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CC BY-NC-ND 4.0 · Thromb Haemost 2018; 118(02): 298-308
DOI: 10.1160/TH17-04-0249
Coagulation and Fibrinolysis
Schattauer GmbH Stuttgart

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

Tara M. Stanne
1   Department of Pathology and Genetics, Institute of Biomedicine, Sahlgrenska Academy at University of Gothenburg, Gothenburg, Sweden
,
Maja Olsson
1   Department of Pathology and Genetics, Institute of Biomedicine, Sahlgrenska Academy at University of Gothenburg, Gothenburg, Sweden
,
Erik Lorentzen
2   Bioinformatics Core Facility, University of Gothenburg, Gothenburg, Sweden
,
Annie Pedersen
1   Department of Pathology and Genetics, Institute of Biomedicine, Sahlgrenska Academy at University of Gothenburg, Gothenburg, Sweden
,
Anders Gummesson
1   Department of Pathology and Genetics, Institute of Biomedicine, Sahlgrenska Academy at University of Gothenburg, Gothenburg, Sweden
,
Ann Gils
3   Laboratory for Therapeutic and Diagnostic Antibodies, Department of Pharmaceutical and Pharmacological Sciences, KU Leuven, Brussels, Belgium
,
Katarina Jood
4   Department of Clinical Neuroscience, Institute of Neuroscience and Physiology, Sahlgrenska Academy at University of Gothenburg, Gothenburg, Sweden
,
Gunnar Engström
5   Department of Clinical Sciences, Lund University, Lund, Sweden
,
Olle Melander
5   Department of Clinical Sciences, Lund University, Lund, Sweden
,
Paul J. Declerck
3   Laboratory for Therapeutic and Diagnostic Antibodies, Department of Pharmaceutical and Pharmacological Sciences, KU Leuven, Brussels, Belgium
,
Christina Jern
1   Department of Pathology and Genetics, Institute of Biomedicine, Sahlgrenska Academy at University of Gothenburg, Gothenburg, Sweden
› Author Affiliations
Further Information

Publication History

10 April 2017

10 November 2017

Publication Date:
29 January 2018 (online)

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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 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.

Keywords

thrombin-activatable fibrinolysis inhibitor - fibrinolysis inhibitors - plasma levels - genome-wide association study

Financial Support

The present study was supported by the Swedish Research Council and grants from the Swedish state (ALF), the Swedish Heart-Lung Foundation and the Swedish Stroke Association. The National Institute of Neurological Disorders and Stroke (NINDS) funded the genotyping of patients included in the SiGN study. PI, Steven Kittner.


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