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Targeted sequencing to identify novel genetic risk factors for deep vein thrombosis: a study of 734 genes.
Wednesday,2018-09-19 10:25 America/Los_Angeles — ecterry
| Title | Targeted sequencing to identify novel genetic risk factors for deep vein thrombosis: a study of 734 genes. |
| Publication Type | Journal Article |
| Year of Publication | 2018 |
| Authors | de Haan, HG, A Vlieg, vanHylckama, Lotta, LA, Gorski, MM, Bucciarelli, P, Martinelli, I, Baglin, TP, Peyvandi, F, Rosendaal, FR |
| Corporate/Institutional Authors | INVENT Consortium |
| Journal | J Thromb Haemost |
| Date Published | 2018 Aug 31 |
| ISSN | 1538-7836 |
| Abstract | <p><b>BACKGROUND: </b>Although several genetic risk factors for deep vein thrombosis (DVT) are known, almost all related to hemostasis, a large genetic component remains unexplained.</p><p><b>OBJECTIVES: </b>We aimed to identify novel genetic determinants using targeted DNA sequencing.</p><p><b>PATIENTS/METHODS: </b>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).</p><p><b>RESULTS: </b>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).</p><p><b>CONCLUSIONS: </b>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.</p> |
| DOI | 10.1111/jth.14279 |
| Alternate Journal | J. Thromb. Haemost. |
| PubMed ID | 30168256 |
ePub date:
18/08