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Int. J. Mol. Sci. 2017, 18(6), 1266; doi:10.3390/ijms18061266

Hypoxia Inducible Factor-2 Alpha and Prolinhydroxylase 2 Polymorphisms in Patients with Acute Respiratory Distress Syndrome (ARDS)

1
Klinik für Anästhesiologie und Intensivmedizin, Universitätsklinikum Essen, Hufelandstraße 55, D-45122 Essen, Germany
2
Institut für Medizinische Informatik, Biometrie und Epidemiologie, D-45122 Essen, Germany
3
Institut für Pharmakogenetik, Universitätsklinikum Essen and Universität Duisburg-Essen, D-45122 Essen, Germany
4
Klinik für Anästhesiologie, Intensivmedizin und Schmerztherapie; Universitätsklinikum, Knappschaftskrankenhaus Bochum and Ruhruniversität Bochum, In der Schornau 23-25, D-44892 Bochum, Germany
5
Klinik für Anaesthesiologie, Ludwig-Maximilians-Universität München, Marchioninistrasse 15, D-81377 München, Germany
*
Author to whom correspondence should be addressed.
Received: 12 May 2017 / Revised: 7 June 2017 / Accepted: 8 June 2017 / Published: 14 June 2017
(This article belongs to the Special Issue Sepsis)
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Abstract

Hypoxia-inducible-factor-2α (HIF-2α) and HIF-2 degrading prolyl-hydroxylases (PHD) are key regulators of adaptive hypoxic responses i.e., in acute respiratory distress syndrome (ARDS). Specifically, functionally active genetic variants of HIF-2α (single nucleotide polymorphism (SNP) [ch2:46441523(hg18)]) and PHD2 (C/T; SNP rs516651 and T/C; SNP rs480902) are associated with improved adaptation to hypoxia i.e., in high-altitude residents. However, little is known about these SNPs’ prevalence in Caucasians and impact on ARDS-outcome. Thus, we tested the hypotheses that in Caucasian ARDS patients SNPs in HIF-2α or PHD2 genes are (1) common, and (2) independent risk factors for 30-day mortality. After ethics-committee approval, 272 ARDS patients were prospectively included, genotyped for PHD2 (Taqman SNP Genotyping Assay) and HIF-2α-polymorphism (restriction digest + agarose-gel visualization), and genotype dependent 30-day mortality was analyzed using Kaplan-Meier-plots and multivariate Cox-regression analyses. Frequencies were 99.62% for homozygous HIF-2α CC-carriers (CG: 0.38%; GG: 0%), 2.3% for homozygous PHD2 SNP rs516651 TT-carriers (CT: 18.9%; CC: 78.8%), and 3.7% for homozygous PHD2 SNP rs480902 TT-carriers (CT: 43.9%; CC: 52.4%). PHD2 rs516651 TT-genotype in ARDS was independently associated with a 3.34 times greater mortality risk (OR 3.34, CI 1.09–10.22; p = 0.034) within 30-days, whereas the other SNPs had no significant impact (p = ns). The homozygous HIF-2α GG-genotype was not present in our Caucasian ARDS cohort; however PHD2 SNPs exist in Caucasians, and PHD2 rs516651 TT-genotype was associated with an increased 30-day mortality suggesting a relevance for adaptive responses in ARDS. View Full-Text
Keywords: acute respiratory distress syndrome; hypoxia inducible factors; prolylhydroxylases; genetic variants; polymorphism acute respiratory distress syndrome; hypoxia inducible factors; prolylhydroxylases; genetic variants; polymorphism
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MDPI and ACS Style

Dötsch, A.; Eisele, L.; Rabeling, M.; Rump, K.; Walstein, K.; Bick, A.; Cox, L.; Engler, A.; Bachmann, H.S.; Jöckel, K.-H.; Adamzik, M.; Peters, J.; Schäfer, S.T. Hypoxia Inducible Factor-2 Alpha and Prolinhydroxylase 2 Polymorphisms in Patients with Acute Respiratory Distress Syndrome (ARDS). Int. J. Mol. Sci. 2017, 18, 1266.

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