title: Genetic determinants of tissue factor pathway inhibitor plasma levels.
abstract: Tissue factor pathway inhibitor (TFPI) impedes early stages of the blood coagulation response, and low TFPI plasma levels increase the risk of thrombosis. TFPI plasma levels are heritable, but specific genetic determinants are unclear. We conducted a comprehensive review of genetic risk factors for TFPI plasma levels and identified 26 studies. We included 16 studies, as well as results from two unpublished genome-wide studies, in random effects meta-analyses of four commonly reported genetic variants in TFPI and its promoter (rs5940, rs7586970/rs8176592, rs10931292, and rs10153820) and 10 studies were summarised narratively. rs5940 was associated with all measures of TFPI (free, total, and activity), and rs7586970 was associated with total TFPI. Neither rs10931292 nor rs10153820 showed evidence of association. The narrative summary included 6 genes and genetic variants (P151L mutation in TFPI, PROS1, F5, APOE, GLA, and V617F mutation in JAK2) as well as a genome-wide linkage study, and suggested future research directions. A limitation of the systematic review was the heterogeneous measurement of TFPI. Nonetheless, our review found robust evidence that rs5940 and rs7586970 moderate TFPI plasma levels and are candidate risk factors for thrombosis, and that the regulation of TFPI plasma levels involves genetic factors beyond the TFPI gene.
authors: J
authors: J
authors: Dennis
authors: I
authors: I
authors: Kassam
authors: P-E
authors: PE
authors: Morange
authors: D-A
authors: DA
authors: Trégouët
authors: France Gagnon, MSc, PhD, Dalla Lana School of Public Health, University of Toronto, 155 College St., Toronto, ON M5T3M7, Canada, Tel.: +1 416 978 0130, E-mail: france.gagnon@utoronto.ca.
authors: F
authors: F
authors: Gagnon
mesh_terms: D001798:Blood Proteins / Q000235:genetics; D020022:Genetic Predisposition to Disease; D055106:Genome-Wide Association Study; D006801:Humans; D053614:Janus Kinase 2 / Q000235:genetics; D008074:Lipoproteins / Q000097:blood* / Q000235:genetics; D015201:Meta-Analysis as Topic; D009154:Mutation; D020641:Polymorphism, Single Nucleotide; D011401:Promoter Regions, Genetic / Q000235:genetics; D012307:Risk Factors; D019851:Thrombophilia / Q000097:blood / Q000235:genetics*; D000519:alpha-Galactosidase / Q000235:genetics
chemical_list: D001798:Blood Proteins; D008074:Lipoproteins; C051928:lipoprotein-associated coagulation inhibitor; C507924:JAK2 protein, human; D053614:Janus Kinase 2; C576330:GLA protein, human; D000519:alpha-Galactosidase
keywords: Coagulation; genetic; meta-analysis; systematic review; tissue factor pathway inhibitor