Dataset Information

Prospective study of circulating factor XI and incident venous thromboembolism: The Longitudinal Investigation of Thromboembolism Etiology (LITE).

ABSTRACT: Elevated plasma concentrations of coagulation factor XI may increase risk of venous thromboembolism (VTE), but prospective data are limited. We studied prospectively the associations of plasma factor XI and a key F11 genetic variant with incident VTE in whites and African-Americans. We measured factor XI in 16,299 participants, initially free of VTE, in two prospective population cohorts. We also measured the F11 single nucleotide polymorphism rs4241824, which a genome-wide association study had linked to factor XI concentration. During follow-up, we identified 606 VTEs. The age, race, sex, and study-adjusted hazard ratio of VTE increased across factor XI quintiles (P?

SUBMITTER: Folsom AR

PROVIDER: S-EPMC4618026 | biostudies-literature | 2015 Nov

REPOSITORIES: biostudies-literature

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Prospective study of circulating factor XI and incident venous thromboembolism: The Longitudinal Investigation of Thromboembolism Etiology (LITE).

Folsom Aaron R AR Tang Weihong W Roetker Nicholas S NS Heckbert Susan R SR Cushman Mary M Pankow James S JS

American journal of hematology 20151101 11

Elevated plasma concentrations of coagulation factor XI may increase risk of venous thromboembolism (VTE), but prospective data are limited. We studied prospectively the associations of plasma factor XI and a key F11 genetic variant with incident VTE in whites and African-Americans. We measured factor XI in 16,299 participants, initially free of VTE, in two prospective population cohorts. We also measured the F11 single nucleotide polymorphism rs4241824, which a genome-wide association study had ...[more]

PMID: 26260105

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Project description:BackgroundVenous thromboembolism (VTE) is a life-threatening vascular event with environmental and genetic determinants. Recent VTE genome-wide association studies (GWAS) meta-analyses involved nearly 30 000 VTE cases and identified up to 40 genetic loci associated with VTE risk, including loci not previously suspected to play a role in hemostasis. The aim of our research was to expand discovery of new genetic loci associated with VTE by using cross-ancestry genomic resources.MethodsWe present new cross-ancestry meta-analyzed GWAS results involving up to 81 669 VTE cases from 30 studies, with replication of novel loci in independent populations and loci characterization through in silico genomic interrogations.ResultsIn our genetic discovery effort that included 55 330 participants with VTE (47 822 European, 6320 African, and 1188 Hispanic ancestry), we identified 48 novel associations, of which 34 were replicated after correction for multiple testing. In our combined discovery-replication analysis (81 669 VTE participants) and ancestry-stratified meta-analyses (European, African, and Hispanic), we identified another 44 novel associations, which are new candidate VTE-associated loci requiring replication. In total, across all GWAS meta-analyses, we identified 135 independent genomic loci significantly associated with VTE risk. A genetic risk score of the significantly associated loci in Europeans identified a 6-fold increase in risk for those in the top 1% of scores compared with those with average scores. We also identified 31 novel transcript associations in transcriptome-wide association studies and 8 novel candidate genes with protein quantitative-trait locus Mendelian randomization analyses. In silico interrogations of hemostasis and hematology traits and a large phenome-wide association analysis of the 135 GWAS loci provided insights to biological pathways contributing to VTE, with some loci contributing to VTE through well-characterized coagulation pathways and others providing new data on the role of hematology traits, particularly platelet function. Many of the replicated loci are outside of known or currently hypothesized pathways to thrombosis.ConclusionsOur cross-ancestry GWAS meta-analyses identified new loci associated with VTE. These findings highlight new pathways to thrombosis and provide novel molecules that may be useful in the development of improved antithrombosis treatments.

Dataset Information

Prospective study of circulating factor XI and incident venous thromboembolism: The Longitudinal Investigation of Thromboembolism Etiology (LITE).

Publications

Prospective study of circulating factor XI and incident venous thromboembolism: The Longitudinal Investigation of Thromboembolism Etiology (LITE).

Similar Datasets

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