title: Genome-wide association study with additional genetic and post-transcriptional analyses reveals novel regulators of plasma factor XI levels.
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.
authors.affiliation: Cardiovascular Medicine Unit, Department of Medicine, Karolinska Institutet, Stockholm, Sweden.|Science for Life Laboratory, Department of Biochemistry and Biophysics, Stockholm University, Sweden.
authors.forename: Bengt
authors.initials: B
authors.lastname: Sennblad
authors.affiliation: University of Minnesota School of Public Health, Division of Biostatistics, MN, USA.
authors.forename: Saonli
authors.initials: S
authors.lastname: Basu
authors.affiliation: University Medical Center Mainz, Johannes Gutenberg University Mainz, Mainz, Germany.
authors.forename: Johanna
authors.initials: J
authors.lastname: Mazur
authors.affiliation: 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.
authors.forename: Pierre
authors.initials: P
authors.lastname: Suchon
authors.affiliation: Unitat de Genòmica de Malalties Complexes. Institut d'Investigació Biomèdica Sant Pau (IIB-Sant Pau), Barcelona, Spain.
authors.forename: Angel
authors.initials: A
authors.lastname: Martinez-Perez
authors.affiliation: Department of Clinical Epidemiology, Leiden University Medical Center, Leiden, the Netherlands.
authors.forename: Astrid
authors.initials: A
authors.lastname: van Hylckama Vlieg
authors.affiliation: Dalla Lana School of Public Health, University of Toronto, Toronto, Ontario, Canada.
authors.forename: Vinh
authors.initials: V
authors.lastname: Truong
authors.affiliation: Cardiovascular Medicine Unit, Department of Medicine, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Yuhuang
authors.initials: Y
authors.lastname: Li
authors.affiliation: Cardiovascular Medicine Unit, Department of Medicine, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Jesper R
authors.initials: JR
authors.lastname: Gådin
authors.affiliation: University of Minnesota School of Public Health, Division of Epidemiology and Community Health, Minneapolis, MN, USA.
authors.forename: Weihong
authors.initials: W
authors.lastname: Tang
authors.affiliation: University Medical Center Mainz, Johannes Gutenberg University Mainz, Mainz, Germany.
authors.forename: Vera
authors.initials: V
authors.lastname: Grossman
authors.affiliation: Department of Clinical Epidemiology, Leiden University Medical Center, Leiden, the Netherlands.
authors.forename: Hugoline G
authors.initials: HG
authors.lastname: de Haan
authors.affiliation: Cardiovascular Medicine Unit, Department of Medicine, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Niklas
authors.initials: N
authors.lastname: Handin
authors.affiliation: Cardiovascular Medicine Unit, Department of Medicine, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Angela
authors.initials: A
authors.lastname: Silveira
authors.affiliation: Unitat de Trombosi i Hemostàsia, Hospital de Sant Pau, Barcelona, Spain.
authors.forename: Juan Carlos
authors.initials: JC
authors.lastname: Souto
authors.affiliation: Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Anders
authors.initials: A
authors.lastname: Franco-Cereceda
authors.affiliation: 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.
authors.forename: Pierre-Emmanuel
authors.initials: PE
authors.lastname: Morange
authors.affiliation: Dalla Lana School of Public Health, University of Toronto, Toronto, Ontario, Canada.
authors.forename: France
authors.initials: F
authors.lastname: Gagnon
authors.affiliation: Unitat de Genòmica de Malalties Complexes. Institut d'Investigació Biomèdica Sant Pau (IIB-Sant Pau), Barcelona, Spain.
authors.forename: Jose Manuel
authors.initials: JM
authors.lastname: Soria
authors.affiliation: Cardiovascular Medicine Unit, Department of Medicine, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Per
authors.initials: P
authors.lastname: Eriksson
authors.affiliation: Cardiovascular Medicine Unit, Department of Medicine, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Anders
authors.initials: A
authors.lastname: Hamsten
authors.affiliation: Cardiovascular Medicine Unit, Department of Medicine, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Lars
authors.initials: L
authors.lastname: Maegdefessel
authors.affiliation: Department of Clinical Epidemiology, Leiden University Medical Center, Leiden, the Netherlands.
authors.forename: Frits R
authors.initials: FR
authors.lastname: Rosendaal
authors.affiliation: University Medical Center Mainz, Johannes Gutenberg University Mainz, Mainz, Germany.|Preventive Cardiology and Preventive Medicine, Center for Cardiology, University Medical Center of the Johannes Gutenberg-University Mainz, Mainz, Germany.|DZHK (German Center for Cardiovascular Research), partner site RhineMain, Mainz, Germany.
authors.forename: Philipp
authors.initials: P
authors.lastname: Wild
authors.affiliation: University of Minnesota School of Public Health, Division of Epidemiology and Community Health, Minneapolis, MN, USA.
authors.forename: Aaron R
authors.initials: AR
authors.lastname: Folsom
authors.affiliation: Sorbonne Universités, UPMC Univ. Paris 06, INSERM, UMR_S 1166, Team Genomics & Pathophysiology of Cardiovascular Diseases, Paris, France.|ICAN Institute for Cardiometabolism and Nutrition, Paris, France.
authors.forename: David-Alexandre
authors.initials: DA
authors.lastname: Trégouët
authors.affiliation: Cardiovascular Medicine Unit, Department of Medicine, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Maria
authors.initials: M
authors.lastname: Sabater-Lleal
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics*; D015815:Cell Adhesion Molecules / Q000097:blood* / Q000235:genetics; D003198:Computer Simulation; D005260:Female; D005786:Gene Expression Regulation / Q000235:genetics; D053263:Gene Regulatory Networks / Q000235:genetics; D020022:Genetic Predisposition to Disease; D055106:Genome-Wide Association Study; D006801:Humans; D007704:Kininogens / Q000235:genetics*; D008297:Male; D010314:Partial Thromboplastin Time; D020641:Polymorphism, Single Nucleotide; D011499:Protein Processing, Post-Translational / Q000235:genetics; D011956:Receptors, Cell Surface / Q000097:blood* / Q000235:genetics; D013927:Thrombosis / Q000097:blood / Q000235:genetics* / Q000503:physiopathology
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D015815:Cell Adhesion Molecules; C407243:F11R protein, human; C485100:GCKR protein, human; C000591034:KNG1 protein, human; D007704:Kininogens; D011956:Receptors, Cell Surface