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

作者：Rocanin Arjo Ares; Cohen William; Carcaillon Laure; Frere Corinne; Saut Noemie; 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; Tregouet David Alexandre^*; Morange Pierre Emmanuel

来源：Blood, 2014, 123(5): 777-785.

DOI：10.1182/blood-2013-10-529628

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 X 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 X 10(-10)) and macrophages (P = 3.2 X 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.

• 出版日期2014-1-30