Project 13

primary: Prof. Pierre Morange (C2VN), secondary: Prof. Dr. Sven Danckwardt (CTH), tertiary: Dr. Stefan Heitmeier (Bayer)

C2VN (Marseille, France), CTH (Mainz, Germany), Bayer (Wuppertal, Germany)

Universities of Marseille and Mainz

Thrombin is the central coagulation protease implicated in thrombosis and inflammation. Thrombin generation tests are widely used for assessing thrombosis risk, but limited data are available on their predictive value for thrombo-inflammatory and vascular diseases. Our hypothesis is that the integration of multi-omics data and a system biology approach will disclose how thrombin generation profiles are altered in the plasma from patients with thrombo-inflammatory disease.

At the primary host C2VN, ESR13 will identify new determinants of thrombin generation by using a multi-omics approach and information from several study cohorts. Thrombin generation will be measured in plasma from 750 patients with venous thrombosis from the Marseille Thrombosis Association (MARTHA) study, for which genome-wide genotype data and whole blood DNA methylation patterns are available, as well as plasma miRNA profiling. ESR13 will apply advanced statistical methods to identify miRNA patterns related to thrombin generation, and then verify positive associations in independent groups of patients. ESR13 will integrate the omics data available in MARTHA together with the coagulation, inflammation and clinical phenotypes to come to a more comprehensive analysis of the regulatory mechanisms of coagulation pathways. Associations will be compared and verified against those found by ESR14 in different patient cohorts available within TICARDIO. At Bayer, ESR13 will perform additional bioinformatics analysis to link the miRNA to effects of anticoagulants in preclinical and clinical data sets. ESR13 will then functionally validate candidate miRNA patterns at CTH, using an established miRNA-target interaction atlas in combination with regulatory assays, RNA-binding proteins and other post-genomic changes. The new possible biomarkers will again be validated by collaboration with ESR14 in the cohorts of Gutenberg Health Study, SCACORO and AtheroGene studies.

• Rocanin-Arjo A, Cohen W, Carcaillon L, Frère C, Saut N, Letenneur L, Alhenc-Gelas M, Dupuy AM, Bertrand M, Alessi MC, Germain M, Wild PS, Zeller T, Cambien F, Goodall AH, Amouyel P, Scarabin PY, Trégouët DA, Morange PE. A meta-analysis of genome-wide association studies identifies ORM1 as a novel gene controlling thrombin generation potential. Blood. 2014;123:777-85.
• Nourse J, Braun J, Lackner K, Hüttelmaier S, Danckwardt S. Large-scale identification of functional microRNA targeting reveals cooperative regulation of the hemostatic system. J Thromb Haemost. 2018;16:2233-2245.
• Ward-Caviness CK, Huffman JE, Everett K, Germain M, van Dongen J, Hill WD, Jhun MA, Brody JA, Ghanbari M, Du L, Roetker NS, de Vries PS, Waldenberger M, Gieger C, Wolf P, Prokisch H, Koenig W, O'Donnell CJ, Levy D, Liu C, Truong V, Wells PS, Trégouët DA, Tang W, Morrison AC, Boerwinkle E, Wiggins KL, McKnight B, Guo X, Psaty BM, Sotoodenia N, Boomsma DI, Willemsen G, Ligthart L, Deary IJ, Zhao W, Ware EB, Kardia SLR, Van Meurs JBJ, Uitterlinden AG, Franco OH, Eriksson P, Franco-Cereceda A, Pankow JS, Johnson AD, Gagnon F, Morange PE, de Geus EJC, Starr JM, Smith JA, Dehghan A, Björck HM, Smith NL, Peters A. DNA methylation age is associated with an altered hemostatic profile in a multiethnic meta-analysis. Blood. 2018;132:1842-1850.