02601nas a2200229 4500008004100000022001400041245011100055210006900166260001600235520189100251100001802142700002502160700001602185700002202201700001902223700001802242700001702260700001602277700002002293710002202313856003602335 2018 eng d a1538-783600aTargeted sequencing to identify novel genetic risk factors for deep vein thrombosis: a study of 734 genes.0 aTargeted sequencing to identify novel genetic risk factors for d c2018 Aug 313 a

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.

1 ade Haan, H, G1 aVlieg, van, Hylckama1 aLotta, L, A1 aGorski, Marcin, M1 aBucciarelli, P1 aMartinelli, I1 aBaglin, T, P1 aPeyvandi, F1 aRosendaal, F, R1 aINVENT Consortium uhttps://chs-nhlbi.org/node/7789