Genetic Determinants of Thrombin Generation and Their Relation to Venous Thrombosis: Results from the GAIT-2 Project

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.

Effects of thromboprophylactic doses of apixaban and rivaroxaban on coagulation and thrombin generation in association with total hip replacement

“…TG measures the overall net effect of anticoagulant drugs and native pro-and anticoagulants on the capacity to generate thrombin. It is a parameter increasingly linked to the development of VTE and has the potential to overcome the shortcomings of coagulation assays PT and APTT [14][15][16]. Anticoagulant effects were measured over a broad time period with 30-day follow-up.…”

The Unravelling of the Genetic Architecture of Plasminogen Deficiency and its Relation to Thrombotic Disease

“…Thus, plasminogen deficiency could not be ruled out as an additional risk factor. It is noteworthy that thromboembolism is a common disease with more than 60% of the variation due to genetic risk factors2223. However, genetic scores explain only 15% of the variance15, so there is still a “missing heritability” that might have hampered the discrimination of plasminogen deficiency as an additional risk factor of thrombotic disease.…”

lme4qtl: linear mixed models with flexible covariance structure for genetic studies of related individuals

“…The samples were genotyped with a combination of two chips, that resulted in 395,556 single-nucleotide polymorphisms (SNPs) after merging the data. We performed the same quality control pre-processing steps as in the original study [14]: phenotypic values were log-transformed; two fixed effects, age and gender, and two random effects, genetic additive and shared house-hold, were included in the model; individuals with missing phenotype values were removed and all genotypes with a minimum allele frequency below 1% were filtered out, leaving 263,764 genotyped SNPs in 903 individuals available for GWAS. We compared the performances between our package and SOLAR [2,21], one of the standard tool in family-based QTL mapping analysis.…”

“…The sample from the Genetic Analysis of Idiopathic Thrombophilia 2 (GAIT2) project consisted of 935 individuals from 35 extended families, recruited through a proband with idiopathic thrombophilia [10]. We conducted a genome-wide screening of activated partial thromboplastin time (APTT), which is a clinical test used to screen for coagulation-factor deficiencies [17].…”