title: A functional single nucleotide polymorphism in the thrombin-activatable fibrinolysis inhibitor (TAFI) gene associates with outcome of meningococcal disease.
abstract: In meningococcal sepsis, disseminated intravascular coagulation with deposition of fibrin and formation of microthrombi occurs in various organs and enhanced inhibition of fibrinolysis is associated with adverse outcome. Recently, TAFI (thrombin-activatable fibrinolysis inhibitor) was identified as a link between coagulation and fibrinolysis, as TAFI can be activated by thrombin and once activated potently attenuates fibrinolysis. On the basis of this one would predict that DNA polymorphisms that increase TAFI activity would deteriorate the outcome in meningococcal sepsis. Therefore, we studied the prevalence of the Thr325Ile dimorphism in the TAFI gene, which is associated with increased TAFIa stability and activity in 50 patients who survived meningococcal disease, in 176 first-degree relatives of a consecutive patient series with meningococcal disease and 212 controls from the same geographic region. The TAFI 325 Ile/Ile genotype was slightly more common among parents of patients with meningococcal disease than in controls (11% vs. 7.1%, P= 0.24). This difference was pronounced among the subgroup of parents of non-surviving patients (19.2%, P= 0.03). Patients whose parents were carriers of the TAFI 325 Ile/Ile genotype had a 1.6-fold (95% CI 0.7-3.7) higher risk to contract meningococcal disease and a 3.1-fold (95% CI 1.0-9.5) increased risk to die from the infection compared with all other genotypes. Survivors had a genotype frequency (4.0%) that was lower than in the general population. TAFI 325 variants affect the outcome of meningococcal disease.
authors.affiliation: Laboratory for Experimental Internal Medicine, Academic Medical Center, Amsterdam, The Netherlands.
authors.forename: J A
authors.initials: JA
authors.lastname: Kremer Hovinga
authors.forename: R F
authors.initials: RF
authors.lastname: Franco
authors.forename: M A
authors.initials: MA
authors.lastname: Zago
authors.forename: Hugo
authors.initials: H
authors.lastname: Ten Cate
authors.forename: R G J
authors.initials: RG
authors.lastname: Westendorp
authors.forename: P H
authors.initials: PH
authors.lastname: Reitsma
mesh_terms: D000483:Alleles; D001483:Base Sequence; D025901:Carboxypeptidase B2 / Q000235:genetics*; D016022:Case-Control Studies; D017931:DNA Primers / Q000235:genetics; D005260:Female; D005787:Gene Frequency; D005838:Genotype; D006801:Humans; D008297:Male; D008589:Meningococcal Infections / Q000201:enzymology* / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide
chemical_list: D017931:DNA Primers; D025901:Carboxypeptidase B2