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

Zhang, Zhiying; Ma, Lifeng; Fan, Xinjian; Wang, Kun; Liu, Lijun; Zhao, Yiduo; Zhao, Zhipeng; Zhang, Han; Liang, Tian; Dong, Wenxue; Cai, Peng; Li, Yansong; Li, Jing; Song-hua, Zhou; Kang, Longli

doi:10.1007/s12288-021-01474-1

Cited by 6 publications

(4 citation statements)

References 45 publications

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“…The mRNA of AKT1 was higher in the CMS group than in the non-CMS group (Zhao et al 2017). Furthermore, the PI3K-AKT signaling pathway appears to be involved in the mechanism of reduced erythrocyte apoptosis (Zhang et al 2022), resulting in increased erythrocyte accumulation and promoting HAPC. VEGFR was higher in participants with versus without excessive erythrocytosis in high-altitude Peru (Painschab et al 2015).…”

Section: Introductionmentioning

confidence: 90%

Hypermethylation of BMPR2 and TGF-β Promoter Regions in Tibetan Patients with High-Altitude Polycythemia at Extreme Altitude

Zhaxi,

Gesang,

Huang

et al. 2024

Biochem Genet

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Although the expression of many genes is associated with adaptation to high-altitude hypoxic environments, the role of epigenetics in the response to this harsh environmental stress is currently unclear. We explored whether abnormal DNA promoter methylation levels of six genes, namely, ABCA1, SOD2, AKT1, VEGFR2, TGF-β, and BMPR2, affect the occurrence and development of high-altitude polycythemia (HAPC) in Tibetans. The methylation levels of HAPC and the control group of 130 Tibetans from very high altitudes (> 4500 m) were examined using quantitative methylation-specific real-time PCR (QMSP). Depending on the type of data, the Pearson chi-square test, Wilcoxon rank-sum test, and Fisher exact test were used to assess the differences between the two groups. The correlation between the methylation levels of each gene and the hemoglobin content was explored using a linear mixed model. Our experiment revealed that the methylation levels of the TGF-β and BMPR2 genes differed significantly in the two groups (p < 0.05) and linear mixed model analysis showed that the correlation between the hemoglobin and methylation of ABCA1, TGF-β, and BMPR2 was statistically significant (p < 0.05). Our study suggests that levels of TGF-β and BMPR2 methylation are associated with the occurrence of HAPC in extreme-altitude Tibetan populations among 6 selected genes. Epigenetics may be involved in the pathogenesis of HAPC, and future experiments could combine gene and protein levels to verify the diagnostic value of TGF-β and BMPR2 methylation levels in HAPC.

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Section: Introductionmentioning

confidence: 90%

Hypermethylation of BMPR2 and TGF-β Promoter Regions in Tibetan Patients with High-Altitude Polycythemia at Extreme Altitude

Zhaxi,

Gesang,

Huang

et al. 2024

Biochem Genet

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“…Our selection signature analyses for Arsi-Bale and Keffa goats revealed several strong signatures that spanned genes such as RUNDC3B , TIGAR , PTPMT1 , STXBP4, and ALOX5AP relating to hypoxia adaptation. It has been shown that RUNDC3B is amongst genes with variants associated with increased risk of high-altitude polycythemia (HAPC) in Tibetan dwellers 72 . HAPC is characterized by excessive proliferation of circulating erythrocytes due to high-altitude hypobaric hypoxia.…”

Section: Discussionmentioning

confidence: 99%

Anthropogenic events and responses to environmental stress are shaping the genomes of Ethiopian indigenous goats

Belay,

Nigussie

et al. 2024

Sci Rep

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Anthropological and biophysical processes have shaped livestock genomes over Millenia and can explain their current geographic distribution and genetic divergence. We analyzed 57 Ethiopian indigenous domestic goat genomes alongside 67 equivalents of east, west, and north-west African, European, South Asian, Middle East, and wild Bezoar goats. Cluster, ADMIXTURE (K = 4) and phylogenetic analysis revealed four genetic groups comprising African, European, South Asian, and wild Bezoar goats. The Middle Eastern goats had an admixed genome of these four genetic groups. At K = 5, the West African Dwarf and Moroccan goats were separated from East African goats demonstrating a likely historical legacy of goat arrival and dispersal into Africa via the coastal Mediterranean Sea and the Horn of Africa. FST, XP-EHH, and Hp analysis revealed signatures of selection in Ethiopian goats overlaying genes for thermo-sensitivity, oxidative stress response, high-altitude hypoxic adaptation, reproductive fitness, pathogen defence, immunity, pigmentation, DNA repair, modulation of renal function and integrated fluid and electrolyte homeostasis. Notable examples include TRPV1 (a nociception gene); PTPMT1 (a critical hypoxia survival gene); RETREG (a regulator of reticulophagy during starvation), and WNK4 (a molecular switch for osmoregulation). These results suggest that human-mediated translocations and adaptation to contrasting environments are shaping indigenous African goat genomes.

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“…Our results showed that GALNT13 interacts with multiple miR targets related to histamine secretion and hypoxia-induced activities in erythrocytes and T cells, suggesting its potential effects in pulmonary vascular and ventricular injuries. More importantly, as miR products of RHEBL1 (a member of Ras superfamily) 48 , both hsa-miR-19a-3p and hsa-miR-19b-3p were indicated as mediators of HIF1A 49 , 50 , suggesting important roles in hypoxia-related biological processes. Furthermore, the EPHB3 (a proliferation suppressor in ambient and hypoxic environments) 51 -(hsa-miR-149-5p)-IL6 pathway was also believed to be essential for hypoxic responses as the underlying association between hypoxia and inflammation.…”

Section: Discussionmentioning

confidence: 99%

Establishing a prediction model of severe acute mountain sickness using machine learning of support vector machine recursive feature elimination

Yang¹,

Wu²,

Yang³

et al. 2023

Sci Rep

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Severe acute mountain sickness (sAMS) can be life-threatening, but little is known about its genetic basis. The study was aimed to explore the genetic susceptibility of sAMS for the purpose of prediction, using microarray data from 112 peripheral blood mononuclear cell (PBMC) samples of 21 subjects, who were exposed to very high altitude (5260 m), low barometric pressure (406 mmHg), and hypobaric hypoxia (VLH) at various timepoints. We found that exposure to VLH activated gene expression in leukocytes, resulting in an inverted CD4/CD8 ratio that interacted with other phenotypic risk factors at the genetic level. A total of 2286 underlying risk genes were input into the support vector machine recursive feature elimination (SVM-RFE) system for machine learning, and a model with satisfactory predictive accuracy and clinical applicability was established for sAMS screening using ten featured genes with significant predictive power. Five featured genes (EPHB3, DIP2B, RHEBL1, GALNT13, and SLC8A2) were identified upstream of hypoxia- and/or inflammation-related pathways mediated by microRNAs as potential biomarkers for sAMS. The established prediction model of sAMS holds promise for clinical application as a genetic screening tool for sAMS.

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

Cited by 6 publications

References 45 publications

Hypermethylation of BMPR2 and TGF-β Promoter Regions in Tibetan Patients with High-Altitude Polycythemia at Extreme Altitude

Hypermethylation of BMPR2 and TGF-β Promoter Regions in Tibetan Patients with High-Altitude Polycythemia at Extreme Altitude

Anthropogenic events and responses to environmental stress are shaping the genomes of Ethiopian indigenous goats

Establishing a prediction model of severe acute mountain sickness using machine learning of support vector machine recursive feature elimination

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