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Protein C promoter polymorphisms associate with sepsis in children with systemic meningococcemia

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Abstract

Meningococcal disease may present as sepsis, meningitis or a combination of both. Protein C (PC) is an important regulator of thrombin activity. Two polymorphisms in the promoter region of PC (C-1654T, A-1641G) have been shown to affect PC levels. In patients with meningococcal sepsis, low PC levels have been correlated with increased severity and poor outcome. We established a multicenter case–control study to determine whether PC promoter polymorphisms are associated with occurrence and outcome of meningococcal disease and sepsis. 288 previously healthy children with meningococcal infection from 97 pediatric hospitals in Germany, Switzerland, Italy, and Austria and 309 healthy controls were included in the study. A strong age-dependant effect was found. Patients younger than 1 year carried significantly more often the CG–CG genotype than healthy controls (28.6% vs. 17.8%, P = 0.04). Carriers of the CG allele showed a 3.43-fold increased odds ratio (OR) to develop sepsis (95% CI: 1.05–11.20; 85.7% vs. 63.6%, P = 0.036). The TA–TA genotype conferred a protective role for the development of sepsis (P = 0.017) with a Haldane OR of 0.09 (95% CI: 0.01–0.94). Systolic blood pressure values were significantly decreased in patients carrying the CG–CG genotype (70 vs. 86 mmHg, P = 0.005), and the need for adrenergic support significantly higher (70% vs. 26%, P = 0.018), resulting in an OR of 6.61 (95% CI: 1.28–34.14). These findings show that in young children PC promoter genotype is associated with susceptibility for meningococcal disease, the development of meningococcal sepsis, lower blood pressure, and need for adrenergic support.

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Abbreviations

PC:

Protein C

APC:

Activated protein C

CSF:

Cerebrospinal fluid

HWE:

Hardy–Weinberg equilibrium

CEMR:

Central European Meningococcal Research

SBP:

Systolic blood pressure

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Authors and Affiliations

  1. Department of General Pediatrics, Medical University of Graz, Auenbruggerplatz 30, 8036, Graz, Austria

    Alexander Binder, Gotho Geishofer & Werner Zenz

  2. Clinical Institute of Medical and Chemical Laboratory Diagnostics, Medical University Vienna, Vienna, Austria

    Georg Endler, Sandra Rieger & Christine Mannhalter

  3. Department of Neonatology, Medical University of Graz, Graz, Austria

    Bernhard Resch

Authors
  1. Alexander Binder
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  2. Georg Endler
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  3. Sandra Rieger
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  4. Gotho Geishofer
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  5. Bernhard Resch
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  6. Christine Mannhalter
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  7. Werner Zenz
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Consortia

for the Central European Meningococcal Genetic Study Group

Corresponding author

Correspondence to Werner Zenz.

Additional information

Funding Sources: This study was supported by the Jubiläumsfond der Österreichischen Nationalbank, grant 8842 and 10112.

Additional Investigators Participating in the Central European Meningococcal Study Group

Additional Investigators Participating in the Central European Meningococcal Study Group

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

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Binder, A., Endler, G., Rieger, S. et al. Protein C promoter polymorphisms associate with sepsis in children with systemic meningococcemia. Hum Genet 122, 183–190 (2007). https://doi.org/10.1007/s00439-007-0392-5

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