Chronic mountain sickness (CMS) is estimated at 1.2% in Tibetans living at the Qinghai–Tibetan Plateau. Eighteen single-nucleotide polymorphisms (SNPs) from nine nuclear genes that have an association with CMS in Tibetans have been analyzed by using pairwise linkage disequilibrium (LD). The SNPs included are the angiotensin-converting enzyme (rs4340), the angiotensinogen (rs699), and the angiotensin II type 1 receptor (AGTR1) (rs5186) from the renin–angiotensin system. A low-density lipoprotein apolipoprotein B (rs693) SNP was also included. From the hypoxia-inducible factor oxygen signaling pathway, the endothetal Per-Arnt-Sim domain protein 1 (EPAS1) and the egl nine homolog 1 (ENGL1) (rs480902) SNPs were included in the study. SNPs from the vascular endothelial growth factor (VEGF) signaling pathway included are the v-akt murine thymoma viral oncogene homolog 3 (rs4590656 and rs2291409), the endothelial cell nitric oxide synthase 3 (rs1007311 and rs1799983), and the (VEGFA) (rs699947, rs34357231, rs79469752, rs13207351, rs28357093, rs1570360, rs2010963, and rs3025039). An increase in LD occurred in 40 pairwise comparisons, whereas a decrease in LD was found in 55 pairwise comparisons between the controls and CMS patients. These changes were found to occur within and between signaling pathways, which suggests that there is an interaction between SNP alleles from different areas of the genome that affect CMS.
Abstract:Could the intrinsic characteristics of tolerance to hypoxia be retained in Tibetan high-altitude natives after they had migrated to a low altitude? To answer this question, we undertook a study of 33 healthy male adolescent Tibetans born and raised in a high plateau (3,700 m [12,140 ft] above sea level) who migrated to Shanghai (sea level) for 4 years. Ten agematched healthy male Han adolescents born and raised in Shanghai were regarded as the control group. Acute hypoxia was induced in a hypobaric chamber for 2 h to simulate the 3,700 m altitude. At sea level, maximal oxygen consumption (VO 2 max ) was not significantly different between the two groups. During acute hypoxia, the values of VO 2 max , tissue oxygen extraction, arterial oxygen pressure, and the arterial oxygen saturation showed markedly higher in Tibetan subjects than in Han subjects (1.41 ± 0.04 l/min/M 2 vs.1.25 ± 0.04 l/min/M 2 , 55.0 ± 4.2% vs. 47.3 ± 9.1%, 7.2 ± 0.6 vs. 5.5 ± 0.2 kPa, and 87.9 ± 3.3% vs. 78.2 ± 1.6%, respectively, P < 0.05). The calculated "oxygen reserve capacity" and "cardiac reserve capacity" were better in the Tibetans than in the Han natives (P < 0.05), which suggests that physical work capacity is greater in the Tibetan group. The sympathetic stimulation was less, and there was no noticeable change in cardiac function during acute hypoxia in the Tibetan group. The results indicate that the better tolerance to hypoxia in the Tibetans is retained during the 4-year stay at sea level, implying that the intrinsic hypoxic adaptation still exists in the Tibetan high-altitude natives.Key words: adaptation, high altitude, hypobaric chamber, oxygen transport, physical workload.For thousands of years, the overwhelming majority of Tibetans have been living at the roof of the world, characterized by an average altitude in excess of 4,000 m (13,123 ft). It is necessary that mechanisms be developed to compensate for low oxygen levels and to facilitate metabolism and other physiological functions in this hypoxic environment for both humans and animals.Our previous study has demonstrated that there exists a close relationship between the "cardiac pump function test" and hypoxic tolerance or climbing performance during a Mt. Everest expedition, and that Tibetans have a significantly better preservation of cardiac pump function [1]. We have also reported that compared to lowlanders, Tibetans have fewer incidents of excessive polycythemia, hypoventilation, and low pulmonary diffusion capacity than were observed in the lowlander's mountain sickness [2]. It is unclear whether the better hypoxic tolerance in the Tibetans is a result of the body's processes (physiological acclimatization) or of an intrinsic characteristic tolerance (genetic adaptation), or both. A comparison of the differences in the physiological responses to hypoxic stress in certain circumstances between Tibetans and lowlanders may reveal some essential facts about the possible mechanisms underlying the Tibetans' hypoxic tolerance.This study is one of our long-term...
The rSNPs for the genes AKT3 (rs4590656), EGLN1 (rs480902), eNOS3 (rs1007311), and VEGFA (rs699947, rs13207311, rs1570360, rs2010963) have been significantly associated with the physiological parameters in high altitude sickness Han or Tibetan Chinese patients at the Qinghai-Tibetan plateau. The alleles of each rSNP have been found to create unique transcriptional factor binding sites for transcription factors that affect the process of hypoxia gene expression in this high altitude hypoxia environment.
Circulating miRNAs isolated from dried blood spots (DBS) were found to be associated with high altitude sickness (HAS) patients in Tibet. HAS arises from two different diseases which are acute (AMS) and chronic (CMS) mountain sickness. Circulating miRNAs differences were found between AMS Han Chinese patients and normal Han controls and between CMS Tibetan Chinese patients and normal Tibetan controls. HAS arises from hypoxia which afflicts some high altitude inhabitants or visitors and not others. The difference results from each individual's genetic makeup where hypoxia related genes have been shown to be a major contributor to these sicknesses. Several fold changes increases (up regulation) were found in the hypoxia associated miRNAs let-7f-5p, miR-9-5p, miR-19a-3p, miR-23a-3p, miR-98-5p, miR-125a-5p, miR-181b-5p, mir-202-3p, miR-372, miR-381-3p, miR-519d, miR-520d-3p, and miR-656 for both HAS groups compared to their controls. Other miRNAs (miR-19a-3p, 302c-3p and 875-3p) were found to be up regulated in one HAS group and down regulated in the other HAS group indicating the genetic differences between the two sickness groups.
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