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Essentials    Deep vein thrombosis (DVT) has a large unknown genetic component.  We sequenced coding areas of 734 hemostasis‐related genes in 899  DVT  patients and 599 controls.  Variants in  F5 ,  FGA‐FGG ,  CYP4V2 ‐ KLKB1 ‐ F11 , and  ABO  were associated with DVT risk.  Associations in   KLKB 1  and  F5  suggest a more complex genetic architecture than previously thought.Summary   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   CYP 4V2 –  KLKB 1 – 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   KLKB 1  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   MASP 1 , 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   CYP 4V2 –  KLKB 1 – F11 , and observed secondary signals in  F5  and   CYP 4V2 –  KLKB 1 – F11  that warrant replication and fine‐mapping in larger studies.

Targeted sequencing to identify novel genetic risk factors for deep vein thrombosis: a study of 734 genes