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Recent discoveries indicate a genetic basis for high-altitude adaptation among human groups who have resided at high altitude for millennia, including Andeans, Tibetans, and Ethiopians. Yet, genetics alone does not explain the extent of variation in altitude-adaptive phenotypes. Current and past environments may also play a role, and one way to determine the effect of the environment is through the epigenome. To characterize if Andean adaptive responses to high altitude have an epigenetic component, we analyzed DNA methylation of the promoter region of EPAS1 and LINE-1 repetitive element among 572 Quechua individuals from high- (4,388 m) and low-altitude (0 m) in Peru. Participants recruited at high altitude had lower EPAS1 DNA methylation and higher LINE-1 methylation. Altitude of birth was associated with higher LINE-1 methylation, not with EPAS1 methylation. The number of years lived at high altitude was negatively associated with EPAS1 methylation and positively associated with LINE-1 methylation. We found four one-carbon metabolism SNPs (MTHFD1 rs2236225, TYMS rs502396, FOLH1 rs202676, GLDC rs10975681) that cumulatively explained 11.29% of the variation in average LINE-1 methylation. And identified an association between LINE-1 methylation and genome-wide SNP principal component 1 that distinguishes European from Indigenous American ancestry suggesting that European admixture decreases LINE-1 methylation. Our results indicate that both current and lifetime exposure to high-altitude hypoxia have an effect on EPAS1 and LINE-1 methylation among Andean Quechua, suggesting that epigenetic modifications may play a role in high-altitude adaptation.

Chronic mountain sickness (CMS) results from chronic hypoxia. It is unclear why certain highlanders develop CMS. We hypothesized that modest increases in fetal hemoglobin (HbF) are associated with lower CMS severity. In this cross-sectional study, we found that HbF levels were normal (median = 0.4%) in all 153 adult Andean natives in Cerro de Pasco, Peru. Compared with healthy adults, the borderline elevated hemoglobin group frequently had symptoms (headaches, tinnitus, cyanosis, dilatation of veins) of CMS. Although the mean hemoglobin level differed between the healthy (17.1 g/dL) and CMS (22.3 g/dL) groups, mean plasma erythropoietin (EPO) levels were similar (healthy, 17.7 mIU/mL; CMS, 12.02 mIU/mL). Sanger sequencing determined that single-nucleotide polymorphisms in endothelial PAS domain 1 (EPAS1) and egl nine homolog 1 (EGLN1), associated with lower hemoglobin in Tibetans, were not identified in Andeans. Sanger sequencing of sentrin-specific protease 1 (SENP1) and acidic nuclear phosphoprotein 32 family, member D (ANP32D), in healthy and CMS individuals revealed that non-G/G genotypes were associated with higher CMS scores. No JAK2 V617F mutation was detected in CMS individuals. Thus, HbF and other classic erythropoietic parameters did not differ between healthy and CMS individuals. However, the non-G/G genotypes of SENP1 appeared to differentiate individuals with CMS from healthy Andean highlanders., (Published by Elsevier Inc.)

Chronic intermittent hypoxia (CIH) and chronic hypoxia (CH) are associated with high-altitude pulmonary hypertension (HAPH). Asymmetric dimethylarginine (ADMA), a NO synthase (NOS) inhibitor, may contribute to HAPH. This study assessed changes in the ADMA/NO pathway and the underlying mechanisms in rat lungs following exposure to CIH or CH simulated in a hypobaric chamber at 428 Torr. Twenty-four adult Wistar rats were randomly assigned to three groups: CIH2x2 (2 days of hypoxia/2 days of normoxia), CH, and NX (permanent normoxia), for 30 days. All analyses were performed in whole lung tissue. L-Arginine and ADMA were analyzed using LC-MS/MS. Under both hypoxic conditions right ventricular hypertrophy was observed (p < 0.01) and endothelial NOS mRNA increased (p < 0.001), but the phosphorylated/nonphosphorylated vasodilator-stimulated phosphoprotein (VASP) ratio was unchanged. ADMA increased (p < 0.001), whereas dimethylarginine dimethylaminohydrolase (DDAH) activity decreased only under CH (p < 0.05). Although arginase activity increased (p < 0.001) and L-arginine exhibited no changes, the L-arginine/ADMA ratio decreased significantly (p < 0.001). Moreover, NOX4 expression increased only under CH (p < 0.01), but malondialdehyde (MDA) increased (up to 2-fold) equally in CIH2x2 and CH (p < 0.001). Our results suggest that ADMA and oxidative stress likely reduce NO bioavailability under altitude hypoxia, which implies greater pulmonary vascular reactivity and tone, despite the more subdued effects observed under CIH.

Although an increase in hemoglobin concentration [Hb] in high altitude residents assists oxygen transport, excessive polycythemia ([Hb] > or = 21 g/100 mL) may cause the syndrome of chronic mountain sickness (CMS). A recent theoretical analysis has suggested that increasing [Hb] above 18 g/100 mL provides no further benefit in oxygen transport at rest. To test this hypothesis, we examined oxygen transport at rest for given arterial oxygen saturations (Sa(O2), in classes at intervals of 5%) as reported in 206 residents of various altitudes. For Sa(O2) of 97% versus 87%, [Hb] and a-v oxygen content difference increased (respectively, 14.5 to 17.5 g/100 mL and 4.11 to 5.03 volume %). As Sa(O2) fell further to 66%, a-v progressively decreased to 3.77 volume %, despite an increase in [Hb] to 24.2 g/100 mL. Over the Sa(O2) range of 97% to 66%, the a-v difference changed little (-8%) compared to other subjects made acutely hypoxic (-33%), for Sa(O2) change from 97% to 75%. The results suggest that increasing [Hb] allows greater oxygen extraction (a cardiac output sparing effect), which is maximal at Sa(O2) of 87% and a [Hb] of 17.5 g/100 mL. For more severe hypoxemia, even to Sa(O2) of 66%, both increasing [Hb] and increasing output are utilized for oxygen transport.

Polycythemia is one of the key factors involved in the chronic mountain sickness syndrome, a condition frequent in Andean natives but whose causes still remain unclear. In theory, polycythemia may be secondary to abnormalities in ventilation, occurring during day or night (e.g. due to sleep abnormalities) stimulating excessive erythropoietin (Epo) production, or else it may result from either autogenous production, or from co-factors like cobalt. To assess the importance of these points, we studied subjects with or without polycythemia, born and living in Cerro de Pasco (Peru, 4330m asl, CP) and evaluated the relationship between Epo and respiratory variables both in CP and sea level. We also assessed the relationship between sleep abnormalities and the circadian rhythm of Epo. Polycythemic subjects showed higher Epo in all conditions, lower SaO2 and hypoxic ventilatory response, higher physiological dead space and higher CO2, suggesting ventilatory inefficiency. Epo levels could be highly modified by the level of oxygenation, and were related to similar directional changes in SaO2. Cobalt levels were normal in all subjects and correlated poorly with hematologic variables. The diurnal variations in Epo were grossly abnormal in polycythemic subjects, with complete loss of the circadian rhythm. These abnormalities correlated with the levels of hypoxemia during the night, but not with sleep abnormalities, which were only minor even in polycythemic subjects. The increased Epo production is mainly related to a greater ventilatory inefficiency, and not to altered sensitivity to hypoxia, cobalt or sleep abnormalities. Improving oxygenation can represent a possible therapeutic option for this syndrome.