@article {7789, title = {Targeted sequencing to identify novel genetic risk factors for deep vein thrombosis: a study of 734 genes.}, journal = {J Thromb Haemost}, year = {2018}, month = {2018 Aug 31}, abstract = {

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.

}, issn = {1538-7836}, doi = {10.1111/jth.14279}, author = {de Haan, H G and van Hylckama Vlieg, A and Lotta, L A and Gorski, Marcin M and Bucciarelli, P and Martinelli, I and Baglin, T P and Peyvandi, F and Rosendaal, F R} }