A meta-analysis of genome-wide association studies identifies ORM1 as a novel gene controlling thrombin generation potential

TY - JOUR

T1 - A meta-analysis of genome-wide association studies identifies ORM1 as a novel gene controlling thrombin generation potential

AU - Rocanin-Arjo, Ares

AU - Cohen, William

AU - Carcaillon, Laure

AU - Frère, Corinne

AU - Saut, Noémie

AU - Letenneur, Luc

AU - Alhenc-Gelas, Martine

AU - Dupuy, Anne-Marie

AU - Bertrand, Marion

AU - Alessi, Marie-Christine

AU - Germain, Marine

AU - Wild, Philipp S

AU - Zeller, Tanja

AU - Cambien, Francois

AU - Goodall, Alison H

AU - Amouyel, Philippe

AU - Scarabin, Pierre-Yves

AU - Trégouët, David-Alexandre

AU - Morange, Pierre-Emmanuel

AU - CardioGenics Consortium

PY - 2014/1/30

Y1 - 2014/1/30

N2 - 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.

AB - 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.

KW - Adult

KW - Blood Coagulation Tests

KW - Female

KW - Genome-Wide Association Study

KW - Humans

KW - Male

KW - Middle Aged

KW - Orosomucoid/genetics

KW - Polymorphism, Single Nucleotide

KW - Thrombin/metabolism

U2 - 10.1182/blood-2013-10-529628

DO - 10.1182/blood-2013-10-529628

M3 - SCORING: Journal article

C2 - 24357727

VL - 123

SP - 777

EP - 185

JO - BLOOD

JF - BLOOD

SN - 0006-4971

IS - 5

ER -