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With over 14 million people living above 3,500 m, the study of acclimatization and adaptation to high altitude in human populations is of increasing importance, where exposure to high altitude (HA) imposes a blood oxygenation and acid–base challenge. A sustained and augmented hypoxic ventilatory response protects oxygenation through ventilatory acclimatization, but elicits hypocapnia and respiratory alkalosis. A subsequent renally mediated compensatory metabolic acidosis corrects pH toward baseline values, with a high degree of interindividual variability. Differential renal compensation between acclimatizing lowlanders (LL) and Tibetan highlanders (TH; Sherpa) with ascent was previously unknown. We assessed ventilatory and renal acclimatization between unacclimatized LL and TH during incremental ascent from 1,400 m to 4,300 m in age- and sex-matched groups of 15-LL (8F) and 14-TH (7F) of confirmed Tibetan ancestry. We compared respiratory and renally mediated blood acid–base acclimatization (PCO₂, [HCO₃⁻], pH) in both groups before (1,400 m) and following day 8 to 9 of incremental ascent to 4,300 m. We found that following ascent to 4,300 m, LL had significantly lower PCO₂(P<0.0001) and [HCO₃⁻] (P<0.0001), and higher pH (P= 0.0037) than 1,400 m, suggesting respiratory alkalosis and only partial renal compensation. Conversely, TH had significantly lower PCO₂(P< 0.0001) and [HCO₃⁻] (P< 0.0001), but unchanged pH (P= 0.1), suggesting full renal compensation, with significantly lower PCO₂(P= 0.01), [HCO₃⁻] (P< 0.0001) and pH (P= 0.005) than LL at 4,300 m. This demonstration of differential integrative respiratory–renal responses between acclimatizing LL and TH may indicate selective pressure on TH, and highlights the important role of the kidneys in acclimatization. 

High altitude native populations exhibit physiological adaptations to environmental hypoxia. It has been hypothesized that two of these populations, Andeans and Tibetans, demonstrate distinct adaptive modes with the former characterized by increased blood oxygen content, and the latter characterized by increased blood flow. To investigate this hypothesis, we recruited two groups of healthy adults (ages 18-35) with highland ancestry who were born and currently reside at high altitude. The groups were: Andean Quechuas recruited in Cerro de Pasco, Peru (AND, n = 301) and Tibetan Sherpas recruited in Pheriche, Nepal (SHP, n = 64). Participants were tested in field laboratories using identical equipment and protocols, at nearly identical altitudes (4,330m and 4,371m, respectively). We assessed a wide variety of physiological variables at rest, submaximal exercise, and maximal exercise. We found that although some phenotypes aligned with the above hypothesis, the majority did not. For example, as predicted, AND displayed significantly lower (p<0.001) ventilatory equivalents for oxygen (VE/VO2) at rest. However, this trend reversed at maximal exercise, with AND displaying significantly higher (p<0.001) VE/VO2 than SHP. Further, contrary to the above hypothesis, we found no statistically significant differences in flow-mediated dilation between the groups. These results suggest that the adaptive modes of these populations are perhaps not as distinct as previously supposed. Given that this hypothesis was formulated on the basis of data taken at rest, our data highlights the importance of assessing physiology both at rest and exercise, to gain a more complete understanding of adaptation to high altitude. 

Abstract ObjectivesThe Sherpa ethnic group living at altitude in Nepal may have experienced natural selection in response to chronic hypoxia. We have previously shown that Sherpa in Kathmandu (1400 m) possess larger spleens and a greater apnea‐induced splenic contraction compared to lowland Nepalis. This may be significant for exercise capacity at altitude as the human spleen responds to stress‐induced catecholamine secretion by an immediate contraction, which results in transiently elevated hemoglobin concentration ([Hb]). MethodsTo investigate splenic contraction in response to exercise at high‐altitude (4300 m; P_b = ~450 Torr), we recruited 63 acclimatized Sherpa (29F) and 14 Nepali non‐Sherpa (7F). Spleen volume was measured before and after maximal exercise on a cycle ergometer by ultrasonography, along with [Hb] and oxygen saturation (SpO₂). ResultsResting spleen volume was larger in the Sherpa compared with Nepali non‐Sherpa (237 ± 62 vs. 165 ± 34 mL,p < .001), as was the exercise‐induced splenic contraction (Δspleen volume, 91 ± 40 vs. 38 ± 32 mL,p < .001). From rest to exercise, [Hb] increased (1.2 to 1.4 g.dl⁻¹), SpO₂decreased (~9%) and calculated arterial oxygen content (CaO₂) remained stable, but there were no significant differences between groups. In Sherpa, both resting spleen volume and the Δspleen volume were modest positive predictors of the change (Δ) in [Hb] and CaO₂with exercise (p‐values from .026 to .037 and R²values from 0.059 to 0.067 for the predictor variable). ConclusionsLarger spleens and greater splenic contraction may be an adaptive characteristic of Nepali Sherpa to increase CaO₂during exercise at altitude, but the direct link between spleen size/function and hypoxia tolerance remains unclear. 

Highland native Andeans have resided at altitude for millennia. They display high aerobic capacity (VO 2 max) at altitude, which may be a reflection of genetic adaptation to hypoxia. Previous genomewide (GW) scans for natural selection have nominated Egl-9 homolog 1 gene ( EGLN1 ) as a candidate gene. The encoded protein, EGLN1/PHD2, is an O 2 sensor that controls levels of the Hypoxia Inducible Factor-α (HIF-α), which regulates the cellular response to hypoxia. From GW association and analysis of covariance performed on a total sample of 429 Peruvian Quechua and 94 US lowland referents, we identified 5 EGLN1 SNPs associated with higher VO 2 max (L⋅min −1 and mL⋅min −1 ⋅kg −1 ) in hypoxia (rs1769793, rs2064766, rs2437150, rs2491403, rs479200). For 4 of these SNPs, Quechua had the highest frequency of the advantageous (high VO 2 max) allele compared with 25 diverse lowland comparison populations from the 1000 Genomes Project. Genotype effects were substantial, with high versus low VO 2 max genotype categories differing by ∼11% (e.g., for rs1769793 SNP genotype TT = 34.2 mL⋅min −1 ⋅kg −1 vs. CC = 30.5 mL⋅min −1 ⋅kg −1 ). To guard against spurious association, we controlled for population stratification. Findings were replicated for EGLN1 SNP rs1769793 in an independent Andean sample collected in 2002. These findings contextualize previous reports of natural selection at EGLN1 in Andeans, and support the hypothesis that natural selection has increased the frequency of an EGLN1 causal variant that enhances O 2 delivery or use during exercise at altitude in Peruvian Quechua.