Associations of high altitude polycythemia with polymorphisms in EPAS1, ITGA6 and ERBB4 in Chinese Han and Tibetan populations

Abstract

High altitude polycythemia (HAPC) is a common chronic disease at high altitude, which is characterized by excessive erythrocytosis (females, hemoglobin ≥ 190 g/L; males, hemoglobin ≥ 210 g/L). It is the most common disease in chronic mountain sickness casued primarily by persistent arterial hypoxia and ventilatory impairment. However, the disease is still unmanageable and related molecular mechanisms remain largely unclear. This study aims to explore the genetic basis of HAPC in the Chinese Han and Tibetan populations. Subjects were screened for HAPC using the latest approved diagnostic criteria. To explore the hereditary basis of HAPC and investigate the association between three genes (EPAS1, ITGA6, ERBB4) and HAPC in Chinese Han and Tibetan populations. We enrolled 100 patients (70 Han, 30 Tibetan) with HAPC and 100 healthy control subjects (30 Han, 70 Tibetan). Subjects were screened for HAPC using the latest approved diagnostic criteria combined with excessive erythrocytosis and clinical symptoms. Analysis of variance was used to evaluate the impact of polymorphism on HAPC based on genetic variation. The Chi-squared test and analyses of genetic models, rs75591953 and rs75984373 in EPAS1, rs6744873 in ITGA6, rs17335043 in ERBB4 showed associations with reduced HAPC susceptibility in Han populations. Additionally, in Tibetan populations, rs3749148 in ITGA6, rs934607 and rs141267844 in ERBB4 showed a reduced risk of HAPC, whereas rs6710946 in ERBB4 increased the risk of HAPC. Our study suggest that the polymorphisms in the EPAS1, ITGA6 and ERBB4 correlate with susceptibility to HAPC.

Evidence of polygenic adaptation to high altitude from Tibetan and Sherpa genomes

“…2008 ). Interestingly, some ITGA6 variants were recently found to be associated with differential risk of developing polycythemia ( Zhao et al. 2017 ) and it has been proposed that such a gene is directly regulated by hypoxia-inducible factors ( Brooks et al.…”

Safety and Efficacy of Therapeutic Erythrocytapheresis Treatment in Chronic Mountain Sickness Patients in Shigatse, Tibet, China

“…Despite this, they still develop CMS in the plateau area. Additionally, both high-altitude natives and Han migrants show susceptibility to CMS in the plateau, but the prevalence of CMS among migrants was significantly higher compared to high-altitude natives [ 4 , 5 , 26 ]. At high altitude (the average altitude is 4000 m in Shigatse, Tibet, China), the partial pressure of oxygen is low.…”

Genetic variability of hypoxia‐inducible factor alpha (HIFA) genes in familial erythrocytosis: Analysis of the literature and genome databases

“…1,14 Moreover, several genome-wide association studies (GWAS) have reported on genetic differences in the EPAS1 gene between high-altitude and lowland populations and provided evidence for association of variants in non-coding regions of the EPAS1 gene with adaptation to the hypoxic environment. [32][33][34][35] Nucleotide alterations of EPAS1 gene contribute to the lower RBC overproduction and protect Tibetan high-altitude populations from development of chronic mountain sickness. 36,37 Furthermore, another major erythropoietic rate-limiting step, iron metabolism, is controlled by the EPAS1 gene.…”

“…However, genetic screening of patients with inherited form of erythrocytosis strengthened the notion that EPAS1 is a key regulator of EPO production, as variants in coding regions of the EPAS1 gene have been recognized as a principle cause of ECYT4 . Moreover, several genome‐wide association studies (GWAS) have reported on genetic differences in the EPAS1 gene between high‐altitude and lowland populations and provided evidence for association of variants in non‐coding regions of the EPAS1 gene with adaptation to the hypoxic environment . Nucleotide alterations of EPAS1 gene contribute to the lower RBC overproduction and protect Tibetan high‐altitude populations from development of chronic mountain sickness …”