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Targeted sequencing to identify novel genetic risk factors for deep vein thrombosis: a study of 734 genes.

TitleTargeted sequencing to identify novel genetic risk factors for deep vein thrombosis: a study of 734 genes.
Publication TypeJournal Article
Year of Publication2018
Authorsde Haan HG, A Vlieg vanHylckama, Lotta LA, Gorski MM, Bucciarelli P, Martinelli I, Baglin TP, Peyvandi F
Secondary AuthorsRosendaal FR
Corporate AuthorsINVENT Consortium
JournalJ Thromb Haemost
Date Published2018 12
KeywordsAdult, Blood Coagulation, Case-Control Studies, Female, Gene Frequency, Genetic Association Studies, Genetic Predisposition to Disease, Humans, Male, Middle Aged, Phenotype, Polymorphism, Single Nucleotide, Risk Factors, Sequence Analysis, DNA, Venous Thrombosis

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 KLKB1 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 0.2). 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.

Alternate JournalJ Thromb Haemost
PubMed ID30168256
PubMed Central IDPMC6467059
Grant ListR01 HL059367 / HL / NHLBI NIH HHS / United States