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Genetic variation 25.1 Mb upstream of tissue factor pathway inhibitor is associated with TFPI plasma levels and venous thromboembolism
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International audience. BackgroundTissue factor pathway inhibitor (TFPI) regulates fibrin clot formation, and low TFPI plasma levels increase the risk of arterial and venous thromboembolism (VTE). TFPI plasma levels are also heritable, and a previous linkage scan implicated the chromosome 2q region, but no specific genes.ObjectivesWe sought to replicate the linkage region in an independent sample and to identify the causal locus. MethodsWe first ran a linkage analysis of microsatellite markers and TFPI plasma levels in 251 individuals from the F5L Family Study and replicated the linkage peak on chromosome 2q (LOD=3.06). We next defined a follow-up region that included 112603 SNPs under the linkage peak, and meta-analyzed associations between these SNPs and TFPI plasma levels across the F5L Family Study and MARTHA, a study of 1033 unrelated VTE patients. SNPs with FDR q<0.10 were tested for association with TFPI plasma levels in 892 patients with coronary artery disease in the AtheroGene study.Results and ConclusionsOne SNP, rs62187992, was associated with TFPI plasma levels in all three samples (β=+0.14 P=4.23x10-6 combined; β=+0.16, P=0.02 in F5L Family Study; β=+0.13, P=6.3x10-4 in MARTHA; β=+0.17, P=0.03 in AtheroGene) and contributed to the linkage peak in the F5L Family Study. rs62187992 was also associated with clinical VTE (odds ratio=0.90, P=0.03) in the INVENT consortium of over 7000 cases and their controls and was marginally associated with TFPI expression (β=+0.19, P=0.08) in human aortic endothelial cells, a primary site of TFPI synthesis. The biological mechanisms underlying these associations remain to be elucidated.
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