Single Nucleotide Variant rs2232710 in the Protein Z-Dependent Protease Inhibitor (ZPI, SERPINA10) Gene Is Not Associated with Deep Vein Thrombosis

Abstract

Rare mutations in PROC, PROS1 or SERPINC1 as well as common variants in F5, F2, F11 and SERPINC1 have been identified as risk factors for deep vein thrombosis (DVT). To identify novel genetic risk factors for DVT, we have developed and applied next-generation DNA sequencing (NGS) of the coding area of hemostatic and proinflammatory genes. Using this strategy, we previously identified a single nucleotide variant (SNV) rs6050 in the FGA gene and novel, rare SNVs in the ADAMTS13 gene associated with DVT. To identify novel coding variants in the genetic predisposition to DVT, we applied NGS analysis of the coding area of 186 hemostatic and proinflammatory genes in 94 DVT cases and 98 controls and we identified 18 variants with putative role in DVT. A group of 585 Italian idiopathic DVT patients and 550 healthy controls was used to genotype all the 18 risk-associated variants identified by NGS. Replication study in the Italian population identified the rs2232710 variant in the protein Z-dependent protease inhibitor (ZPI) gene to be associated with an increased risk of DVT (OR 2.74; 95% CI 1.33–5.65; P = 0.0045; Bonferroni P = 0.081). However, the rs2232710 SNV showed no association with DVT in two Dutch replication cohorts the LETS study (454 patients and 451 controls) and the MEGA study (3799 patients and 4399 controls), indicating that the rs2232710 variant is not a risk factor for DVT.

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

“…Several other polymorphisms/genes have been proposed as risk factors for VTE but these lack compelling evidence, including robust statistical replication in independent studies, to be definitively claimed as susceptibility variants/genes for the disease. These include the rs2232710 of SERPINA10 , which encodes the Protein Z‐Dependent Protease Inhibitor of coagulation factors Xa and XIa (Folsom et al , ; Gorski et al , ); SERPINE1 rs2227631, influencing circulating plasminogen activator inhibitor‐1 (PAI‐1) levels (Huang et al , ); C4BPB/C4BPA rs3813948, affecting PS associated phenotypes (Buil et al , ); the rs7080536 of the HABP2 gene, encoding factor VII (FVII) activating protease (Ahmad‐Nejad et al , ); HIVEP1 rs169713 with, as yet, no associated intermediate phenotype (Morange et al , ); F13A1 rs5985 (Val34Leu) (Wells et al , ), influencing FXIII activity (Kohler et al , ; Wartiovaara et al , ); APOH rs8178847, associated with thrombin generation (Tang et al , ); genetic variations at the STAB 2 , STX2 and TC2N loci with suggestive impact on VTE risk (Germain et al , ; Morange et al , ; Smith et al , ; Desch et al , ) via their influence on VWF levels (Smith et al , ); and the rs4602861 (Germain et al , ; Klarin et al , ) at the ZFPM2 locus, whose suspected association with VTE could involve platelet count (Gieger et al , ) and vascular endothelial growth factor (Debette et al , ). Some of these associations, if true, could be restricted to some specific ethnic populations.…”

Assessment of the Procoagulant Activity of Microparticles and the Protein Z System in Patients Undergoing Off-Pump Coronary Artery Bypass Surgery

“…It forms a complex with the plasma protein Z-dependent protease inhibitor (ZPI) and inhibits activated factor X (Xa). 11 The results of a recent meta-analysis reported that low PZ levels are associated with an increased risk of thrombosis. 12 In this pilot study, we assessed whether OPCAB surgery has an impact on the procoagulant activity of MPs, MPs-TF, and the PZ system levels.…”

Deep sequencing of circulating miRNAs and target mRNAs level in deep venous thrombosis patients

“…It has been demonstrated that PRKCA is involved in atherosclerosis [ 19 ]. In addition, intron and synonymous variants of PRKCA gene is found in deep vein thrombosis [ 20 ]. Previous reports uncovered direct functional cooperation between SP1 and Kruppel like factor 6 (KLF6) in response to vascular injury [ 21 , 22 , 23 ].…”