Thrombomodulin (THBD) gene variants and thrombotic risk in a population-based cohort study
(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.
(Less)
- author
- Manderstedt, Eric ; Halldén, Christer ; Lind-Halldén, Christina ; Elf, Johan LU ; Svensson, Peter J. LU ; Engström, Gunnar LU ; Melander, Olle LU ; Baras, Aris ; Lotta, Luca A. and Zöller, Bengt LU
- author collaboration
- organization
-
- Clinical Coagulation, Malmö (research group)
- EpiHealth: Epidemiology for Health
- Cardiovascular Research - Epidemiology (research group)
- Cardiovascular Research - Hypertension (research group)
- EXODIAB: Excellence of Diabetes Research in Sweden
- MultiPark: Multidisciplinary research focused on Parkinson´s disease
- Family medicine, cardiovascular medicine and genetics (research group)
- publishing date
- 2022-04
- 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
-
- scopus:85126802164
- pmid:34970867
- 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
- 2024-09-19 23:49:33
@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 <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}}, }