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

Bengt Sennblad , Saonli Basu , Johanna Mazur , Pierre Suchon (1) , Per Martinez-Perez , Astrid van Hylckama Vlieg (2) , Vinh Truong (3) , Yuhuang Li , Jesper Gådin , Weihong Tang , Vera Grossman , Hugoline de Haan (4) , Niklas Handin , Angela Silveira (5) , Juan Carlos Souto (6) , Anders Franco-Cereceda , Pierre-Emmanuel Morange (7, 1) , France Gagnon (3) , José Manuel Soria , Per Eriksson (8) , Anders Hamsten (9) , Lars Maegdefessel , Frits Rosendaal (2) , Philipp S. Wild (10) , Aaron Folsom , David-Alexandre Trégouët (11) , Maria Sabater-Lleal

1 NORT - Nutrition, obésité et risque thrombotique
2 LUMC - Leiden University Medical Center
3 University of Toronto
4 Department of Thrombosis and Haemostasis
5 Atherosclerosis Research Unit
6 CIBERESP - Centro de Investigación Biomédica en Red de Epidemiología y Salud Pública = Consortium for Biomedical Research of Epidemiology and Public Health
7 TIMONE - Hôpital de la Timone [CHU - APHM]
8 Karolinska Institutet [Stockholm]
9 Cardiovascular Genetics Group
10 Medizinische Klinik und Poliklinik
11 ICAN - Unité de Recherche sur les Maladies Cardiovasculaires, du Métabolisme et de la Nutrition = Research Unit on Cardiovascular and Metabolic Diseases

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.

Domaines: Génomique, Transcriptomique et Protéomique [q-bio.GN]; Cardiologie et système cardiovasculaire

Bengt Sennblad, Saonli Basu, Johanna Mazur, Pierre Suchon, Per Martinez-Perez, et al.. Genome-wide association study with additional genetic and post-transcriptional analyses reveals novel regulators of plasma factor XI levels. Human Molecular Genetics, 2017, 26 (3), pp.637-649. ⟨10.1093/hmg/ddw401⟩. ⟨hal-01745859⟩