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

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.

Mechanisms of Pulmonary Hypertension in Acute Respiratory Distress Syndrome (ARDS)

“…This duality is perhaps best highlighted by studies that determined the prevalence of HIF2A and PHD2 polymorphisms that are associated with improved adaptation to hypoxia in high-altitude residents in patients with ARDS. This study demonstrated that the PHD2 polymorphism PHD2 RS516651-TT , which is associated with increased adaptation to high altitude, was associated with a higher 30-days mortality risk within 30 days of the onset of ARDS (Dötsch et al, 2017 ).…”

Hypoxic-Inflammatory Responses under Acute Hypoxia: In Vitro Experiments and Prospective Observational Expedition Trial

“…In this context, we have previously shown that additionally to the extent of hypoxic or inflammatory stimuli or their duration, genetic variants in HIF-1, HIF-2, and HIF-degrading PHD-2 alter human adaptation to hypoxia [15][16][17][18][19]. High altitude residents thus have blunted hypoxic ventilatory response and diminished pulmonary hypertension under hypoxia [20,21], increased heart rate, improved peripheral oxygen saturation, and reduced incidence of mountain sickness, as assessed using the Lake Louise Score (LLS) [15,16,[22][23][24]. LLS, which has recently been revised, is a well-established tool to evaluate the severity of acute mountain sickness (AMS) [25,26].…”

Genomics and the Acute Respiratory Distress Syndrome: Current and Future Directions

“…In this context, Dötsch and colleagues observed that a variant of the Egl-9 family hypoxia inducible factor 1 ( EGLN1 ) gene was independently associated with greater ARDS mortality risk within 30-days in Europeans [36]. EGLN1 and the hypoxia inducible factor degrading prolyl-hydroxylases (PHD) are key regulators of the human response to a low oxygen environment, which provide a link between tissue hypoxia and the inflammatory response [46].…”

“…EGLN1 and the hypoxia inducible factor degrading prolyl-hydroxylases (PHD) are key regulators of the human response to a low oxygen environment, which provide a link between tissue hypoxia and the inflammatory response [46]. Despite the biological plausibility, further studies should be carried out to assess the functional impact of the genotype in EGLN1 in the mechanisms leading to ARDS [36]. Consonant to the fact that pulmonary fibrosis develops during the intermediate or late stages of ARDS, another study [37] reported the association of the strongest common risk gene variant for idiopathic pulmonary fibrosis (IPF) known to date [47] with ARDS susceptibility.…”