title: A meta-analysis of genome-wide association studies identifies ORM1 as a novel gene controlling thrombin generation potential.
abstract: Thrombin, the major enzyme of the hemostatic system, is involved in biological processes associated with several human diseases. The capacity of a given individual to generate thrombin, called the thrombin generation potential (TGP), can be robustly measured in plasma and was shown to associate with thrombotic disorders. To investigate the genetic architecture underlying the interindividual TGP variability, we conducted a genome-wide association study in 2 discovery samples (N = 1967) phenotyped for 3 TGP biomarkers, the endogenous thrombin potential, the peak height, and the lag time, and replicated the main findings in 2 independent studies (N = 1254). We identified the ORM1 gene, coding for orosomucoid, as a novel locus associated with lag time variability, reflecting the initiation process of thrombin generation with a combined P value of P = 7.1 × 10(-15) for the lead single nucleotide polymorphism (SNP) (rs150611042). This SNP was also observed to associate with ORM1 expression in monocytes (P = 8.7 × 10(-10)) and macrophages (P = 3.2 × 10(-3)). In vitro functional experiments further demonstrated that supplementing normal plasma with increasing orosomucoid concentrations was associated with impaired thrombin generation. These results pave the way for novel mechanistic pathways and therapeutic perspectives in the etiology of thrombin-related disorders.
authors.affiliation: Pierre and Marie Curie University, INSERM, UMR_S 1166, Paris, France;
authors.forename: Ares
authors.initials: A
authors.lastname: Rocanin-Arjo
authors.forename: William
authors.initials: W
authors.lastname: Cohen
authors.forename: Laure
authors.initials: L
authors.lastname: Carcaillon
authors.forename: Corinne
authors.initials: C
authors.lastname: Frère
authors.forename: Noémie
authors.initials: N
authors.lastname: Saut
authors.forename: Luc
authors.initials: L
authors.lastname: Letenneur
authors.forename: Martine
authors.initials: M
authors.lastname: Alhenc-Gelas
authors.forename: Anne-Marie
authors.initials: AM
authors.lastname: Dupuy
authors.forename: Marion
authors.initials: M
authors.lastname: Bertrand
authors.forename: Marie-Christine
authors.initials: MC
authors.lastname: Alessi
authors.forename: Marine
authors.initials: M
authors.lastname: Germain
authors.forename: Philipp S
authors.initials: PS
authors.lastname: Wild
authors.forename: Tanja
authors.initials: T
authors.lastname: Zeller
authors.forename: Francois
authors.initials: F
authors.lastname: Cambien
authors.forename: Alison H
authors.initials: AH
authors.lastname: Goodall
authors.forename: Philippe
authors.initials: P
authors.lastname: Amouyel
authors.forename: Pierre-Yves
authors.initials: PY
authors.lastname: Scarabin
authors.forename: David-Alexandre
authors.initials: DA
authors.lastname: Trégouët
authors.forename: Pierre-Emmanuel
authors.initials: PE
authors.lastname: Morange
mesh_terms: D000328:Adult; D001780:Blood Coagulation Tests; D005260:Female; D055106:Genome-Wide Association Study; D006801:Humans; D008297:Male; D008875:Middle Aged; D009961:Orosomucoid / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide; D013917:Thrombin / Q000378:metabolism*
chemical_list: D009961:Orosomucoid; D013917:Thrombin