title: Genetic Determinants of Thrombin Generation and Their Relation to Venous Thrombosis: Results from the GAIT-2 Project.
abstract: BACKGROUND
  Venous 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.
  
  
  OBJECTIVE
  To investigate the genetic basis of distinct quantitative phenotypes of thrombin generation and its relationship to the risk of VTE.
  
  
  METHODS
  Lag 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.
  
  
  RESULTS
  The 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.
  
  
  CONCLUSIONS
  The 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.
authors.affiliation: Unit of Genomics of Complex Diseases, Biomedical Research Institute Sant Pau (IIB-Sant Pau), Barcelona, Spain.
authors.forename: Laura
authors.initials: L
authors.lastname: Martin-Fernandez
authors.affiliation: Unit of Genomics of Complex Diseases, Biomedical Research Institute Sant Pau (IIB-Sant Pau), Barcelona, Spain.
authors.forename: Andrey
authors.initials: A
authors.lastname: Ziyatdinov
authors.affiliation: Unit of Hemostasis and Thrombosis, Department of Hematology, IIB-Sant Pau, Hospital de la Santa Creu i Sant Pau, Barcelona, Spain.
authors.forename: Marina
authors.initials: M
authors.lastname: Carrasco
authors.affiliation: Unit of Hemostasis and Thrombosis, Department of Hematology, IIB-Sant Pau, Hospital de la Santa Creu i Sant Pau, Barcelona, Spain.
authors.forename: Juan Antonio
authors.initials: JA
authors.lastname: Millon
authors.affiliation: Unit of Genomics of Complex Diseases, Biomedical Research Institute Sant Pau (IIB-Sant Pau), Barcelona, Spain.
authors.forename: Angel
authors.initials: A
authors.lastname: Martinez-Perez
authors.affiliation: Unit of Hemostasis and Thrombosis, Department of Hematology, IIB-Sant Pau, Hospital de la Santa Creu i Sant Pau, Barcelona, Spain.
authors.forename: Noelia
authors.initials: N
authors.lastname: Vilalta
authors.affiliation: Unit of Genomics of Complex Diseases, Biomedical Research Institute Sant Pau (IIB-Sant Pau), Barcelona, Spain.
authors.forename: Helena
authors.initials: H
authors.lastname: Brunel
authors.affiliation: Unit of Hemostasis and Thrombosis, Department of Hematology, IIB-Sant Pau, Hospital de la Santa Creu i Sant Pau, Barcelona, Spain.
authors.forename: Montserrat
authors.initials: M
authors.lastname: Font
authors.affiliation: Cardiovascular Genetics and Genomics Group, Atherosclerosis Research Unit, Department of Medicine, Karolinska Institutet, Karolinska University Hospital Solna, Stockholm, Sweden.
authors.forename: Anders
authors.initials: A
authors.lastname: Hamsten
authors.affiliation: Unit of Hemostasis and Thrombosis, Department of Hematology, IIB-Sant Pau, Hospital de la Santa Creu i Sant Pau, Barcelona, Spain.
authors.forename: Juan Carlos
authors.initials: JC
authors.lastname: Souto
authors.affiliation: Unit of Genomics of Complex Diseases, Biomedical Research Institute Sant Pau (IIB-Sant Pau), Barcelona, Spain.
authors.forename: José Manuel
authors.initials: JM
authors.lastname: Soria
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D002648:Child; D002675:Child, Preschool; D005260:Female; D020022:Genetic Predisposition to Disease; D055106:Genome-Wide Association Study; D005838:Genotype; D006801:Humans; D008297:Male; D008875:Middle Aged; D013917:Thrombin / Q000235:genetics*; D019851:Thrombophilia / Q000097:blood / Q000235:genetics*; D020246:Venous Thrombosis / Q000097:blood / Q000235:genetics*; D055815:Young Adult
chemical_list: D013917:Thrombin