Journal
JOURNAL OF THROMBOSIS AND HAEMOSTASIS
Volume 16, Issue 12, Pages 2432-2441Publisher
WILEY
DOI: 10.1111/jth.14279
Keywords
deep vein thrombosis; DNA sequencing; genetics; risk factors; single-nucleotide polymorphisms
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Funding
- Netherlands Heart Foundation [NHS98.113, NHS208B086]
- Dutch Cancer Foundation [RUL 99/1992]
- Netherlands Organization for Scientific Research [916.56.157, 912-03-033vertical bar2003]
- Fondazione Cariplo [2011-0524]
- Italian Ministry of Health [RF-2009-1530493]
- NATIONAL HEART, LUNG, AND BLOOD INSTITUTE [R01HL059367] Funding Source: NIH RePORTER
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Background Although several genetic risk factors for deep vein thrombosis (DVT) are known, almost all related to hemostasis, a large genetic component remains unexplained. Objectives To identify novel genetic determinants by using targeted DNA sequencing. Patients/Methods We included 899 DVT patients and 599 controls from three case-control studies (DVT-Milan, Multiple Environmental and Genetic Assessment of risk factors for venous thrombosis [MEGA], and the Thrombophilia, Hypercoagulability and Environmental Risks in Venous Thromboembolism [THE-VTE] study) for sequencing of the coding regions of 734 genes involved in hemostasis or related pathways. We performed single-variant association tests for common variants (minor allele frequency [MAF] >= 1%) and gene-based tests for rare variants (MAF <= 1%), accounting for multiple testing by use of the false discovery rate (FDR). Results Sixty-two of 3617 common variants were associated with DVT risk (FDR < 0.10). Most of these mapped to F5,ABO,FGA-FGG, and CYP4V2-KLKB1-F11. The lead variant at F5 was rs6672595 (odds ratio [OR] 1.58, 95% confidence interval [CI] 1.29-1.92), in moderate linkage with the known variant rs4524. Reciprocal conditional analyses suggested that intronic variation might drive this association. We also observed a secondary association at the F11 region: missense KLKB1 variant rs3733402 remained associated conditional on known variants rs2039614 and rs2289252 (OR 1.36, 95% CI 1.10-1.69). Two novel variant associations were observed, in CBS and MASP1, but these were not replicated in the meta-analysis data from the International Network against Thrombosis (INVENT) consortium. There was no support for a burden of rare variants contributing to DVT risk (FDR > 0.2). Conclusions We confirmed associations between DVT and common variants in F5,ABO,FGA-FGG, and CYP4V2-KLKB1-F11, and observed secondary signals in F5 and CYP4V2-KLKB1-F11 that warrant replication and fine-mapping in larger studies.
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