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

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 ex...

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Autores principales: Stanne, Tara M., Olsson, Maja, Lorentzen, Erik, Pedersen, Annie, Gummesson, Anders, Gils, Ann, Jood, Katarina, Engström, Gunnar, Melander, Olle, Declerck, Paul J., Jern, Christina
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Schattauer GmbH 2018
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6260132/
https://www.ncbi.nlm.nih.gov/pubmed/29378355
http://dx.doi.org/10.1160/TH17-04-0249
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author Stanne, Tara M.
Olsson, Maja
Lorentzen, Erik
Pedersen, Annie
Gummesson, Anders
Gils, Ann
Jood, Katarina
Engström, Gunnar
Melander, Olle
Declerck, Paul J.
Jern, Christina
author_facet Stanne, Tara M.
Olsson, Maja
Lorentzen, Erik
Pedersen, Annie
Gummesson, Anders
Gils, Ann
Jood, Katarina
Engström, Gunnar
Melander, Olle
Declerck, Paul J.
Jern, Christina
author_sort Stanne, Tara M.
collection PubMed
description 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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spelling pubmed-62601322018-11-29 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 Melander, Olle Declerck, Paul J. Jern, Christina Thromb Haemost 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. Schattauer GmbH 2018-02 2018-01-29 /pmc/articles/PMC6260132/ /pubmed/29378355 http://dx.doi.org/10.1160/TH17-04-0249 Text en https://creativecommons.org/licenses/by-nc-nd/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivatives License, which permits unrestricted reproduction and distribution, for non-commercial purposes only; and use and reproduction, but not distribution, of adapted material for non-commercial purposes only, provided the original work is properly cited.
spellingShingle Stanne, Tara M.
Olsson, Maja
Lorentzen, Erik
Pedersen, Annie
Gummesson, Anders
Gils, Ann
Jood, Katarina
Engström, Gunnar
Melander, Olle
Declerck, Paul J.
Jern, Christina
A Genome-wide Study of Common and Rare Genetic Variants Associated with Circulating Thrombin Activatable Fibrinolysis Inhibitor
title A Genome-wide Study of Common and Rare Genetic Variants Associated with Circulating Thrombin Activatable Fibrinolysis Inhibitor
title_full A Genome-wide Study of Common and Rare Genetic Variants Associated with Circulating Thrombin Activatable Fibrinolysis Inhibitor
title_fullStr A Genome-wide Study of Common and Rare Genetic Variants Associated with Circulating Thrombin Activatable Fibrinolysis Inhibitor
title_full_unstemmed A Genome-wide Study of Common and Rare Genetic Variants Associated with Circulating Thrombin Activatable Fibrinolysis Inhibitor
title_short A Genome-wide Study of Common and Rare Genetic Variants Associated with Circulating Thrombin Activatable Fibrinolysis Inhibitor
title_sort genome-wide study of common and rare genetic variants associated with circulating thrombin activatable fibrinolysis inhibitor
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6260132/
https://www.ncbi.nlm.nih.gov/pubmed/29378355
http://dx.doi.org/10.1160/TH17-04-0249
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