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Next-generation sequencing of 17 genes associated with venous thromboembolism reveals a deficit of non-synonymous variants in procoagulant genes
Kristianstad University, Faculty of Natural Science, Avdelningen för miljö- och biovetenskap. Kristianstad University, Faculty of Natural Science, Forskningsmiljön Biomedicin.
Kristianstad University, Faculty of Natural Science, Forskningsmiljön Biomedicin. Kristianstad University, Faculty of Natural Science, Avdelningen för miljö- och biovetenskap.
Lund University.
Lund University.
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2019 (English)In: Thrombosis and haemostasis, ISSN 2567-689XArticle in journal (Refereed) Epub ahead of print
Abstract [en]

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.

Place, publisher, year, edition, pages
2019.
Keywords [en]
venous thromboembolism - blood coagulation factors - anticoagulant - procoagulant - next-generation sequencing
National Category
Biological Sciences
Identifiers
URN: urn:nbn:se:hkr:diva-19788DOI: 10.1055/s-0039-1693130PubMedID: 31352677OAI: oai:DiVA.org:hkr-19788DiVA, id: diva2:1344207
Available from: 2019-08-20 Created: 2019-08-20 Last updated: 2019-08-20Bibliographically approved

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Manderstedt, EricLind-Halldén, ChristinaHalldén, C
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