A meta-analysis of genome-wide association studies identifies ORM1 as a novel gene controlling thrombin generation potential
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A meta-analysis of genome-wide association studies identifies ORM1 as a novel gene controlling thrombin generation potential. / Rocanin-Arjo, Ares; Cohen, William; Carcaillon, Laure; Frère, Corinne; Saut, Noémie; Letenneur, Luc; Alhenc-Gelas, Martine; Dupuy, Anne-Marie; Bertrand, Marion; Alessi, Marie-Christine; Germain, Marine; Wild, Philipp S; Zeller, Tanja; Cambien, Francois; Goodall, Alison H; Amouyel, Philippe; Scarabin, Pierre-Yves; Trégouët, David-Alexandre; Morange, Pierre-Emmanuel; CardioGenics Consortium.
in: BLOOD, Jahrgang 123, Nr. 5, 30.01.2014, S. 777-185.Publikationen: SCORING: Beitrag in Fachzeitschrift/Zeitung › SCORING: Zeitschriftenaufsatz › Forschung › Begutachtung
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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 -