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Thromb Haemost. 2019 Sep;119(9):1441-1450. doi: 10.1055/s-0039-1693130. Epub 2019 Jul 28.

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

Author information

1
Department of Environmental Science and Bioscience, Kristianstad University, Kristianstad, Sweden.
2
Department of Coagulation Disorders, Skåne University Hospital, Lund University, Lund, Sweden.
3
Centre for Primary Health Care Research, Department of Clinical Sciences, Skåne University Hospital, Lund University, Malmö, Sweden.

Abstract

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.

PMID:
31352677
DOI:
10.1055/s-0039-1693130

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