Association Between Genetic Polymorphism And Hypoxia Adaptation In Tibetan

High-altitude hypoxia adaptation is the adaptation of the body while residing at high altitudes in a hypoxic environment, and which has adverse effects on various systems, especially the respiratory system. With human migration on a global scale during tens of thousands of years, modern humans are facing severe environmental pressures, particularly at high altitude. Exposure factors include low atmospheric pressure, low oxygen content, cold, and solar radiation in high altitude areas, while extreme hypobaric hypoxia is one of the main features. At a height of4000meters above sea level, the oxygen content in the air is only60%of that at sea level. Travelers from low-altitude areas often suffer from hypoxic symptoms and may develop mountain sickness, such as high-altitude pulmonary hypertension and pulmonary edema. However, aborigines in high-altitude areas have already adapted to such a hypobaric hypoxia environment. The Qinghai-Tibet Plateau is the highest and the largest plateau in the world, with an average altitude of more than4000meters and an area of more than2.5million square kilometers. The Tibetans mainly distribute in China’s Tibet Autonomous Region and some other provinces, including Qinghai, Gansu, Sichuan, and Yunnan province. The level of carbon monoxide and pulmonary ventilation of Tibetans is higher than populations living at sea level, while oxygen saturation and hemoglobin levels of Tibetan is lower than populations living at sea level. These physiological differences suggest that the Tibetans have already adapted to a high-altitude hypoxic environment. Therefore, Tibetans are good subjects to study high-altitude hypoxic adaptation.To investigate the association between genome diversity and high altitude hypoxia adaptation.We did three studys below:(1) Mitochondrial haplogroup classification and mutation genotyping were performed in Tibetan (Xizang Tibetan:3650m; Qinghai Tibetan:3100m; Yunnan Tibetan:1500m) and Han Chinese (Shandong Han:50m) living at different altitudes.(2)18SNPs located in prolyl hydroxylase2(EGLN1or PHD2) gene of152unrelated healthy Tibetan individuals (3650m altitude) and192Han (500m altitude) were genotyped using Sequenom MassArray genotyping system, and the haplotypes of these SNPs were constructed and analyzed.(3) ACE gene insert/deletion phlymorphism were genotyping were performed in Tibetan (Xizang Tibetan:3650m;Qinghai Tibetan:3100m;Yunnan Nujiang Tibetan:1500m)and Han Chinese(Shandong Han:50m; Hubei Han:500m)living at different altitudes.We found that:(1) the frequencies of mitochondrial haplogroup B and haplogroup M7in the high-altitude population were significantly lower than those in the low-altitude population (P=0.003and0.03), while the frequencies of haplogroup G and haplogroup M9alalclb in the high-altitude population were significantly higher than those in the low-altitude population (P=0.01and0.002). The frequencies of3394C and7697A which were the division site of haplogroup M9alalclb in the high-altitude population were significantly higher than those in the low-altitude population (P=0.012and0.02).(2) All the homozygous genotypes of13SNPs loci located in5’UTR region or intron region of EGLNl gene were significantly different between the two groups (P<0.05). The frequencies of haplotype GTG (rs2066140, rs2739516and rs2808584) and TGCCACAT (rs2572248, rs2739513, rs2808586, rs2486741,rs2437147, rsl0489610, rs2749699and rs2486734) of high altitude group were significantly different from low altitude group (P<0.05). In addition, the frequencies of haplotype GTG (rs2066140,rs2739516and rs2808584)and CATGGACC (rs2572248, rs2739513, rs2808586, rs2486741, rs2437147, rsl0489610, rs2749699and rs2486734) of high altitude group were significant lower than that in low altitude group (P<0.05).(3)There is no significant difference of ACE gene insert/deletion phlymorphism between high altitude group and low altitude group.Our results suggested that(1) Mitochondrial haplogroup B and M7are associated with inadaptability to a hypoxic environment. Haplogroup G and M9alalclb may be associated with hypoxic adaptation. In particular,3394C and7697A mutations of haplogroup M9ala1c1b may be the primary cause of adaptation to hypoxia.(2) The homozygous genotype in13SNPs located in5’UTR region or intron region of EGLN1and whose haplotypes were associated with high altitude hypoxia adaptation.(3) ACE gene insert/deletion phlymorphism was not associated with high altitude hypoxia adaptation.