Abstract
Background The hypoxic conditions at high altitudes are great threats to survival, causing pressure for adaptation. More and more high-altitude denizens are not adapted with the condition known as high-altitude polycythemia (HAPC) that featured excessive erythrocytosis. As a high-altitude sickness, the etiology of HAPC is still unclear. Methods In this study, we reported the whole-genome sequencing-based study of 10 native Tibetans with HAPC and 10 control subjects followed by genotyping of selected 21 variants from discovered single nucleotide variants (SNVs) in an independent cohort (232 cases and 266 controls). Results We discovered the egl nine homologue 3 (egln3/phd3) (14q13.1, rs1346902, P = 1.91 × 10−5) and PPP1R2P1 (Protein Phosphatase 1 Regulatory Inhibitor Subunit 2) gene (6p21.32, rs521539, P = 0.012). Our results indicated an unbiased framework to identify etiological mechanisms of HAPC and showed that egln3/phd3 and PPP1R2P1 may be associated with the susceptibility to HAPC. Egln3/phd3b is associated with hypoxia-inducible factor subunit α (HIFα). Protein Phosphatase 1 Regulatory Inhibitor is associated with reactive oxygen species (ROS) and oxidative stress. Conclusions Our genome sequencing conducted in Tibetan HAPC patients identified egln3/phd3 and PPP1R2P1 associated with HAPC.
Highlights
In excess of 140 million humans have primarily lived in the high-altitude regions of various locations around the world, including the Qinghai-Tibet plateau in Asia, the Andes Mountains of South America, and the Ethiopian plateau in East Africa [1]
high-altitude polycythemia (HAPC) is diagnosed with excessive erythrocytosis encountered by around 10% of the population residing at the Qinghai-Tibet plateau [6, 7]
After extracting DNA from the peripheral blood, the whole-genome sequencing of 10 native Tibetans with HAPC and 10 adapted subjects without HAPC was performed by using next-generation sequencing technology (Supplementary Table S1)
Summary
In excess of 140 million humans have primarily lived in the high-altitude regions of various locations around the world, including the Qinghai-Tibet plateau in Asia, the Andes Mountains of South America, and the Ethiopian plateau in East Africa [1]. All dwellers in plateaus like native Tibetans of the Qinghai-Qinghai-Tibet plateau are regarded as one of the best dwellers adapted to high altitudes. They possess heritable adaptations to the hypoxic condition [2], as they display lower hemoglobin and hematocrit [3], higher oxygen saturation of blood [4], and better work efficiency [5], which are conducive to adapting the high-altitude and hypoxic situations. Our results indicated an unbiased framework to identify etiological mechanisms of HAPC and showed that egln3/phd and PPP1R2P1 may be associated with the susceptibility to HAPC. Our genome sequencing conducted in Tibetan HAPC patients identified egln3/phd and PPP1R2P1 associated with HAPC
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