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

TitleGenome-wide association study with additional genetic and post-transcriptional analyses reveals novel regulators of plasma factor XI levels.
Publication TypeJournal Article
Year of Publication2017
AuthorsSennblad B, Basu S, Mazur J, Suchon P, Martinez-Perez A, Vlieg Avan Hylcka, Truong V, Li Y, Gådin JR, Tang W, Grossman V, de Haan HG, Handin N, Silveira A, Souto JCarlos, Franco-Cereceda A, Morange P-E, Gagnon F, Soria JManuel, Eriksson P, Hamsten A, Maegdefessel L, Rosendaal FR, Wild P, Folsom AR, Tregouet D-A
Secondary AuthorsSabater-Lleal M
JournalHum Mol Genet
Volume26
Issue3
Pagination637-649
Date Published2017 02 01
ISSN1460-2083
KeywordsAdaptor Proteins, Signal Transducing, Cell Adhesion Molecules, Computer Simulation, Female, Gene Expression Regulation, Gene Regulatory Networks, Genetic Predisposition to Disease, Genome-Wide Association Study, Humans, Kininogens, Male, Partial Thromboplastin Time, Polymorphism, Single Nucleotide, Protein Processing, Post-Translational, Receptors, Cell Surface, Thrombosis
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.

DOI10.1093/hmg/ddw401
Alternate JournalHum Mol Genet
PubMed ID28053049
PubMed Central IDPMC5703348
Grant ListHHSN268201100012C / HL / NHLBI NIH HHS / United States
HHSN268201100009I / HL / NHLBI NIH HHS / United States
HHSN268201100010C / HL / NHLBI NIH HHS / United States
UL1 RR025005 / RR / NCRR NIH HHS / United States
HHSN268201100008C / HL / NHLBI NIH HHS / United States
HHSN268201100005G / HL / NHLBI NIH HHS / United States
HHSN268201100008I / HL / NHLBI NIH HHS / United States
R01 HL059367 / HL / NHLBI NIH HHS / United States
HHSN268201100007C / HL / NHLBI NIH HHS / United States
HHSN268201100011I / HL / NHLBI NIH HHS / United States
HHSN268201100011C / HL / NHLBI NIH HHS / United States
R01 HL086694 / HL / NHLBI NIH HHS / United States
U01 HG004402 / HG / NHGRI NIH HHS / United States
HHSN268201100006C / HL / NHLBI NIH HHS / United States
HHSN268201100005I / HL / NHLBI NIH HHS / United States
HHSN268201100009C / HL / NHLBI NIH HHS / United States
HHSN268201100005C / HL / NHLBI NIH HHS / United States
HHSN268201100007I / HL / NHLBI NIH HHS / United States
/ / Wellcome Trust / United Kingdom
R01 HL087641 / HL / NHLBI NIH HHS / United States