Targeted Sequencing Identifies the Genetic Variants Associated with High-altitude Polycythemia in the Tibetan Population

Zhiying Zhang,Yiduo Zhao,Wenxue Dong,Xiaowei Fan,Yansong Li,Peng Cai,Lifeng Ma,Zhipeng Zhao,Kun Wang,Tian Liang,Jing Li,Han Zhang,Songhua Zhou,Lijun Liu,Longli Kang

doi:10.1007/s12288-021-01474-1

Abstract

High-altitude polycythemia (HAPC) is characterized by excessive proliferation of erythrocytes, resulting from the hypobaric hypoxia condition in high altitude. The genetic variants and molecular mechanisms of HAPC remain unclear in highlanders. We recruited 141 Tibetan dwellers, including 70 HAPC patients and 71 healthy controls, to detect the possible genetic variants associated with the disease; and performed targeted sequencing on 529 genes associated with the oxygen metabolism and erythrocyte regulation, utilized unconditional logistic regression analysis and GO (gene ontology) analysis to investigate the genetic variations of HAPC. We identified 12 single nucleotide variants, harbored in 12 genes, associated with the risk of HAPC (4.7 ≤ odd ratios ≤ 13.6; 7.6E − 08 ≤ p-value ≤ 1E − 04). The pathway enrichment study of these genes indicated the three pathways, the PI3K-AKT pathway, JAK-STAT pathway, and HIF-1 pathway, are essential, which p-values as 3.70E − 08, 1.28 E − 07, and 3.98 E − 06, respectively. We are hopeful that our results will provide a reference for the etiology research of HAPC. However, additional genetic risk factors and functional investigations are necessary to confirm our results further.

Highlights

The Qinghai-Tibet Plateau, namely the ‘‘roof of the world,’’ is a high-altitude area with an elevation between 3000 and 5000 m
We are hopeful that our results will provide a reference for the etiology research of High-altitude polycythemia (HAPC)
Twelve genes were enriched in 16 signal pathways, including the PI3K-AKT pathway, Janus kinase (JAK)-signal transducer and activator of transcription (STAT) pathway, HIF-1 pathway, pathways in cancer, axon guidance, focal adhesion, proteoglycans in cancer, cytokinecytokine receptor interaction, et al Enrichment pathway information is shown in Figs. 3 and 2

Summary

Introduction

The Qinghai-Tibet Plateau, namely the ‘‘roof of the world,’’ is a high-altitude area with an elevation between 3000 and 5000 m. Hypoxia is one of the most critical characteristics of the high-altitude environment. Highaltitude polycythemia (HAPC) is one of the chronic highaltitude diseases developed in Tibetan dwellers, characterized by an excessive number of circulating erythrocytes. The clinical diagnosis of HAPC requires a hemoglobin concentration (Hb) no less than 19 g/dL for females and 21 g/dL for males, respectively [1]. HAPC is often commonly accompanied by the symptoms, headache, dizziness, dyspnea, sleep disorders, or venous dilatation [1]. The incidence of HAPC in the Tibetan Plateau ranges from 5 to 18%, increasing with altitude, a severe public health problem in China and other Andean countries [2]

Results

Discussion

Conclusion