Circulating microRNAs predict recurrence and death following venous thromboembolism.

Background: Recurrent events frequently occur after venous thromboembolism (VTE) and remain difficult to predict based on established genetic, clinical, and proteomic contributors. The role of circulating microRNAs (miRNAs) has yet to be explored in detail.
Objectives: To identify circulating miRNAs predictive of recurrent VTE or death, and to interpret their mechanistic involvement.
Methods: Data from 181 participants of a cohort study of acute VTE and 302 individuals with a history of VTE from a population-based cohort were investigated. Next-generation sequencing was performed on EDTA plasma samples to detect circulating miRNAs. The endpoint of interest was recurrent VTE or death. Penalized regression was applied to identify an outcome-relevant miRNA signature, and results were validated in the population-based cohort. The involvement of miRNAs in coregulatory networks was assessed using principal component analysis, and the associated clinical and molecular phenotypes were investigated. Mechanistic insights were obtained from target gene and pathway enrichment analyses.
Results: A total of 1950 miRNAs were detected across cohorts after postprocessing. In the discovery cohort, 50 miRNAs were associated with recurrent VTE or death (cross-validated C-index, 0.65). A weighted miRNA score predicted outcome over an 8-year follow-up period (HR _SD , 2.39; 95% CI, 1.98-2.88; P < .0001). The independent validation cohort validated 20 miRNAs (OR _SD for score, 3.47; 95% CI, 2.37-5.07; P < .0001; cross-validated-area under the curve, 0.61). Principal component analysis revealed 5 miRNA networks with distinct relationships to clinical phenotype and outcome. Mapping of target genes indicated regulation via transcription factors and kinases involved in signaling pathways associated with fibrinolysis.
Conclusion: Circulating miRNAs predicted the risk of recurrence or death after VTE over several years, both in the acute and chronic phases.
Competing Interests: Declaration of competing interests None of the authors report any conflicts of interest with respect to the content of this article. P.S.W. reports grants from Bayer AG within the submitted work. Outside the submitted work, he reports nonfinancial grants from Philips Medical Systems, grants and consulting fees from Boehringer Ingelheim, Novartis Pharma, Sanofi-Aventis, Daiichi Sankyo Europe, grants, consulting, and lecturing fees from Bayer Health Care, lecturing fees from Pfizer Pharma and Bristol-Myers Squibb, consulting fees from Astra Zeneca, consulting fees and nonfinancial support from Diasorin, and nonfinancial support from I.E.M. P.S.W. was funded by the Ministry of Education and Research (BMBF 01EO1003 and 01EO1503). J.H.P. has received honoraria for lectures from Bayer AG, Boehringer Ingelheim, Daiichi Sankyo GmbH, and Sanofi-Aventis GmbH, and research grants from the Federal Ministry of Education and Research (BMBF 01EO1503) and the German Center for Cardiovascular Research (DZHK) outside the topic of the present study. S.K. reports grants and consulting fees from Bayer AG, Daiichi-Sankyo, Boston Scientific, and Inari Medical, and lecture fees from Pfizer – Bristol-Myers Squibb and MSD. The remaining authors report no conflict of interest. P.S.W. and T.M. are the principal investigators of the German Center for Cardiovascular Research (DZHK), and P.S.W. is the principal investigator of the DIASyM research core (BMBF DIASyM research core [BMBF 161L0217A]).
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