Genetic Determinants of Thrombin Generation and Their Relation to Venous Thrombosis: Results from the GAIT-2 Project |
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Authors: | Laura Martin-Fernandez Andrey Ziyatdinov Marina Carrasco Juan Antonio Millon Angel Martinez-Perez Noelia Vilalta Helena Brunel Montserrat Font Anders Hamsten Juan Carlos Souto José Manuel Soria |
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Affiliation: | 1. Unit of Genomics of Complex Diseases, Biomedical Research Institute Sant Pau (IIB-Sant Pau), Barcelona, Spain;2. Unit of Hemostasis and Thrombosis, Department of Hematology, IIB-Sant Pau, Hospital de la Santa Creu i Sant Pau, Barcelona, Spain;3. Cardiovascular Genetics and Genomics Group, Atherosclerosis Research Unit, Department of Medicine, Karolinska Institutet, Karolinska University Hospital Solna, Stockholm, Sweden;Ottawa Hospital Research Institute, CANADA |
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Abstract: | BackgroundVenous thromboembolism (VTE) is a common disease where known genetic risk factors explain only a small portion of the genetic variance. Then, the analysis of intermediate phenotypes, such as thrombin generation assay, can be used to identify novel genetic risk factors that contribute to VTE.ObjectivesTo investigate the genetic basis of distinct quantitative phenotypes of thrombin generation and its relationship to the risk of VTE.Patients/MethodsLag time, thrombin peak and endogenous thrombin potential (ETP) were measured in the families of the Genetic Analysis of Idiopathic Thrombophilia 2 (GAIT-2) Project. This sample consisted of 935 individuals in 35 extended families selected through a proband with idiopathic thrombophilia. We performed also genome wide association studies (GWAS) with thrombin generation phenotypes.ResultsThe results showed that 67% of the variation in the risk of VTE is attributable to genetic factors. The heritabilities of lag time, thrombin peak and ETP were 49%, 54% and 52%, respectively. More importantly, we demonstrated also the existence of positive genetic correlations between thrombin peak or ETP and the risk of VTE. Moreover, the major genetic determinant of thrombin generation was the F2 gene. However, other suggestive signals were observed.ConclusionsThe thrombin generation phenotypes are strongly genetically determined. The thrombin peak and ETP are significantly genetically correlated with the risk of VTE. In addition, F2 was identified as a major determinant of thrombin generation. We reported suggestive signals that might increase our knowledge to explain the variability of this important phenotype. Validation and functional studies are required to confirm GWAS results. |
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