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.
Highlights
Deep vein thrombosis (DVT) of the lower extremities has a strong genetic basis, with an estimated hereditary component of 60%, but established genetic risk factors for DVT explain only a fraction of disease heritability [1,2]
To assess the potential role of rare coding variants underlying genetic predisposition to venous thrombosis, we have recently developed and successfully applied targeted next-generation DNA sequencing-based (NGS) strategy and analysis of the coding area of 186 hemostatic and proinflammatory genes in Italian idiopathic DVT cases and controls
DVT cases were selected according to the following criteria: (i) objective diagnosis of DVT; (ii) Caucasian ethnicity born from Caucasian parent; (iii) absence of cancer or surgery associated with DVT; (iv) absence of natural anticoagulant deficiencies determined by natural levels of protein C, protein S and antithrombin in routine testing; (v) absence of factor V Leiden and prothrombin G20120A variants determined by sequencing; and (vi) signed informed consent
Summary
Deep vein thrombosis (DVT) of the lower extremities has a strong genetic basis, with an estimated hereditary component of 60%, but established genetic risk factors for DVT explain only a fraction of disease heritability [1,2]. Rs2232710 Variant and Deep Vein Thrombosis symposia and educational meetings organized by Bayer, Biotest, CSL Behring, Grifols, Novo Nordisk, and Sobi. The other authors do not have any conflict of interests to disclose. This does not alter the authors’ adherence to the PLOS ONE policies on sharing data and materials
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