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A Genome-wide Study of Common and Rare Genetic Variants Associated with Circulating Thrombin Activatable Fibrinolysis Inhibitor

Stanne, Tara M.; Olsson, Maja; Lorentzen, Erik; Pedersen, Annie; Gummesson, Anders; Gils, Ann; Jood, Katarina; Engström, Gunnar LU ; Melander, Olle LU and Declerck, Paul J., et al. (2018) In Thrombosis and Haemostasis 118(2). p.298-308
Abstract

Thrombin-activatable fibrinolysis inhibitor (TAFI) plays a central role in haemostasis, and plasma TAFI concentrations are heritable. Candidate gene studies have identified several variants within the gene encoding TAFI, CPB2, that explain part of the estimated heritability. Here, we describe an exploratory genome-wide association study to identify novel variants within and outside of the CPB2 locus that influence plasma concentrations of intact TAFI and/or the extent of TAFI activation (measured by released TAFI activation peptide, TAFI-AP) amongst 3,260 subjects from Southern Sweden. We also explored the role of rare variants on the HumanExome BeadChip. We confirmed the association with previously reported common variants in CPB2 for... (More)

Thrombin-activatable fibrinolysis inhibitor (TAFI) plays a central role in haemostasis, and plasma TAFI concentrations are heritable. Candidate gene studies have identified several variants within the gene encoding TAFI, CPB2, that explain part of the estimated heritability. Here, we describe an exploratory genome-wide association study to identify novel variants within and outside of the CPB2 locus that influence plasma concentrations of intact TAFI and/or the extent of TAFI activation (measured by released TAFI activation peptide, TAFI-AP) amongst 3,260 subjects from Southern Sweden. We also explored the role of rare variants on the HumanExome BeadChip. We confirmed the association with previously reported common variants in CPB2 for both intact TAFI and TAFI-AP, and discovered novel associations with variants in putative CPB2 enhancers. We identified a gene-based association with intact TAFI at CPB2 (P SKAT-O = 2.8 × 10 -8), driven by two novel rare nonsynonymous single nucleotide polymorphisms (SNPs; I420N and D177G). Carriers of the rare variant of D177G (rs140446990; MAF 0.2%) had lower intact TAFI and TAFI-AP concentrations compared with non-carriers (intact TAFI, geometric mean 53 vs. 78%, P T-test = 5 × 10 -7; TAFI-AP 63 vs. 99%, P T-test = 7.2 × 10 -4). For TAFI-AP, we identified a genome-wide significant association at an intergenic region of chromosome 3p14.1 and five gene-based associations (all P SKAT-O < 5 × 10 -6). Using well-characterized assays together with a genome-wide association study and a rare-variant approach, we verified CPB2 to be the primary determinant of TAFI concentrations and identified putative secondary loci (candidate variants and genes) associated with intact TAFI and TAFI-AP that require independent validation.

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publication status
published
subject
keywords
fibrinolysis inhibitors, genome-wide association study, plasma levels, thrombin-activatable fibrinolysis inhibitor
in
Thrombosis and Haemostasis
volume
118
issue
2
pages
298 - 308
publisher
F K Schattauer Verlag Gmbh
external identifiers
  • scopus:85050597229
ISSN
0340-6245
DOI
10.1160/TH17-04-0249
language
English
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yes
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efc1cdcd-6994-4d42-90ae-271e84c25eba
date added to LUP
2018-10-01 11:34:37
date last changed
2019-02-20 11:28:31
@article{efc1cdcd-6994-4d42-90ae-271e84c25eba,
  abstract     = {<p>Thrombin-activatable fibrinolysis inhibitor (TAFI) plays a central role in haemostasis, and plasma TAFI concentrations are heritable. Candidate gene studies have identified several variants within the gene encoding TAFI, CPB2, that explain part of the estimated heritability. Here, we describe an exploratory genome-wide association study to identify novel variants within and outside of the CPB2 locus that influence plasma concentrations of intact TAFI and/or the extent of TAFI activation (measured by released TAFI activation peptide, TAFI-AP) amongst 3,260 subjects from Southern Sweden. We also explored the role of rare variants on the HumanExome BeadChip. We confirmed the association with previously reported common variants in CPB2 for both intact TAFI and TAFI-AP, and discovered novel associations with variants in putative CPB2 enhancers. We identified a gene-based association with intact TAFI at CPB2 (P <sub>SKAT-O</sub> = 2.8 × 10 <sup>-8</sup>), driven by two novel rare nonsynonymous single nucleotide polymorphisms (SNPs; I420N and D177G). Carriers of the rare variant of D177G (rs140446990; MAF 0.2%) had lower intact TAFI and TAFI-AP concentrations compared with non-carriers (intact TAFI, geometric mean 53 vs. 78%, P <sub>T-test</sub> = 5 × 10 <sup>-7</sup>; TAFI-AP 63 vs. 99%, P <sub>T-test</sub> = 7.2 × 10 <sup>-4</sup>). For TAFI-AP, we identified a genome-wide significant association at an intergenic region of chromosome 3p14.1 and five gene-based associations (all P <sub>SKAT-O</sub> &lt; 5 × 10 <sup>-6</sup>). Using well-characterized assays together with a genome-wide association study and a rare-variant approach, we verified CPB2 to be the primary determinant of TAFI concentrations and identified putative secondary loci (candidate variants and genes) associated with intact TAFI and TAFI-AP that require independent validation.</p>},
  author       = {Stanne, Tara M. and Olsson, Maja and Lorentzen, Erik and Pedersen, Annie and Gummesson, Anders and Gils, Ann and Jood, Katarina and Engström, Gunnar and Melander, Olle and Declerck, Paul J. and Jern, Christina},
  issn         = {0340-6245},
  keyword      = {fibrinolysis inhibitors,genome-wide association study,plasma levels,thrombin-activatable fibrinolysis inhibitor},
  language     = {eng},
  number       = {2},
  pages        = {298--308},
  publisher    = {F K Schattauer Verlag Gmbh},
  series       = {Thrombosis and Haemostasis},
  title        = {A Genome-wide Study of Common and Rare Genetic Variants Associated with Circulating Thrombin Activatable Fibrinolysis Inhibitor},
  url          = {http://dx.doi.org/10.1160/TH17-04-0249},
  volume       = {118},
  year         = {2018},
}