH
Department of Cardiovascular Science, University of Leicester, Clinical Sciences Wing, Glenfield Hospital, Leicester, UK. ahg5@le.ac.uk
Burns
Philippa
P
Salles
Isabelle
I
Macaulay
Iain C
IC
Jones
Chris I
CI
Ardissino
Diego
D
de Bono
Bernard
B
Bray
Sarah L
SL
Deckmyn
Hans
H
Dudbridge
Frank
F
Fitzgerald
Desmond J
DJ
Garner
Stephen F
SF
Gusnanto
Arief
A
Koch
Kerstin
K
Langford
Cordelia
C
O'Connor
Marie N
MN
Rice
Catherine M
CM
Stemple
Derek
D
Stephens
Jonathan
J
Trip
Mieke D
MD
Zwaginga
Jaap-Jan
JJ
Samani
Nilesh J
NJ
Watkins
Nicholas A
NA
Maguire
Patricia B
PB
Ouwehand
Willem H
WH
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
C554946:Commd7 protein, zebrafish; C114370:LRRFIP1 protein, human; D020543:Proteome; D016601:RNA-Binding Proteins; D012097:Repressor Proteins; D029961:Zebrafish Proteins