title: Hypoxia inducible factor-1 alpha and prolinhydroxlase 2 polymorphisms in patients with severe sepsis: a prospective observational trial.
abstract: Hypoxia-inducible-factor-1α (HIF-1α) and HIF-1 degrading prolyl-hydroxylases (PHD) are key regulators of the hypoxic-inflammatory response. Functionally active genetic variants in the HIF-1α (C/T; Single Nucleotide Polymorphism (SNP) rs11549465) and the PHD2 gene (EGLN1; C/T; SNP rs516651 and T/C; SNP rs480902) are associated with altered HIF-1α mRNA nuclear translocation and an altered adaptation to hypoxia. Furthermore, the HIF system is important in surviving inflammatory disorders and sepsis. Thus, we tested the hypotheses, that SNPs in the HIF-1α or PHD2 genes are (1) common in Caucasians, with 2) the HIF-1α genetic variant being associated with an altered HIF-1α mRNA expression; and 3) independent risk factors for 30-day mortality in severe sepsis.
  
  
  
  After ethics approval, 128 septic patients (Caucasian descent) were included prospectively within 24 h after first diagnosing sepsis. Patients characteristics and severity of illness (simplified acute physiology score II), genotypes (Taqman assay), and their influence on leukocyte HIF-1α-mRNA-expression (Real-Time PCR) and 30-day mortality were determined.
  
  
  
  Frequencies were 0.8 % for homozygous HIF-1α TT-carriers (CT 17.6 %; CC 81.6 %), 2.5 % for homozygous PHD2 SNP rs516651 TT-allele carriers (CT 17.5 % and CC 80 %), and 9.4 % for homozygous PHD2 SNP rs480902 TT-allele carriers (CT 34.4 % and CC 56.3 %). While HIF-1α T-allele carriers had a borderline decrease in HIF-1α-mRNA-expression (p = 0.06) neither HIF-1α nor PHD2 SNPs were (independent) risk factors for 30-day mortality.
  
  
  
  Genetic variants in HIF-1α and PHD2 genes exist in Caucasians but do not appear to alter 30-day mortality in sepsis.
authors: Klinik für Anästhesiologie und Intensivmedizin, Universitätsklinikum Essen and Universität Duisburg-Essen, Hufelandstraße 55, D-45122, Essen, Germany.
authors: Annika
authors: A
authors: Höcker
authors: Klinik für Anästhesiologie und Intensivmedizin, Universitätsklinikum Essen and Universität Duisburg-Essen, Hufelandstraße 55, D-45122, Essen, Germany.
authors: Miriam
authors: M
authors: Rabeling
authors: Klinik für Anästhesiologie und Intensivmedizin, Universitätsklinikum Essen and Universität Duisburg-Essen, Hufelandstraße 55, D-45122, Essen, Germany.
authors: Alexandra
authors: A
authors: Bick
authors: Klinik für Anästhesiologie und Intensivmedizin, Universitätsklinikum Essen and Universität Duisburg-Essen, Hufelandstraße 55, D-45122, Essen, Germany.
authors: Linda
authors: L
authors: Cox
authors: Klinik für Anästhesiologie und Intensivmedizin, Universitätsklinikum Essen and Universität Duisburg-Essen, Hufelandstraße 55, D-45122, Essen, Germany.
authors: Maximiliane
authors: M
authors: Kreuzer
authors: Klinik für Anästhesiologie und Intensivmedizin, Universitätsklinikum Essen and Universität Duisburg-Essen, Hufelandstraße 55, D-45122, Essen, Germany.
authors: Andrea
authors: A
authors: Engler
authors: Klinik für Anästhesiologie und Intensivmedizin, Universitätsklinikum Essen and Universität Duisburg-Essen, Hufelandstraße 55, D-45122, Essen, Germany.
authors: Kai
authors: K
authors: Walstein
authors: Institut für Pharmakogenetik, Universitätsklinikum Essen and Universität Duisburg-Essen, Essen, Germany.
authors: Hagen S
authors: HS
authors: Bachmann
authors: Institut für Medizinische Informatik, Biometrie und Epidemiologie, Universitätsklinikum Essen and Universität Duisburg-Essen, Essen, Germany.
authors: Karl-Heinz
authors: KH
authors: Jöckel
authors: Institut für Medizinische Informatik, Biometrie und Epidemiologie, Universitätsklinikum Essen and Universität Duisburg-Essen, Essen, Germany.
authors: Lewin
authors: L
authors: Eisele
authors: Klinik für Anästhesiologie und Intensivmedizin, Universitätsklinikum Essen and Universität Duisburg-Essen, Hufelandstraße 55, D-45122, Essen, Germany.
authors: Michael
authors: M
authors: Adamzik
authors: Klinik für Anästhesiologie und Intensivmedizin, Universitätsklinikum Essen and Universität Duisburg-Essen, Hufelandstraße 55, D-45122, Essen, Germany.
authors: Jürgen
authors: J
authors: Peters
authors: Klinik für Anästhesiologie und Intensivmedizin, Universitätsklinikum Essen and Universität Duisburg-Essen, Hufelandstraße 55, D-45122, Essen, Germany. simon.schaefer@uk-essen.de.
authors: Simon T
authors: ST
authors: Schäfer
mesh_terms: D000368:Aged; D005260:Female; D014644:Genetic Variation; D005838:Genotype; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000235:genetics*; D064799:Hypoxia-Inducible Factor-Proline Dioxygenases / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide; D011446:Prospective Studies; D012333:RNA, Messenger / Q000378:metabolism; D060888:Real-Time Polymerase Chain Reaction; D012307:Risk Factors; D018805:Sepsis / Q000235:genetics / Q000401:mortality / Q000503:physiopathology*; D012720:Severity of Illness Index; D044465:White People / Q000235:genetics
chemical_list: D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D012333:RNA, Messenger; C490190:EGLN1 protein, human; D064799:Hypoxia-Inducible Factor-Proline Dioxygenases
keywords: Genetic variants; HIF; Hypoxia inducible factor; Polymorphism; Sepsis