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Genetic variation of the blood coagulation regulator tissue factor pathway inhibitor and venous thromboembolism among middle-aged and older adults: A population-based cohort study

Manderstedt, E. ; Elf, J. LU ; Svensson, P.J. LU ; Engström, G. LU ; Melander, O. LU orcid and Zöller, B. LU orcid (2022) In Research and practice in thrombosis and haemostasis 6(7).
Abstract
Background: Tissue factor is the main initiator of blood coagulation, and tissue factor pathway inhibitor (TFPI) is the primary inhibitor of the initiation of blood coagulation. The genetic variation of TFPI and the relation to venous thromboembolism (VTE), that is, venous thrombosis and pulmonary embolism, remains to be clarified. This exome sequencing study aimed to determine the molecular epidemiology of the TFPI gene and the relation to VTE in a large population-based cohort of middle-aged and older adults. Methods: The exomes of TFPI were analyzed for variants in 28,794 subjects without previous VTE (born 1923–1950, 60% women), who participated in the Malmö Diet and Cancer Study (1991–1996). Patients were followed until the first... (More)
Background: Tissue factor is the main initiator of blood coagulation, and tissue factor pathway inhibitor (TFPI) is the primary inhibitor of the initiation of blood coagulation. The genetic variation of TFPI and the relation to venous thromboembolism (VTE), that is, venous thrombosis and pulmonary embolism, remains to be clarified. This exome sequencing study aimed to determine the molecular epidemiology of the TFPI gene and the relation to VTE in a large population-based cohort of middle-aged and older adults. Methods: The exomes of TFPI were analyzed for variants in 28,794 subjects without previous VTE (born 1923–1950, 60% women), who participated in the Malmö Diet and Cancer Study (1991–1996). Patients were followed until the first event of VTE, death, or 2018. Qualifying variants were defined as loss-of-function or nonbenign (PolyPhen-2) missense variants with minor allele frequency less than 0.1%. Results: No common variant was associated with VTE. Nine rare variants (two loss-of-function and seven nonbenign missense) were classified as qualifying and included in collapsing analysis. Prevalence of qualifying variants was 0.09%. Five individuals with VTE compared to 17 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 ancestry showed a hazard ratio of 2.9 (95% CI, 1.2–7.1) for rare qualifying variants. Conclusion: Rare qualifying TFPI variants were associated with VTE, suggesting that rare variants in TFPI contribute to the development of VTE. The qualifying TFPI gene variants were very rare, suggesting a constrained gene. © 2022 The Authors. Research and Practice in Thrombosis and Haemostasis published by Wiley Periodicals LLC on behalf of International Society on Thrombosis and Haemostasis (ISTH). (Less)
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published
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keywords
blood coagulation, genetic variation, molecular epidemiology, thrombophilia, venous thromboembolism, tissue factor pathway inhibitor, adult, Article, blood clotting, deep vein thrombosis, exosome, female, gene frequency, gene mutation, genetic analysis, genetic screening, haplotype, human, ICD-10, ICD-9, loss of function mutation, major clinical study, male, missense mutation, principal component analysis, single nucleotide polymorphism, thrombophlebitis, vein thrombosis, whole exome sequencing
in
Research and practice in thrombosis and haemostasis
volume
6
issue
7
article number
e12842
publisher
Wiley
external identifiers
  • scopus:85142056157
  • pmid:36381289
ISSN
2475-0379
DOI
10.1002/rth2.12842
language
English
LU publication?
yes
id
a8c5cd0c-0824-49ce-9feb-3d73771f6e8f
date added to LUP
2023-01-12 12:27:14
date last changed
2024-01-18 17:57:04
@article{a8c5cd0c-0824-49ce-9feb-3d73771f6e8f,
  abstract     = {{Background: Tissue factor is the main initiator of blood coagulation, and tissue factor pathway inhibitor (TFPI) is the primary inhibitor of the initiation of blood coagulation. The genetic variation of TFPI and the relation to venous thromboembolism (VTE), that is, venous thrombosis and pulmonary embolism, remains to be clarified. This exome sequencing study aimed to determine the molecular epidemiology of the TFPI gene and the relation to VTE in a large population-based cohort of middle-aged and older adults. Methods: The exomes of TFPI were analyzed for variants in 28,794 subjects without previous VTE (born 1923–1950, 60% women), who participated in the Malmö Diet and Cancer Study (1991–1996). Patients were followed until the first event of VTE, death, or 2018. Qualifying variants were defined as loss-of-function or nonbenign (PolyPhen-2) missense variants with minor allele frequency less than 0.1%. Results: No common variant was associated with VTE. Nine rare variants (two loss-of-function and seven nonbenign missense) were classified as qualifying and included in collapsing analysis. Prevalence of qualifying variants was 0.09%. Five individuals with VTE compared to 17 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 ancestry showed a hazard ratio of 2.9 (95% CI, 1.2–7.1) for rare qualifying variants. Conclusion: Rare qualifying TFPI variants were associated with VTE, suggesting that rare variants in TFPI contribute to the development of VTE. The qualifying TFPI gene variants were very rare, suggesting a constrained gene. © 2022 The Authors. Research and Practice in Thrombosis and Haemostasis published by Wiley Periodicals LLC on behalf of International Society on Thrombosis and Haemostasis (ISTH).}},
  author       = {{Manderstedt, E. and Elf, J. and Svensson, P.J. and Engström, G. and Melander, O. and Zöller, B.}},
  issn         = {{2475-0379}},
  keywords     = {{blood coagulation; genetic variation; molecular epidemiology; thrombophilia; venous thromboembolism; tissue factor pathway inhibitor; adult; Article; blood clotting; deep vein thrombosis; exosome; female; gene frequency; gene mutation; genetic analysis; genetic screening; haplotype; human; ICD-10; ICD-9; loss of function mutation; major clinical study; male; missense mutation; principal component analysis; single nucleotide polymorphism; thrombophlebitis; vein thrombosis; whole exome sequencing}},
  language     = {{eng}},
  number       = {{7}},
  publisher    = {{Wiley}},
  series       = {{Research and practice in thrombosis and haemostasis}},
  title        = {{Genetic variation of the blood coagulation regulator tissue factor pathway inhibitor and venous thromboembolism among middle-aged and older adults: A population-based cohort study}},
  url          = {{http://dx.doi.org/10.1002/rth2.12842}},
  doi          = {{10.1002/rth2.12842}},
  volume       = {{6}},
  year         = {{2022}},
}