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Hum Mol Genet. 2017 Feb 1;26(3):637-649. doi: 10.1093/hmg/ddw401.

Genome-wide association study with additional genetic and post-transcriptional analyses reveals novel regulators of plasma factor XI levels.

Author information

1
Cardiovascular Medicine Unit, Department of Medicine, Karolinska Institutet, Stockholm, Sweden.
2
Science for Life Laboratory, Department of Biochemistry and Biophysics, Stockholm University, Sweden.
3
University of Minnesota School of Public Health, Division of Biostatistics, MN, USA.
4
University Medical Center Mainz, Johannes Gutenberg University Mainz, Mainz, Germany.
5
Institut National pour la Santé et la Recherche Médicale (INSERM), Unité Mixte de Recherche en Santé (UMR_S) 1062, Nutrition Obesity and Risk of Thrombosis, Marseille, France; Aix-Marseille University.
6
Unitat de Genòmica de Malalties Complexes. Institut d'Investigació Biomèdica Sant Pau (IIB-Sant Pau), Barcelona, Spain.
7
Department of Clinical Epidemiology, Leiden University Medical Center, Leiden, the Netherlands.
8
Dalla Lana School of Public Health, University of Toronto, Toronto, Ontario, Canada.
9
University of Minnesota School of Public Health, Division of Epidemiology and Community Health, Minneapolis, MN, USA.
10
Unitat de Trombosi i Hemostàsia, Hospital de Sant Pau, Barcelona, Spain.
11
Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden.
12
Preventive Cardiology and Preventive Medicine, Center for Cardiology, University Medical Center of the Johannes Gutenberg-University Mainz, Mainz, Germany.
13
DZHK (German Center for Cardiovascular Research), partner site RhineMain, Mainz, Germany.
14
Sorbonne Universités, UPMC Univ. Paris 06, INSERM, UMR_S 1166, Team Genomics & Pathophysiology of Cardiovascular Diseases, Paris, France.
15
ICAN Institute for Cardiometabolism and Nutrition, Paris, France.

Abstract

Coagulation factor XI (FXI) has become increasingly interesting for its role in pathogenesis of thrombosis. While elevated plasma levels of FXI have been associated with venous thromboembolism and ischemic stroke, its deficiency is associated with mild bleeding. We aimed to determine novel genetic and post-transcriptional plasma FXI regulators.We performed a genome-wide association study (GWAS) for plasma FXI levels, using novel data imputed to the 1000 Genomes reference panel. Individual GWAS analyses, including a total of 16,169 European individuals from the ARIC, GHS, MARTHA and PROCARDIS studies, were meta-analysed and further replicated in 2,045 individuals from the F5L family, GAIT2 and MEGA studies. Additional association with activated partial thromboplastin time (aPTT) was tested for the top SNPs. In addition, a study on the effect of miRNA on FXI regulation was performed using in silico prediction tools and in vitro luciferase assays.Three loci showed robust, replicating association with circulating FXI levels: KNG1 (rs710446, P-value = 2.07 × 10-302), F11 (rs4253417, P-value  = 2.86 × 10-193), and a novel association in GCKR (rs780094, P-value  = 3.56 ×10-09), here for the first time implicated in FXI regulation. The two first SNPs (rs710446 and rs4253417) also associated with aPTT. Conditional and haplotype analyses demonstrated a complex association signal, with additional novel SNPs modulating plasma FXI levels in both the F11 and KNG1 loci. Finally, eight miRNAs were predicted to bind F11 mRNA. Over-expression of either miR-145 or miR-181 significantly reduced the luciferase activity in cells transfected with a plasmid containing FXI-3'UTR.These results should open the door to new therapeutic targets for thrombosis prevention.

PMID:
28053049
PMCID:
PMC5703348
DOI:
10.1093/hmg/ddw401
[Indexed for MEDLINE]
Free PMC Article

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