%0 Journal Article %J J Thromb Haemost %D 2018 %T Targeted sequencing to identify novel genetic risk factors for deep vein thrombosis: a study of 734 genes. %A de Haan, H G %A van Hylckama Vlieg, A %A Lotta, L A %A Gorski, Marcin M %A Bucciarelli, P %A Martinelli, I %A Baglin, T P %A Peyvandi, F %A Rosendaal, F R %X

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: We aimed to identify novel genetic determinants using targeted DNA sequencing.

PATIENTS/METHODS: We included 899 DVT patients and 599 controls from three case-control studies (DVT-Milan, MEGA, and THE-VTE) 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 the false discovery rate (FDR).

RESULTS: Sixty-two out of 3,617 common variants were associated with DVT risk (FDR<0.10). Most of these mapped to F5, ABO, FGA-FGG, and CYP4V2-KLKB1-F11. Lead variant at F5 was rs6672595 (odds ratio [OR] 1.58, 95% confidence interval [CI] 1.29-1.92), in moderate linkage with 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 did not replicate in the meta-analysis data from the 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. This article is protected by copyright. All rights reserved.

%B J Thromb Haemost %8 2018 Aug 31 %G eng %R 10.1111/jth.14279