Kaleb Barker

Background: An individual’s response after rapid ascent to high altitude (HA) depends on external factors (ascent rate, metabolic demands, environmental factors) and the individual’s physiology (genetics, underlying etiologies, hydration, nutrition)^1,2. Given this multifaceted etiology, predicting an individual’s response to HA prior to ascent remains challenging¹. Quantifying susceptibility to acute mountain sickness (AMS) based on genetic factors shows promise. Various genes involved in the hypoxia-inducible factor (HIF) pathways may be useful in assessing individual risk and treatment selection for AMS. Potential targets include HIF hydroxylases (PHDs, FIH), HIF2α, VEGF, and their respective genes.

Methods: A PubMed search included terms such as “acute mountain sickness,” “altitude sickness,” “acclimatization,” “hypoxia-inducible factors,” and “high-altitude hypoxia.” Results were limited to within ten years.

Results: There is a wide assortment of studies showing the promise of these four elements in the HIF pathway as potential screening/therapeutic targets. One study showed that EGLN1 (PHDs) and HIF1AN (FIH) expression was upregulated in patients with AMS symptoms upon exposure to HA. Seven risk alleles for EGLN1, three risk alleles for HIF1AN, and two protective alleles for HIF1AN were identified³. A study in mice showed that inactivation of HIF2α (EPAS1) strongly impaired ventilatory acclimatization to hypoxia and carotid body growth over a seven day period, and concludes that the PHD/HIF2α axis is the strongest arbiter of hypoxic ventilatory response⁴. Another study showed that an EPAS1 (HIF2α) transcription factor SNP was associated with gastrointestinal symptoms upon rapid exposure to HA, and identified one protective allele. The same study showed that a VEGFA (transcribes VEGF) transcription factor SNP was associated with headache upon rapid exposure to HA, and identified one risk allele⁵. A separate study showed that HA Sherpas showed a blunted VEGF-A response to hypoxia compared to non-Sherpa lowlanders, which was correlated with three unique SNPs in the promoter region of VEGFA⁶. Numerous studies provide similar evidence in additional human and animal populations.

Conclusions: There is ample evidence of the significance of the HIF pathway in AMS. Screening for protective/risk SNPs in these four pathway genes could help predict responses to HA prior to ascent. Additionally, interventions that target an individual’s risk allele pathways could provide individualized treatment. A blended approach is likely the most effective, but further investigation is needed⁷. Broader applications possibly include inhibition of cancer cell growth and treatment of diseases that impact blood oxygen levels (eg. anemia, COPD, heart failure).

Works Cited:

1.  West JB, Luks AM. Respiratory System Under Stress. In: West’s Respiratory Physiology: The Essentials. 11th ed. Wolters Kluwer; 2021:172-179.
2. Sharma V, Varshney RK, Sethy NK. Human adaptation to high altitude: a review of convergence between genomic and proteomic signatures. Human Genomics. 2022;16(1). doi:10.1186/s40246-022-00395-y
3. Sharma K, Mishra A, Singh HN, et al. High-altitude pulmonary edema is aggravated by risk loci and associated transcription factors in HIF-prolyl hydroxylases. Human Molecular Genetics. 2021;30(18):1734-1749. doi:10.1093/hmg/ddab139
4. Hodson EJ, Nicholls LG, Turner PJ, et al. Regulation of ventilatory sensitivity and carotid body proliferation in hypoxia by the PHD2/HIF‐2 pathway. The Journal of Physiology. 2015;594(5):1179-1195. doi:10.1113/jp271050
5. Zhang J, Shen Y, Liu C, et al. EPAS1 and VEGFA gene variants are related to the symptoms of acute mountain sickness in Chinese Han population: a cross-sectional study. Military Medical Research. 2020;7(1). doi:10.1186/s40779-020-00264-6
6. Droma Y, Hanaoka M, Kinjo T, et al. The blunted vascular endothelial growth factor-A (VEGF-A) response to high-altitude hypoxia and genetic variants in the promoter region of the VEGFA gene in Sherpa highlanders. PeerJ. 2022;10:e13893. Published 2022 Aug 17. doi:10.7717/peerj.13893
7. Chan MC, Ilott NE, Schödel J, et al. Tuning the transcriptional response to hypoxia by inhibiting hypoxia-inducible factor (HIF) prolyl and asparaginyl hydroxylases. Journal of Biological Chemistry. 2016;291(39):20661-20673. doi:10.1074/jbc.m116.749291