Thromb Haemost 2019; 119(09): 1441-1450
DOI: 10.1055/s-0039-1693130
Coagulation and Fibrinolysis
Georg Thieme Verlag KG Stuttgart · New York

Next-Generation Sequencing of 17 Genes Associated with Venous Thromboembolism Reveals a Deficit of Non-Synonymous Variants in Procoagulant Genes

Eric Manderstedt
1  Department of Environmental Science and Bioscience, Kristianstad University, Kristianstad, Sweden
Christina Lind-Halldén
1  Department of Environmental Science and Bioscience, Kristianstad University, Kristianstad, Sweden
Peter Svensson
2  Department of Coagulation Disorders, Skåne University Hospital, Lund University, Lund, Sweden
Bengt Zöller
3  Centre for Primary Health Care Research, Department of Clinical Sciences, Skåne University Hospital, Lund University, Malmö, Sweden
Christer Halldén
1  Department of Environmental Science and Bioscience, Kristianstad University, Kristianstad, Sweden
› Author Affiliations
Funding This work was supported by grants awarded to Dr. Bengt Zöller by the Swedish Heart-Lung Foundation, ALF funding from Skåne Region and by the Swedish Research Council. The funders had no role in the study design; in the collection, analysis and interpretation of data; in the writing of the report; and in the decision to submit the article for publication.
Further Information

Publication History

04 April 2019

22 May 2019

Publication Date:
28 July 2019 (online)


Background The heritability of venous thromboembolism (VTE) is only partially explained by variants in 17 previously VTE-associated genes.

Objective This article screens for additional rare variants in the 17 genes and investigates the relative contributions of pro- and anticoagulant genes to VTE.

Patients and Methods Ninety-six VTE patients from the population-based Malmö Thrombophilia Study were analysed using an AmpliSeq strategy and Ion Torrent sequencing and the variant data were compared with data from public databases.

Results A total of 102 non-synonymous and 76 synonymous variants were identified. Forty-six non-synonymous variants were present in the human gene mutation database. Anticoagulant and procoagulant genes showed 14 and 22 rare non-synonymous variants, respectively. Individual patients showed varying numbers of risk factors; 13 patients had non-synonymous mutations in SERPINC1, PROC and PROS1 genes and 42 had factor V Leiden or prothrombin mutations generating a total of 47 patients with at least one of these risk factors. Ten common VTE-associated variants showed low level enrichments and no correlation to the other risk factors. The enrichment of previously identified risk factors was similar to previous studies. Determination of the nsyn/syn ratio (number of non-synonymous variants per non-synonymous site, nsyn, to the number of synonymous variants per synonymous site, syn) showed, as expected in patients, an increase of non-synonymous relative to synonymous anticoagulant variants compared with controls (nsyn/syn, 0.95 vs. 0.68). In contrast, non-synonymous procoagulant variants (nsyn/syn, 0.31 vs. 0.63) showed a decrease. We suggest that the deficit of non-synonymous variants in procoagulant genes is a novel mechanism contributing to VTE.