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4G/5G promoter polymorphism in the plasminogen-activator-inhibitor-1 gene in children with systemic meningococcaemia

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Abstract

Meningococcal disease may present as sepsis, meningitis or a combination of both. Impaired fibrinolysis and massive elevation of the plasminogen activator inhibitor-1 (PAI-1) is a characteristic feature of meningococcal sepsis. Previously, an association between mortality and the functional 4G/5G promoter polymorphism of the PAI-1gene in a cohort of UK and Dutch children with meningococcal sepsis was reported. We carried out a prospective, multicentre study to investigate the association of the 4G/5G PAI-1 polymorphism, diagnosis, and outcome in meningococcal disease in a Central European and UK population. Blood samples and clinical information of 347 previously healthy children with meningococcal infection were collected from 95 paediatric hospitals in Germany, Switzerland, Italy, the United Kingdom, and Austria from 2000 until 2002. Mortality was significantly associated with the 4G/4G genotype (12 of 90 (13%) vs. 15 of 240 (6%), P =0.037), resulting in an odds ratio of 2.31. The diagnosis of sepsis (independent of symptoms of meningitis) was significantly more frequent in carriers of the 4G/4G genotype (P =0.01), resulting in an odds ratio of 2.21 to develop sepsis. Meningitis was not associated with the PAI-1 4G/5G polymorphism, and allele frequencies were similar in patient and control groups. Conclusion:Our data show a correlation between the 4G/4G genotype in the plasminogen activator inhibitor-1 gene and poor outcome in children with meningococcal infection. In addition, 4G homozygous patients were prone to develop sepsis. We found no influence of the plasminogen activator inhibitor-1 polymorphism on the susceptibility to invasive meningococcal infection.

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Abbreviations

CEMR :

Central European Meningococcal Research

HWE :

Hardy-Weinberg equilibrium

PAI-1 :

plasminogen-activator-inhibitor-1

UKMR :

United Kingdom Meningococcal Research

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Acknowledgements

This study was supported by the Jubiläumsfond der Österreichischen Nationalbank, grants 8842 and 10112.

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Correspondence to Werner Zenz.

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Co-investigators of the Central European Meningococcal Study Group were: Bärbel Töpke (Ostalb-Klinikum, Aalen), Peter Fucik (Krankenhaus Amstetten, Amstetten), Johann M. Penzien (Zentralklinikum Kinderkliniken, Augsburg), Gedeon Diab (Kreiskrankenhaus Bad Hersfeld, Bad Hersfeld), Robert Miething (Diakonie-Krankenhaus, Bad Kreuznach), K.H. Deeg (Klinikum Bamberg, Bamberg), Jürg Hammer (Universitäts-Kinderspital beider Basel, Pädiatrische Intensivmedizin, Basel), Ulrich Heininger (Universitäts-Kinderspital beider Basel, Abt. für Infektiologie, Basel), Verena Varnholt (Uni-Klinikum Charité, Campus Virchow Klinikum, Berlin), Andreas Schmidt (St.-Agnes-Hospital, Bocholt), Lutz Bindl (Rheinische Friedrich-Wilhelms-Universität, Bonn), Ursula Sillaber (Landeskrankenhaus Bregenz, Abt. für Innere Medizin, Bregenz), Christian Huemer (Landeskrankenhaus Bregenz, Abt. für Kinderheilkunde, Bregenz), Primrose Meier (Zentralkrankenhaus Links d. Weser, Bremen), G. Simic-Schleicher (Zentralkrankenhaus Bremen-Nord, Bremen), Markus Markart (Ospedale di Bressanone, Brixen), Eberhard Pfau (DRK-Krankenhaus Chemnitz-Rabenstein, Chemnitz), Hans Broede (Klinikum Lippe-Detmold GmbH, Detmold), Bernd Ausserer (Krankenhaus Dornbirn, Dornbirn), Hermann Kalhoff (Städt. Kliniken Dortmund, Dortmund), Volker Arpe (St. Marien-Hospital Düren-Birkesdorf, Düren), Susanne Schweitzer-Krantz (Evangelisches Krankenhaus, Düsseldorf), Johannes-Martin Kasper (St. Georg Klinikum Eisenach GmbH, Eisenach), Kathrin Loranth (Krankenhaus der Barmherzigen Brüder, Eisenstadt), Hans J. Bittrich (Helios Klinikum Erfurt, Erfurt), Burkhard Simmer (Landeskrankenhaus Feldkirch, Feldkirch), Nicola Weigand (Klinikum Justus-Liebig-Universität, Gießen), Egbert Herting (Georg-August Universitäts-Kinderklinik, Göttingen), Karl-Heinz Smolle (Medizinische Universitätsklinik, Graz), Christoph Fusch (Klinikum d. Ernst-Moritz-Arndt-Universität, Greifswald), Alois Gruber (Krankenhaus der Schulschwestern Grieskirchen, Grieskirchen), Ulf Schimmel (Allg. Krankenhaus Hagen GmbH, Hagen), Suzanne Knaufer-Schiefer (Ohrekreis-Klinikum, Haldensleben), Wolfgang Lässig (Städt. Krankenhaus Martha-Maria Halle-Dölau GmbH, Halle), Axel Hennenberger (Kinderkrankenhaus Wilhelmstift, Hamburg), Axel von der Wense (Altonaer Kinderkrankenhaus, Hamburg), Roland Tillmann (Klinikum Kreis Herford, Herford), Jürgen Schwarick (Kreiskrankenhaus Herzberg, Herzberg), F.C. Sitzmann (Univ. Klinik für Kinder- und Jugendmedizin, Homburg/Saar), Herbert Müller (Klinik Robert-Weixler-Strasse, Kempten), Peter Kurnik (Landeskrankenhaus Klagenfurt, Klagenfurt), Peter Groneck (Kinderklinik der Stadt Köln, Köln), Helene Gröblacher-Roth (Landeskrankenhaus Krems a. d. Donau, Krems a.d. Donau), Jürgen Bensch (Vinzentius-Krankenhaus, Landau), Reinhard Moser (Landeskrankenhaus Leoben, Leoben), Rudolf Schwarz (Landes-Kinderklinik Linz, Linz), Kurt Lenz (Koventhospital der Barmherzigen Brüder, Linz), Thomas Hofmann (Evang. Krankenhaus, Lippstadt), Wolfgang Göpel (Med. Universität zu Lübeck, Lübeck), Thomas Berger (Kantonspital Luzern, Luzern), Erwin Hauser (Landeskrankenhaus Mödling, Mödling), Kai Martin Förster (Städt. Krankenhaus Harlaching, München), Jochen Peters (Kinderklinik der TU München, München), Thomas Nicolai (Klinikum Innenstadt v. Haunersches Kinderspital, München), Björn Kumlien (Kinderklinik des Dritten Ordens, München), Regina Beckmann (Dietrich-Bonhoeffer-Klinikum, Neubrandenburg), Christiane Seitz (FEK-Friedrich-Ebert-Krankenh. Neumünster GmbH, Neumünster), D. Hüseman (Ruppiner Kliniken GmbH, Neuruppin), Roland Schürmann (Städt. Kliniken Neuss Lukaskrankenhaus GmbH, Neuss), Van Hop Ta (Evang. Krankenhaus, Oberhausen), Eckart Weikmann (Landeskrankenhaus Oberwart, Oberwart), W. Evert (Städt. Kliniken Offenbach, Offenbach), Jürgen Hautz (Klinikum Offenburg, Offenburg), Jürgen Seidenberg (Elisabeth-Kinderkrankenhaus, Oldenburg), Lucia Wocko (Krankenhaus Oranienburg, Oranienburg), Petra Luigs (St.Vincenz-Krankenhaus Frauen-u. Kinderklinik, Paderborn), Hans-Ludwig Reiter (Klinik für Kinder und Jugendliche am Städtischen Klinikum, Pforzheim), J. Quietzach (Vogtland-Klinikum Plauen GmbH, Plauen), Michael König (Oberschwaben Klinik gGmbH, Ravensburg), Johanna Herrmann (Kreiskrankenhaus Rendsburg, Rendsburg), Horst Mitter (Krankenhaus der Barmh. Schwestern Ried, Ried i. Innkreis), Ekkehard Seidler (Kreiskrankenhaus Obergöltzsch-Rodewisch, Rodewisch), Bernhard Maak (Thüringen-Klinik “Georgius Agricola” GmbH, Saalfeld), Wolfgang Sperl (Landeskrankenanstalten Salzburg, Salzburg), Manfred Meissl (Landeskrankenhaus Schärding, Schärding), Reinhard Koch (Leopoldina-Krankenhaus, Schweinfurt), Manfred Cremer (DRK-Kinderklinik Siegen, Siegen), H.A. Breuer (Städt. Klinikum Solingen, Solingen), W. Görke (Johanniter Kinderklinik, Stendal), Robert Nossal (Olga Hospital Stuttgart, Stuttgart), Walter Pernice (Kreiskrankenhaus Torgau, Torgau), Hans R. Salzer (Landeskrankenhaus Tulln, Tulln), Hartmut Koch (St. Marien-Hospital, Vechta), Gerhard Schaller (Landeskrankenhaus Villach, Villach), Franz Paky (Landeskrankenhaus Vöcklabruck, Vöcklabruck), Friedrich Straßer (Klinikum Weiden, Weiden), Franz Eitelberger (Krankenhaus d. Barmh. Schwestern v. heiligen Kreuz, Wels), D. Sontheimer (Harz-Klinikum Wernigerode GmbH, Wernigerode), Andreas Lischka (Wilhelminenspital Wien, Wien), Alfred Dilch (Gottfried von Preyersches Kinderspital der Stadt Wien, Wien), Christian Scheibenpflug (Donauspital im SMZ-Ost der Stadt Wien, Wien), Robert Bruckner (Krankenhaus Wiener Neustadt, Wiener Neustadt), Klaus Runge (Zentrum für Kinder- und Jugendmedizin, Wuppertal), Wolfgang Kunze (Krankenhaus Muldentalkreis Wurzen, Wurzen), Peter Schermann (Krankenhaus Zwettl, Zwettl).

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Geishofer, G., Binder, A., Müller, M. et al. 4G/5G promoter polymorphism in the plasminogen-activator-inhibitor-1 gene in children with systemic meningococcaemia. Eur J Pediatr 164, 486–490 (2005). https://doi.org/10.1007/s00431-005-1673-4

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