Abstract
BackgroundHypoxia-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.MethodsAfter 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.ResultsFrequencies 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.ConclusionsGenetic variants in HIF-1α and PHD2 genes exist in Caucasians but do not appear to alter 30-day mortality in sepsis.
Highlights
Hypoxia-inducible-factor-1α (HIF-1α) and Hypoxia inducible factor-1α (HIF-1) degrading prolyl-hydroxylases (PHD) are key regulators of the hypoxic-inflammatory response
Functionally active genetic variants in the Hypoxia-Inducible Factor (HIF)-1α (C/T; Single Nucleotide Polymorphism (SNP) rs11549465) and the PHD2 gene (EGLN1; C/T; SNP rs516651 and T/C; SNP rs480902) were identified [3,4,5] and were associated with increased HIF-1α nuclear translocation and a worse outcome compared to the TTgenotype in several tumors [6]
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
Summary
Hypoxia-inducible-factor-1α (HIF-1α) and HIF-1 degrading prolyl-hydroxylases (PHD) are key regulators of the hypoxic-inflammatory response. 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. Hypoxia inducible factor-1α (HIF-1) and HIF-1 degrading prolyl-hydroxylases (PHD) are key regulators of the hypoxic response but are involved in many cellular actions [1]. 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) were identified [3,4,5] and were associated with increased HIF-1α nuclear translocation and a worse outcome compared to the TTgenotype in several tumors [6]. PHD deficiency is associated with an altered inflammatory response, i.e., suppressed cytokine expression in mice [11]
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