Oxidative stress at high altitude: genotype–phenotype correlations

Abstract

It has been well-documented that the hypobaric hypoxic environment at high altitude (HA) causes stress to both the permanent residents of HA and the sojourners. This oxidative stress primarily disturbs the oxygen-sensing and vascular homeostasis pathways, thereby upsetting normal human physiology, especially in sojourners. These environmental challenges have caused dynamic evolutionary changes within natives of HA, allowing them to develop adaptive plasticity. This review focuses on the genomic and biochemical features of the molecules involved in the oxygen-sensing and vascular homeostasis pathways with respect to HA pulmonary edema (HAPE) and adaptation. We review the role of genetic markers such as HIF-prolyl hydroxylase 2, endothelial PAS domain-containing protein 1, endothelial nitric oxide synthase, endothelin 1, cytochrome b-245 alpha polypeptide, and glutathione S-transferase pi 1, as well as three circulatory biomarkers (nitric oxide, endothelin 1, and 8-iso-prostaglandin F2α), by highlighting approaches such as candidate gene and genome-wide, adopted in deciphering the pathways. A disagreement between the two approaches has also been highlighted. In addition, we discuss that an overrepresentation of wild-type alleles in HA natives and mutant alleles of same polymorphisms in HAPE patients implies that the allelic variants at the same locus are involved in adaptation and HAPE, respectively. Moreover, healthy sojourners present a number of genomic features similar to HA natives, further strengthening the concept of genetic predisposition. A trend in correlation between protective and risk alleles and altered levels of circulatory markers clearly documents the phenomenon of genotype-phenotype correlations. We conclude that the genetic and biochemical markers discussed here both could prove to be potential targets for future diagnostic and therapeutic interventions.

Oxygen in Metabolic Dysfunction and Its Therapeutic Relevance

“…In this respect, some of the genetic variants that could contribute to human adaptation to altitude are linked to hypoxic adaptation (159), while others are related to the antioxidant system and lung function (397). Antioxidant adaptation is needed as hypobaric hypoxia is known to induce oxidative stress, which in turn contributes to endothelial damage and vascular remodeling (291). It is emphasized that we should be cautious in generalizing the effects on highlanders to populations living at moderate to high altitudes.…”