High Altitude and Pre-Eclampsia

Human adaptation to hypoxia is an evolutionary change, evidenced by genetic modifications seen in certain populations such as Tibet in Asia, the Andes of the Americas, and Ethiopia in Africa, who thrive at extremely high altitudes. This is done by a process of natural selection, in which those who possess a higher degree of genetic variability are at an advantage over those with limited variability. There was a study that showed statistically similar genotypic and allelic frequencies in sea-level sojourners who undergo acclimatization on the ascent to high altitude and the adapted high altitude natives, particularly in the variants of the genes EDN1 (endothelin 1), ADRB2 (beta-2 adrenergic receptor, surface), ADRB3 (beta-3 adrenergic receptor), eNOS (nitric oxide synthase, endothelial), SCNN1B (sodium channel, non-voltage gated 1 beta subunit), TH (tyrosine hydroxylase) and VEGF (vascular endothelial growth factor) (Tomar et al. 2015).

Pre-eclampsia is the leading worldwide cause of maternal and fetal morbidity and mortality. However, in spite of extensive research, an exact etiology of pre-eclampsia is unknown. The thought is that there may be insufficient adaptation of spiral arterioles or shallow trophoblastic invasion, resulting in reduced uteroplacental blood flow leading to placental hypoxia. In other words, hypoxia may be a contributing factor to pre-eclampsia. This is shown by higher incidences of pre-eclampsia happening in areas of high altitude, along with higher risks of reproductive loss, intrauterine growth restriction, and other pregnancy complications (Zamudio 2007). Therefore, the main question to ask is, can a hypoxia-induced disorder like pre-eclampsia overcome the scarce microenvironment of oxygen deprivation by “acclimatization,” as a rapid form of adaptation?

A study conducted in 2017 evaluated more than 40 genes that are known to be associated with hypoxia for their genetic variability. A total of 36 RNA-seq samples from the amniotic fluid were retrieved from the NCBI. It involved samples of 19 pre-eclamptic preterm births while the controls were from 17 full-term births. The study revealed that the genes that are well-known to be associated with adaptation to high altitude had almost three times higher genetic variability in cases compared to control. In particular, EPAS1 gene showed the highest number of variants, followed by ADAM9 and EGLN1. This suggests there is higher selective pressure on the deprived cells of preeclampsia that leads to a high degree of genetic variability, which reflects their potency to survive the hypoxic microenvironment (Figure 1 and Figure 2).

Furthermore, while cases of preeclampsia were more hypoxic and had the highest number of hypoxic variants, they still had a lower number of adaptive variants (Table 2). This suggests the role of adaptive variants in relieving hypoxic pressure. Interestingly, there was a kind of reciprocal relation between the number of acclimatized variants and the number of hypoxic variants. In the controls, a higher number of acclimatized variants relieved the high pressure and thus resulted in a lower number of hypoxic variants, whereas in preeclamptic cases, the high number of hypoxic variants existed indicating for persistent signal of high selective pressure.

In summary, our human bodies have an incredible ability to shuffle their genes to win newer and better physiological characteristics in extreme conditions such as high altitude and pre-eclampsia. Samples indicate that those who were pre-eclamptic and therefore in hypoxic states, had higher genetic variability than those with normal pregnancies. This shows that the genes strive to alter and change to better fit their environmental conditions driven by the high selective pressure. Although more studies are required to fully understand the mechanisms of genetic variants in high altitude and preeclampsia, identifying these variants can pave the way to new treatment strategies that can help the body to better overcome challenging situations.

References

Ahmed, S. I., Ibrahim, M. E., & Khalil, E. A. (2017). High altitude and pre-eclampsia: Adaptation or protection. Medical Hypotheses, 104, 128-132. doi:10.1016/j.mehy.2017.05.007

Tomar, A., Malhotra, S., & Sarkar, S. (2015). Polymorphism profiling of nine high altitude relevant candidate gene loci in acclimatized sojourners and adapted natives. BMC Genetics, 16(1). doi:10.1186/s12863-015-0268-y

Zamudio, S. (2007). High-altitude hypoxia and preeclampsia. Frontiers in Bioscience, 12(8-12), 2967. doi:10.2741/2286

Esther Kwag is a second-year Physician Assistant student at the Red Rocks Community College, Colorado. Esther was born in Seoul, South Korea and spent her elementary years there until she moved to Colorado and has been living here since. She graduated from the University of Colorado with B.S. Biology with Cum Laude in 2017. Prior to PA school, she worked as a CNA at a physical rehabilitation facility working primarily with post-operative patients who underwent orthopedic surgeries. Interacting with patients and advocating for healthier lifestyle motivated Esther to further pursue her education in medicine. In her free time, she enjoys spending time with family and friends, reading books, and travelling.

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