Genetic studies in humans
Excellent overviews of the genes identified in population studies as selection targets for high-altitude adaptation is provided by Witt and Huerta-Sanchez (Witt & Huerta-Sanchez, 2019) and Bigham and Lee (Bigham & Lee, 2014; Brutsaert et al., 2019). The nominated genes for Tibetans and for Andeans are distinct but show some overlap. One might anticipate that each population would exhibit a different adaptive response reflecting differences in the genetic backgrounds of the original settler populations; any convergence on a common adaptation would serve to highlight its importance. In that context, genes encoding proteins in the hypoxia-inducible factor (HIF) signalling cascade dominate both lists and speak to the possibility that selection for adaptation to chronic hypoxia as opposed to some other environmental pressure has been most important in permitting survival at altitude (Bigham & Lee, 2014; Brutsaert et al., 2019).
The two genes most consistently identified in studies of Tibetans areEPAS1 and EGLN1 (Beall et al., 2010; Bigham et al., 2010; Peng et al., 2011; Simonson et al., 2010; Wang et al., 2011; Xu et al., 2011; Yi et al., 2010) (Figure 1). EPAS1 encodes HIF2α whileEGLN1 encodes PDH2. The strongest genotype-phenotype association has been the linkage of EPAS1 to lower haemoglobin concentrations (Beall et al., 2010; Yi et al., 2010), which given the contribution of blood vicosity to PVR can be seen as to contribute to cardio-pulmonary adaptation to hypoxia. An association between two EPAS1 variants (rs149594770 and rs73926265) and lower PAP measurements in Tibetans living at 4,700 m has been reported but the extent to which the lower haemoglobin levels account for this is not clear (Peng et al., 2017). The variants reported in EPAS1 are in non-coding space but, in support of reduced function, EPAS1 expression is reduced in endothelial cells derived from umbilical cords (Peng et al., 2017) and lymphocytes (Petousi et al., 2014) from Tibetan subjects.
EGLN1 is a candidate gene for selection in both Tibetans and Andeans, but only linked to haemoglobin levels in Tibetans (Bigham et al., 2013; Simonson et al., 2010; Xiang et al., 2013). Two non-synonymous coding variants are more common in Tibetans than Han Chinese, who are less well adapted to high altitude. The assumption is that these variants are associated with an increase in PHD2 activity. While EGLN1 transcript levels are not altered in lymphocytes of Tibetans at low altitude (Petousi et al., 2014), the PHD2 [Asp4Glu; Cys127Ser] variant enriched in Tibetans exhibits a lower Km for oxygen than wild-type PHD2 (Lorenzo et al., 2014).
Interestingly, another candidate gene for selection common to both Tibetans and Andeans is EDNRA , which encodes endothelin receptor type A, a validated drug target for the treatment of pulmonary hypertension. Neither have been phenotypically linked with pulmonary vascular phenotype in these indigenous populations. Other biologically plausible candidates for a role in the pulmonary vascular response to hypoxia common to both Tibetan and Andean studies include NOS1and NOS2 , IGFBP1 and IGFBP 2 , VEGFA andIL6 . That is not to say that other candidates identified, such asPPARA , encoding the nuclear peroxisome proliferator-activated receptor α (PPARα), PRKAA1 and BRINP3 are not relevant to pulmonary vascular homeostasis. But distinguishing their direct contribution, as opposed to adaptation through energy metabolism and muscle function (Horscroft et al., 2017), is important if any are to be exploited as pharmacological targets for pulmonary hypertension.