Dataset Information

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.

SUBMITTER: Goodall AH

PROVIDER: S-EPMC2996120 | biostudies-literature | 2010 Nov

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

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

Goodall Alison H AH 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

Blood 20100910 22

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 varia ...[more]

PMID: 20833976

Similar Datasets

Project description:Background: Identifying individuals at heightened cardiovascular risk is a priority for reducing the global burden of cardiovascular disease. Aspirin is widely used to prevent cardiovascular events, though with variable results. Therefore, we hypothesized that aspirin exposure would reveal novel biological pathways relevant to the development of cardiovascular events. Methods: We administered aspirin, followed by peripheral blood RNA microarray profiling, in a discovery cohort of healthy volunteers (n = 50, HV1), followed by two validation cohorts of healthy volunteers (n = 53, HV2) or outpatient cardiology (OPC, n = 25) patients, in conjunction with platelet function testing with the platelet functions score (PFS, HV1 and HV2) or the VerifyNow Asprin (VN, OPC) test. Sets of coexpressed genes, or “Factors” were identified via Bayesian sparse factor analysis and associated with platelet function in HV1 and validated in HV2 and OPC. Validated factors were associated with death/MI in observational (n = 191) and case:control (n = 447) patient cohorts with available RNA data collected at the time of cardiac catheterization. Results: Factor analysis yielded 20 Factors, of which one, Factor 14, contained 60 genes and was associated with PFS in HV1 (r = -0.31, p-value = 0.03). Factor 14 was associated with platelet function with the same strength and direction in HV2 (r = -0.34, p-value = 0.02) and OPC (one-sided p-value for aspirin resistant vs. aspirin sensitive = 0.046), thus validating the association. Factor 14 was associated with death/MI in the two patient cohorts, odds ratio (OR) = 1.2, 95% CI [1.02-1.4], p-value = 0.01 and hazard ratio = 1.5, [1.2-1.9], p = 0.001, respectively, independent of known cardiovascular risk factors (combined OR = 1.2, CI = [1.02, 1.4], p = 0.03). Factor 14 and the expression of the Factor 14 transcript most highly correlative of PFS, ITGA2B, improved reclassification compared to traditional risk factors (category-free net reclassification index = 31% and 37%, p ≤ 0.0002 for both). Conclusions: By challenging humans subjects with aspirin, a medication used for cardiovascular risk reduction, we elucidated genes and pathways that may underlie platelet function and mechanisms responsible for cardiovascular death/MI. This accession represents the OPC cohort microarray data 26 subjects selected for microarray analysis were divided into three groups: aspirin resistant (AR, n=8, >550 ARU), high normal (HN, n=9, ARU 500-549) and aspirin sensitive (AS, n=9, ARU<500)

Dataset Information

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

Publications

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

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets