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

Abstract

Key Points• Genetic variations at the ORM1 locus and concentrations of the encoded protein associate with thrombin generation.• These findings may guide the development of novel antithrombotic treatments.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 5 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 5 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 5 7.1 3 10 215 for the lead single nucleotide polymorphism (SNP) (rs150611042). This SNP was also observed to associate with ORM1 expression in monocytes (P 5 8.7 3 10 210 ) and macrophages (P 5 3.2 3 10 23 ). 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. (Blood. 2014;123(5):777-785)

Genetic Determinants of Thrombin Generation and Their Relation to Venous Thrombosis: Results from the GAIT-2 Project

“…In agreement with a previous study [ 37 ] we observed a high significant association between thrombin generation and prothrombin G20210A mutation. This genetic variation is a well-known genetic risk factor for VTE [ 1 ].…”

“…Specifically, thrombin generation phenotypes have been associated significantly with genetic variants in haemostatic genes such as F5 , F2 , FGA , F10 , F12 and TFPI [ 7 , 36 ]. It has been reported recently that there is a new association between thrombin generation variability and the ORM1 locus [ 37 ]. It is important to note that known genetic risk factors have been estimated to account for <30% of VTE cases [ 38 ].…”

Meta-analysis of 65,734 Individuals Identifies TSPAN15 and SLC44A2 as Two Susceptibility Loci for Venous Thromboembolism

“…We did not observe heterogeneity in the effects of the two SNPs according to sex nor to F5 rs6025 or F2 rs1799963 mutations (Tables S3 and S4). Although the six known VTE-associated loci affect VT risk through a modulation of known hemostatic traits (i.e., levels of von Willebrand factor and Factor VIII for ABO, of FXI for F11, of endogenous thrombin potential for F2, of resistance to activated protein C for F5, of fibrinogen for FGG, and of protein C for PROCR [26][27][28][29][30][31][32][33] ), the loci of the two discovered genetic associations were not in or near genes that are currently known to influence hemostasis. We then explored whether these SNPs were associated with well-characterized hemostasis phenotypes that are associated with thrombotic propensity.…”

What is currently known about the genetics of venous thromboembolism at the dawn of next generation sequencing technologies

“…The rare A allele is associated with elevated plasma prothrombin (FII) levels induced by a more efficient translational machinery of the mRNA harbouring the A allele (Gehring et al , ). It is also associated with thrombin generation, as is the intronic F2 rs3136516 G/A, in complete negative LD with the rs1799963 (Rocanin‐Arjo et al , ). In the INVENT study, the rs3136516 A allele, with frequency ~0·40, demonstrated strong statistical evidence ( P = 5·65 10 −6 ) for association with VTE, after adjusting for the effect of the rs1799963 polymorphism.…”