Genetic and immune changes in Tibetan high-altitude populations contribute to biological adaptation to hypoxia.

BACKGROUND

Tibetans have lived at very high altitudes for thousands of years, and have a distinctive suite of physiological traits that enable them to tolerate environmental hypoxia. Expanding awareness and knowledge of the differences in hematology, hypoxia-associated genes, immune system of people living at different altitudes and from different ethnic groups may provide evidence for the prevention of mountain sickness.

METHOD

Ninety-five Han people at mid-altitude, ninety-five Tibetan people at high-altitude and ninety-eight Han people at high-altitude were recruited. Red blood cell parameters, immune cells, the contents of cytokines, hypoxia-associated gene single nucleotide polymorphisms (SNPs) were measured.

RESULTS

The values of Hematocrit (HCT), Mean cell volume (MCV) and Mean cell hemoglobin (MCH) in red blood cell, immune cell CD19 B cell number, the levels of cytokines Erb-B2 receptor tyrosine kinase 3 (ErbB3) and Tumor necrosis factor receptor II (TNF-RII) and the levels of hypoxia-associated factors Hypoxia inducible factor-1α (HIF-1α), Hypoxia inducible factor-2α (HIF-2α) and HIF prolyl 4-hydroxylase 2 (PHD2) were decreased, while the frequencies of SNPs in twenty-six Endothelial PAS domain protein 1 (EPAS1) and Egl-9 family hypoxia inducible factor 1 (EGLN1) were increased in Tibetan people at high-altitude compared with that of Han peoples at high-altitude. Furthermore, compared with mid-altitude individuals, high-altitude individuals showed lower blood cell parameters including Hemoglobin concentration (HGB), HCT, MCV and MCH, higher Mean cell hemoglobin concentration (MCHC), lower immune cells including CD19 B cells, CD4 T cells and CD4/CD8 ratio, higher immune cells containing CD8 T cells and CD16/56NK cells, decreased Growth regulated oncogene alpha (GROa), Macrophage inflammatory protein 1 beta (MIP-1b), Interleukin-8 (IL-8), and increased Thrombomodulin, downregulated hypoxia-associated factors including HIF1α, HIF2α and PHD2, and higher frequency of EGLN1 rs2275279.

CONCLUSIONS

These results indicated that biological adaption to hypoxia at high altitude might have been mediated by changes in immune cells, cytokines, and hypoxia-associated genes during the evolutionary history of Tibetan populations. Furthermore, different responses to high altitude were observed in different ethnic groups, which may provide a useful knowledge to improve the protection of high-altitude populations from mountain sickness.