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, Angel Martinez-Perez, Astrid van Hylckama Vlieg, Vinh Truong, Yuhuang Li, Jesper R. Gådin, Weihong Tang, Vera Grossman, Hugoline G. de Haan, Niklas Handin, Angela Silveira, Juan Carlos Souto, Anders Franco-Cereceda, Pierre Emmanuel Morange, France Gagnon, Jose Manuel Soria, Per ErikssonAnders Hamsten, Lars Maegdefessel, Frits R. Rosendaal, Philipp Wild, Aaron R. Folsom, David Alexandre Trégouët, Maria Sabater-Lleal

Research output: Contribution to journalArticlepeer-review

17 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)637-649
Number of pages13
JournalHuman molecular genetics
Volume26
Issue number3
DOIs
StatePublished - 2017

Bibliographical note

Funding Information:
We are grateful to Mary Cushman for advice in the project design and selection of samples and to Mattias Fra?nberg for valuable discussions on analysis methods. The authors thank the staff and participants of the ARIC study for their important contributions. The Atherosclerosis Risk in Communities (ARIC) Study is carried out as a collaborative study supported by National Heart, Lung, and Blood Institute contracts (HHSN268201100005C, HHSN2682 01100006C, HHSN268201100007C, HHSN268201100008C, HHSN2 68201100009C, HHSN268201100010C, HHSN268201100011C, and HHSN268201100012C), R01HL087641, R01HL59367 and R01HL086694; National Human Genome Research Institute contract U01HG004402; and National Institutes of Health contract HHSN268200625226C. Infrastructure was partly supported by Grant Number UL1RR025005, a component of the National Institutes of Health and NIH Roadmap for Medical Research. PROCARDIS was supported by the European Community SixthFramework Program (LSHM-CT-2007-037273), AstraZeneca, the British Heart Foundation, the Wellcome Trust (Contract No. 075491/Z/04), the Swedish Research Council, the Knut and Alice Wallenberg Foundation, the Swedish Heart-Lung Foundation, the Torsten and Ragnar Soderberg Foundation, the Strategic Cardiovascular and Diabetes Programs of Karolinska Institutet and Stockholm County Council, the Foundation for Strategic Research and the Stockholm County Council. Bengt Sennblad acknowledges funding from the Magnus Bergvall foundation and the foundation for old servants. Maria Sabater-Lleal is recipient of the European Hematology Association and the International Society of Thrombosis and Hemostasis (EHAISTH) fellowship and acknowledges funding from Swedish Heart-Lung Foundation (20130399), A? ke Wiberg (400546009), Lars Hiertas Minne (F02014-0357), and Magnus Bergvall's foundations (2014-00242). The Gutenberg Health Study is funded through the government of Rhineland-Palatinate ('Stiftung Rheinland-Pfalz f?r Innovation', contract AZ 961-386261/733), the research programs 'Wissenschafft Zukunft' and 'Center for Translational Vascular Biology (CTVB)' of the Johannes Gutenberg-University of Mainz, and its contract with Boehringer Ingelheim and PHILIPS Medical Systems, including an unrestricted grant for the Gutenberg Health Study. Philipp S. Wild is funded by the Federal Ministry of Education and Research (BMBF 01EO1503) and he is PI of the German Center for Cardiovascular Research (DZHK). The MARTHA project was supported by grants from the Program Hospitalier de Recherche Clinique. Statistical data analysis in MARTHA was performed on the C2BIG high-performance computing system funded by the Region Ile de France, the Universit? Pierre et Marie Curie and the ICAN Institute for Cardiometabolism and Nutrition (ANR-10-IAHU-05). GAIT2 was supported partially by grants PI-11/0184, Pi-14/0582, RD12/0042/0032 and UIN2013-50833 from the Instituto Carlos III (Fondo de Investigaci?n Sanitaria-FIS). The French-Canadian family study on Factor V Leiden was partially supported by the Canadian Institutes of Health Research and the Heart and Stroke Foundation of Canada; France Gagnon is supported by a Canada Research Chair in Genetic Epidemiology.

Publisher Copyright:
© The Author 2016.

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