Next-Generation Sequencing of 17 Genes Associated with Venous Thromboembolism Reveals a Deficit of Non-Synonymous Variants in Procoagulant Genes
Manderstedt, Eric LU ; Lind-Halldén, Christina ; Svensson, Peter ; Zöller, Bengt LU
and Halldén, Christer
LU
(2019)
In Thrombosis and Haemostasis
119(09).
p.1441-1450
- 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... (More)
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.
(Less)
- author
- Manderstedt, Eric
LU
; Lind-Halldén, Christina
; Svensson, Peter
; Zöller, Bengt
LU
and Halldén, Christer
LU
- organization
- publishing date
- 2019-07-28
- type
- Contribution to journal
- publication status
- published
- subject
- in
- Thrombosis and Haemostasis
- volume
- 119
- issue
- 09
- pages
- 1441 - 1450
- publisher
- Schattauer GmbH
- external identifiers
-
- pmid:31352677
- scopus:85071784492
- ISSN
- 0340-6245
- DOI
- 10.1055/s-0039-1693130
- language
- English
- LU publication?
- yes
- additional info
- Georg Thieme Verlag KG Stuttgart · New York.
- id
- 674f6ae6-6ef7-4b0d-af52-a2a9876f5038
- date added to LUP
- 2019-08-01 13:59:12
- date last changed
- 2024-04-16 17:10:50
@article{674f6ae6-6ef7-4b0d-af52-a2a9876f5038,
abstract = {{<p>BACKGROUND: The heritability of venous thromboembolism (VTE) is only partially explained by variants in 17 previously VTE-associated genes.</p><p>OBJECTIVE: This article screens for additional rare variants in the 17 genes and investigates the relative contributions of pro- and anticoagulant genes to VTE.</p><p>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.</p><p>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.</p>}},
author = {{Manderstedt, Eric and Lind-Halldén, Christina and Svensson, Peter and Zöller, Bengt and Halldén, Christer}},
issn = {{0340-6245}},
language = {{eng}},
month = {{07}},
number = {{09}},
pages = {{1441--1450}},
publisher = {{Schattauer GmbH}},
series = {{Thrombosis and Haemostasis}},
title = {{Next-Generation Sequencing of 17 Genes Associated with Venous Thromboembolism Reveals a Deficit of Non-Synonymous Variants in Procoagulant Genes}},
url = {{http://dx.doi.org/10.1055/s-0039-1693130}},
doi = {{10.1055/s-0039-1693130}},
volume = {{119}},
year = {{2019}},
}