Variants of the Low Oxygen Sensors EGLN1 and HIF-1AN Associated with Acute Mountain Sickness

Abstract

Two low oxygen sensors, Egl nine homolog 1 (EGLN1) and hypoxia-inducible factor 1-α inhibitor (HIF-1AN), play pivotal roles in the regulation of HIF-1α, and high altitude adaption may be involved in the pathology of acute mountain sickness (AMS). Here, we aimed to analyze single nucleotide polymorphisms (SNPs) in the untranslated regions of the EGLN1 and HIF-1AN genes and SNPs chosen from a genome-wide adaptation study of the Han Chinese population. To assess the association between EGLN1 and HIF-1AN SNPs and AMS in a Han Chinese population, a case–control study was performed including 190 patients and 190 controls. In total, thirteen SNPs were genotyped using the MassARRAY® MALDI-TOF system. Multiple genetic models were tested; The Akaike’s information criterion (AIC) and Bayesian information criterion (BIC) values indicated that the dominant model may serve as the best-fit model for rs12406290 and rs2153364 of significant difference. However, these data were not significant after Bonferroni correction. No significant association was noted between AMS and rs12757362, rs1339894, rs1361384, rs2009873, rs2739513 or rs2486729 before and after Bonferroni correction. Further haplotype analyses indicated the presence of two blocks in EGLN1; one block consists of rs12406290-rs2153364, located upstream of the EGLN1 gene. Carriers of the “GG” haplotype of rs12406290-rs2153364 exhibited an increased risk of AMS after adjustments for age and smoking status. However, no significant association was observed among HIF-1AN 3'-untranslated region (3'-UTR) polymorphisms, haplotype and AMS. Our study indicates that variants in the EGLN1 5'-UTR influence the susceptibility to AMS in a Han Chinese population.

In search for better pharmacological prophylaxis for acute mountain sickness: looking in other directions

“…Further analyses suggested that the rs12406290–rs2153364 haplotype is linked to AMS+ (Zhang et al . ). We propose that pharmacological means to stabilize PHDs and FIH in hypoxia might be an interesting alternative way for inhibiting the HIF pathway, and thus perhaps prevent the symptoms of AMS, keeping in mind the same cautionary remark made for direct HIF‐1 repression.…”

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

“…Of note, there is a high interindividual variability in expression of HIF and HIF target genes following inflammatory or hypoxic stimuli, which at least partially can be explained by genetic variants like single nucleotid polymorphisms. 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].…”

Association of EPAS1 and PPARA Gene Polymorphisms with High-Altitude Headache in Chinese Han Population

“…e inhibition of PPARα function may increase organs' susceptibility to oxidative damage [31,32]. Furthermore, HIF1A, HIF1AN, and EGLN1 participate in oxidative stress and the occurrence of metabolic diseases through HIF mediated transcriptional regulatory mechanism [21,[33][34][35]. So, we propose our hypothesis that associations may exist between HIF-related genetic factors and the susceptibility or resistance to HAH in the Chinese Han population.…”

“…Genotyping. We selected 35 SNPs in EPAS1, HIF1A, HIF1AN, EGLN1, and PPARA from the dbSNP database (http://www.ncbi.nlm.nih.gov/projects/ SNP/), and several of them had been reported to be associated with high-altitude illness or hypoxia in previous literatures [29,30,33]. SNPs that participated in adaptability adjustment of hypoxia located in noncoding regions more frequently than in coding regions, so we chose SNPs from introns, 3′ or 5′ untranslated regions, and upstream or downstream region of target genes.…”