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Tissue factor (F3) gene variants and thrombotic risk among middle-aged and older adults : A population-based cohort study

Manderstedt, Eric LU ; Lind-Halldén, Christina LU ; Halldén, Christer LU ; Elf, Johan LU ; Svensson, Peter J. LU ; Engström, Gunnar LU ; Melander, Olle LU orcid ; Baras, Aris ; Lotta, Luca A. and Zöller, Bengt LU orcid (2024) In Thrombosis Update 17.
Abstract

Background: Tissue factor (TF), encoded by the F3 gene, is the main initiator of blood coagulation. The molecular epidemiology of the F3 gene and the relation to venous thromboembolism (VTE) remains to be determined. Objectives: The aim was to determine the molecular epidemiology and the importance of F3 variants for incident VTE by analysis of the population-based MDC study (Malmö Diet and Cancer), consisting of unselected middle-aged and older individuals. Methods: The exons of F3 were analyzed in a total of 28,794 individuals from the MDC cohort, and of these, 2584 (9 %) were affected by VTE during follow-up (1991–2018). Qualifying variants used in gene-collapsing analysis were defined as loss-of-function or non-benign (PolyPhen-2)... (More)

Background: Tissue factor (TF), encoded by the F3 gene, is the main initiator of blood coagulation. The molecular epidemiology of the F3 gene and the relation to venous thromboembolism (VTE) remains to be determined. Objectives: The aim was to determine the molecular epidemiology and the importance of F3 variants for incident VTE by analysis of the population-based MDC study (Malmö Diet and Cancer), consisting of unselected middle-aged and older individuals. Methods: The exons of F3 were analyzed in a total of 28,794 individuals from the MDC cohort, and of these, 2584 (9 %) were affected by VTE during follow-up (1991–2018). Qualifying variants used in gene-collapsing analysis were defined as loss-of-function or non-benign (PolyPhen-2) missense variants with minor allele frequency less than 0.1 %. Results: Exon sequencing of the F3 gene identified 61 different variants, 3′ UTR variants (n = 5), 5′ UTR variants (n = 9) synonymous (n = 10), in frame insertion (n = 1), splice region variants (n = 2), missense (n = 33) or loss-of-function variants (n = 1). No associations between common F3 gene variants and incident VTE were found. Seventeen rare variants were classified as qualifying and included in collapsing analysis (16 non-benign missense and 1 loss-of-function variants). The prevalence of F3 qualifying variants was 0.14 %. Seven individuals with F3 qualifying variants had VTE, while 34 individuals had no VTE. The adjusted VTE model was significant (hazard ratio = 2.1 [95 % confidence interval, 1.02–4.48], P-value = 0.045). Conclusions: Qualifying F3 gene variants are very rare, indicating a constrained gene. Rare but not common variation in the F3 gene may be involved in VTE.

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type
Contribution to journal
publication status
published
subject
keywords
Epidemiology, F3, Genetics, Tissue factor, Venous thromboembolism
in
Thrombosis Update
volume
17
article number
100190
publisher
Elsevier
external identifiers
  • scopus:85206905225
DOI
10.1016/j.tru.2024.100190
language
English
LU publication?
yes
id
b586e8af-78a8-4ba4-b7c2-34fd2ce77067
date added to LUP
2024-12-04 10:11:09
date last changed
2025-04-04 13:53:39
@article{b586e8af-78a8-4ba4-b7c2-34fd2ce77067,
  abstract     = {{<p>Background: Tissue factor (TF), encoded by the F3 gene, is the main initiator of blood coagulation. The molecular epidemiology of the F3 gene and the relation to venous thromboembolism (VTE) remains to be determined. Objectives: The aim was to determine the molecular epidemiology and the importance of F3 variants for incident VTE by analysis of the population-based MDC study (Malmö Diet and Cancer), consisting of unselected middle-aged and older individuals. Methods: The exons of F3 were analyzed in a total of 28,794 individuals from the MDC cohort, and of these, 2584 (9 %) were affected by VTE during follow-up (1991–2018). Qualifying variants used in gene-collapsing analysis were defined as loss-of-function or non-benign (PolyPhen-2) missense variants with minor allele frequency less than 0.1 %. Results: Exon sequencing of the F3 gene identified 61 different variants, 3′ UTR variants (n = 5), 5′ UTR variants (n = 9) synonymous (n = 10), in frame insertion (n = 1), splice region variants (n = 2), missense (n = 33) or loss-of-function variants (n = 1). No associations between common F3 gene variants and incident VTE were found. Seventeen rare variants were classified as qualifying and included in collapsing analysis (16 non-benign missense and 1 loss-of-function variants). The prevalence of F3 qualifying variants was 0.14 %. Seven individuals with F3 qualifying variants had VTE, while 34 individuals had no VTE. The adjusted VTE model was significant (hazard ratio = 2.1 [95 % confidence interval, 1.02–4.48], P-value = 0.045). Conclusions: Qualifying F3 gene variants are very rare, indicating a constrained gene. Rare but not common variation in the F3 gene may be involved in VTE.</p>}},
  author       = {{Manderstedt, Eric and Lind-Halldén, Christina and Halldén, Christer and Elf, Johan and Svensson, Peter J. and Engström, Gunnar and Melander, Olle and Baras, Aris and Lotta, Luca A. and Zöller, Bengt}},
  keywords     = {{Epidemiology; F3; Genetics; Tissue factor; Venous thromboembolism}},
  language     = {{eng}},
  publisher    = {{Elsevier}},
  series       = {{Thrombosis Update}},
  title        = {{Tissue factor (F3) gene variants and thrombotic risk among middle-aged and older adults : A population-based cohort study}},
  url          = {{http://dx.doi.org/10.1016/j.tru.2024.100190}},
  doi          = {{10.1016/j.tru.2024.100190}},
  volume       = {{17}},
  year         = {{2024}},
}