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Identification of Genetic Aberrations in Thrombomodulin Gene in Patients with Recurrent Venous Thromboembolism

Ahmad, Abrar LU ; Sundquist, Kristina LU ; Zöller, Bengt LU orcid ; Svensson, Peter J. LU ; Sundquist, Jan LU and Memon, Ashfaque A. LU orcid (2017) In Clinical and Applied Thrombosis/Hemostasis 23(4). p.319-328
Abstract

Thrombomodulin (THBD) serves as a cofactor for thrombin-mediated activation of anticoagulant protein C pathway. Genetic aberrations in THBD have been studied in arterial and venous thrombosis. However, genetic changes in THBD and their role in the risk assessment of recurrent venous thromboembolism (VTE) are not well understood. The aim of the present study was to identify the genetic aberrations in THBD and their association with the risk of VTE recurrence in a prospective population-based study. We sequenced the entire THBD gene, first in selected patients with VTE (n = 95) by Sanger sequencing and later validated those polymorphisms with minor allele frequency (MAF) ≥5% in the whole study population (n = 1465 with the follow-up... (More)

Thrombomodulin (THBD) serves as a cofactor for thrombin-mediated activation of anticoagulant protein C pathway. Genetic aberrations in THBD have been studied in arterial and venous thrombosis. However, genetic changes in THBD and their role in the risk assessment of recurrent venous thromboembolism (VTE) are not well understood. The aim of the present study was to identify the genetic aberrations in THBD and their association with the risk of VTE recurrence in a prospective population-based study. We sequenced the entire THBD gene, first in selected patients with VTE (n = 95) by Sanger sequencing and later validated those polymorphisms with minor allele frequency (MAF) ≥5% in the whole study population (n = 1465 with the follow-up period of 1998-2008) by Taqman polymerase chain reaction. In total, we identified 8 polymorphisms in THBD, and 3 polymorphisms with MAF ≥5% were further validated. No significant association between THBD polymorphisms and risk of VTE recurrence on univariate or multivariate Cox regression analysis was found (hazard ratio [HR] = 0.89, 95% confidence interval [CI] = 0.62-1.28, HR = 1.27, 95% CI = 0.88-1.85, and HR = 1.15, 95% CI = 0.80-1.66 for THBD rs1962, rs1042580, and rs3176123 polymorphisms, respectively), adjusted for family history, acquired risk factors for VTE, location of deep vein thrombosis, and risk of thrombophilia. Subanalysis of patients with unprovoked first VTE also showed no significant association of identified THBD polymorphisms with the risk of VTE recurrence. Our results show that aberrations in the THBD gene may not be useful for the assessment of VTE recurrence; however, further studies with large sample size are needed to confirm these findings.

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author
; ; ; ; and
organization
publishing date
type
Contribution to journal
publication status
published
subject
keywords
anticoagulant therapy, multivariate analysis, recurrent VTE
in
Clinical and Applied Thrombosis/Hemostasis
volume
23
issue
4
pages
10 pages
publisher
SAGE Publications
external identifiers
  • scopus:85018382962
  • pmid:28049360
  • wos:000399751600002
ISSN
1076-0296
DOI
10.1177/1076029616686716
project
Identification of diagnostic and prognostic biomarkers of venous thromboembolism and its recurrence
Genetic risk factor of venous thromboembolism and its recurrence
language
English
LU publication?
yes
id
212a2674-121a-444b-b0fd-341cfcff43e3
date added to LUP
2017-05-24 15:05:15
date last changed
2025-01-07 14:15:25
@article{212a2674-121a-444b-b0fd-341cfcff43e3,
  abstract     = {{<p>Thrombomodulin (THBD) serves as a cofactor for thrombin-mediated activation of anticoagulant protein C pathway. Genetic aberrations in THBD have been studied in arterial and venous thrombosis. However, genetic changes in THBD and their role in the risk assessment of recurrent venous thromboembolism (VTE) are not well understood. The aim of the present study was to identify the genetic aberrations in THBD and their association with the risk of VTE recurrence in a prospective population-based study. We sequenced the entire THBD gene, first in selected patients with VTE (n = 95) by Sanger sequencing and later validated those polymorphisms with minor allele frequency (MAF) ≥5% in the whole study population (n = 1465 with the follow-up period of 1998-2008) by Taqman polymerase chain reaction. In total, we identified 8 polymorphisms in THBD, and 3 polymorphisms with MAF ≥5% were further validated. No significant association between THBD polymorphisms and risk of VTE recurrence on univariate or multivariate Cox regression analysis was found (hazard ratio [HR] = 0.89, 95% confidence interval [CI] = 0.62-1.28, HR = 1.27, 95% CI = 0.88-1.85, and HR = 1.15, 95% CI = 0.80-1.66 for THBD rs1962, rs1042580, and rs3176123 polymorphisms, respectively), adjusted for family history, acquired risk factors for VTE, location of deep vein thrombosis, and risk of thrombophilia. Subanalysis of patients with unprovoked first VTE also showed no significant association of identified THBD polymorphisms with the risk of VTE recurrence. Our results show that aberrations in the THBD gene may not be useful for the assessment of VTE recurrence; however, further studies with large sample size are needed to confirm these findings.</p>}},
  author       = {{Ahmad, Abrar and Sundquist, Kristina and Zöller, Bengt and Svensson, Peter J. and Sundquist, Jan and Memon, Ashfaque A.}},
  issn         = {{1076-0296}},
  keywords     = {{anticoagulant therapy; multivariate analysis; recurrent VTE}},
  language     = {{eng}},
  month        = {{05}},
  number       = {{4}},
  pages        = {{319--328}},
  publisher    = {{SAGE Publications}},
  series       = {{Clinical and Applied Thrombosis/Hemostasis}},
  title        = {{Identification of Genetic Aberrations in Thrombomodulin Gene in Patients with Recurrent Venous Thromboembolism}},
  url          = {{https://lup.lub.lu.se/search/files/31409379/25940041.pdf}},
  doi          = {{10.1177/1076029616686716}},
  volume       = {{23}},
  year         = {{2017}},
}