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Dötsch, Annika; Eisele, Lewin; Rabeling, Miriam; Rump, Katharina; Walstein, Kai; Bick, Alexandra; Cox, Linda; Engler, Andrea; Bachmann, Hagen S.; Jöckel, Karl-Heinz; Adamzik, Michael; Peters, Jüergen; Schäfer, Simon T. (2017): Hypoxia Inducible Factor-2Alpha and Prolinhydroxylase 2 Polymorphisms in Patients with Acute Respiratory Distress Syndrome (ARDS). In: International Journal of Molecular Sciences, Vol. 18, Nr. 6, 1266
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Abstract

Hypoxia-inducible-factor-2 alpha (HIF-2 alpha) 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-2 alpha (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-2 alpha 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-2 alpha-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-2 alpha 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-2 alpha 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.