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Thrombomodulin (THBD) gene variants and thrombotic risk in a population-based cohort study

Manderstedt, Eric ; Halldén, Christer ; Lind-Halldén, Christina ; Elf, Johan LU ; Svensson, Peter J. LU ; Engström, Gunnar LU ; Melander, Olle LU orcid ; Baras, Aris ; Lotta, Luca A. and Zöller, Bengt LU orcid (2022) In Journal of Thrombosis and Haemostasis 20(4). p.929-935
Abstract

Background: The protein C anticoagulant system plays a key role in maintaining the hemostatic balance. Although several studies have identified thrombomodulin gene (THBD) variants among venous thromboembolism (VTE) patients, the role of THBD in relation to VTE in humans remains to be clarified. Objectives: This study aimed to determine the thrombotic risk of rare and common THBD variants in a large population-based cohort of middle-aged and older adults. Patients/Methods: The exome sequence of THBD was analyzed for qualifying variants in 28,794 subjects (born 1923–1950, 60% women), who participated in the Malmö Diet and Cancer study (1991–1996). Patients were followed from baseline until the first event of VTE, death, or 2018.... (More)

Background: The protein C anticoagulant system plays a key role in maintaining the hemostatic balance. Although several studies have identified thrombomodulin gene (THBD) variants among venous thromboembolism (VTE) patients, the role of THBD in relation to VTE in humans remains to be clarified. Objectives: This study aimed to determine the thrombotic risk of rare and common THBD variants in a large population-based cohort of middle-aged and older adults. Patients/Methods: The exome sequence of THBD was analyzed for qualifying variants in 28,794 subjects (born 1923–1950, 60% women), who participated in the Malmö Diet and Cancer study (1991–1996). Patients were followed from baseline until the first event of VTE, death, or 2018. Qualifying variants were defined as loss-of-function or non-benign (PolyPhen-2) missense variants with minor allele frequency <0.1%. Results: The single common coding variant rs1042579 was not associated with incident VTE. Sixteen rare variants were classified as qualifying and included in collapsing analysis. Seven individuals with VTE compared to 24 individuals without VTE carried one qualifying variant. Cox multivariate regression analysis adjusted for age, sex, body mass index, systolic blood pressure, smoking and alcohol consumption, rs6025, rs1799963, and the top two eigenvectors from a principal components analysis showed a hazard ratio of 3.0 (95% confidence interval 1.4–6.3) for the rare qualifying variants. The distributions of qualifying variants in THBD showed a difference for individuals with and without incident VTE indicating a possible position effect. Conclusions: Rare qualifying THBD variants were associated with VTE, suggesting that rare variants in THBD contribute to development of VTE.

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author
; ; ; ; ; ; ; ; and
author collaboration
organization
publishing date
type
Contribution to journal
publication status
published
subject
keywords
epidemiology, genetics, THBD, thrombomodulin, venous thromboembolism
in
Journal of Thrombosis and Haemostasis
volume
20
issue
4
pages
7 pages
publisher
Wiley-Blackwell
external identifiers
  • pmid:34970867
  • scopus:85126802164
ISSN
1538-7933
DOI
10.1111/jth.15630
language
English
LU publication?
yes
id
5d75bbf9-ce7f-4f7c-8ec0-be6efed03351
date added to LUP
2023-01-02 14:33:42
date last changed
2024-05-02 10:38:54
@article{5d75bbf9-ce7f-4f7c-8ec0-be6efed03351,
  abstract     = {{<p>Background: The protein C anticoagulant system plays a key role in maintaining the hemostatic balance. Although several studies have identified thrombomodulin gene (THBD) variants among venous thromboembolism (VTE) patients, the role of THBD in relation to VTE in humans remains to be clarified. Objectives: This study aimed to determine the thrombotic risk of rare and common THBD variants in a large population-based cohort of middle-aged and older adults. Patients/Methods: The exome sequence of THBD was analyzed for qualifying variants in 28,794 subjects (born 1923–1950, 60% women), who participated in the Malmö Diet and Cancer study (1991–1996). Patients were followed from baseline until the first event of VTE, death, or 2018. Qualifying variants were defined as loss-of-function or non-benign (PolyPhen-2) missense variants with minor allele frequency &lt;0.1%. Results: The single common coding variant rs1042579 was not associated with incident VTE. Sixteen rare variants were classified as qualifying and included in collapsing analysis. Seven individuals with VTE compared to 24 individuals without VTE carried one qualifying variant. Cox multivariate regression analysis adjusted for age, sex, body mass index, systolic blood pressure, smoking and alcohol consumption, rs6025, rs1799963, and the top two eigenvectors from a principal components analysis showed a hazard ratio of 3.0 (95% confidence interval 1.4–6.3) for the rare qualifying variants. The distributions of qualifying variants in THBD showed a difference for individuals with and without incident VTE indicating a possible position effect. Conclusions: Rare qualifying THBD variants were associated with VTE, suggesting that rare variants in THBD contribute to development of VTE.</p>}},
  author       = {{Manderstedt, Eric and Halldén, Christer and Lind-Halldén, Christina and Elf, Johan and Svensson, Peter J. and Engström, Gunnar and Melander, Olle and Baras, Aris and Lotta, Luca A. and Zöller, Bengt}},
  issn         = {{1538-7933}},
  keywords     = {{epidemiology; genetics; THBD; thrombomodulin; venous thromboembolism}},
  language     = {{eng}},
  number       = {{4}},
  pages        = {{929--935}},
  publisher    = {{Wiley-Blackwell}},
  series       = {{Journal of Thrombosis and Haemostasis}},
  title        = {{Thrombomodulin (THBD) gene variants and thrombotic risk in a population-based cohort study}},
  url          = {{http://dx.doi.org/10.1111/jth.15630}},
  doi          = {{10.1111/jth.15630}},
  volume       = {{20}},
  year         = {{2022}},
}