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Targeted sequencing to identify novel genetic risk factors for deep vein thrombosis: a study of 734 genes
Author(s) -
Haan H. G.,
Hylckama Vlieg A.,
Lotta L. A.,
Gorski M. M.,
Bucciarelli P.,
Martinelli I.,
Baglin T. P.,
Peyvandi F.,
Rosendaal F. R.
Publication year - 2018
Publication title -
journal of thrombosis and haemostasis
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.947
H-Index - 178
eISSN - 1538-7836
pISSN - 1538-7933
DOI - 10.1111/jth.14279
Subject(s) - odds ratio , medicine , venous thrombosis , thrombophilia , abo blood group system , thrombosis , deep vein , hemostasis , genetics , biology
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.