[Progress in multiomics research on high altitude polycythemia].

Chronic mountain sickness (CMS) or Monge syndrome is a disease that is prevalent at altitude above 2 500 meters. High altitude polycythemia (HAPC) is one subtype of CMS. EPAS1 and EGNL1 are the most critical high-altitude adaptation genes in the genome of the Tibetan population. The HIF-PHD-VHL system plays an important role in the pathogenesis of HAPC. The protease encoded by the SENP1 gene regulates hypoxia related transcription factors such as HIF and GATA to affect the expression of EPO or EPOR involved in red blood cell generation. With the development of genetic testing and omics technology, new progress in the fields of metabolomics, proteomics and metabolomics has been made in the pathogenesis of HAPC. The above new research results provide a preliminary basis for bone marrow hematoecology and hematopoietic regulation of HAPC. The diagnostic criteria for CMS have certain limitations, especially in patients with excessive erythrocytosis who should undergo genetic testing recommended for congenital and polycythemia vera. This article provides a review of the latest research on HAPC in various omics techniques, hematopoietic regulation and diagnostic processes which is more conducive to understand the pathogenesis. The clinical diagnosis of excessive erythrocytosis emphasizes the importance of genetic testing.

TNF-α and RPLP0 drive the apoptosis of endothelial cells and increase susceptibility to high-altitude pulmonary edema.

High-altitude pulmonary edema (HAPE) is a fatal threat for sojourners who ascend rapidly without sufficient acclimatization. Acclimatized sojourners and adapted natives are both insensitive to HAPE but have different physiological traits and molecular bases. In this study, based on GSE52209, the gene expression profiles of HAPE patients were compared with those of acclimatized sojourners and adapted natives, with the common and divergent differentially expressed genes (DEGs) and their hub genes identified, respectively. Bioinformatic methodologies for functional enrichment analysis, immune infiltration, diagnostic model construction, competing endogenous RNA (ceRNA) analysis and drug prediction were performed to detect potential biological functions and molecular mechanisms. Next, an array of in vivo experiments in a HAPE rat model and in vitro experiments in HUVECs were conducted to verify the results of the bioinformatic analysis. The enriched pathways of DEGs and immune landscapes for HAPE were significantly different between sojourners and natives, and the common DEGs were enriched mainly in the pathways of development and immunity. Nomograms revealed that the upregulation of TNF-α and downregulation of RPLP0 exhibited high diagnostic efficiency for HAPE in both sojourners and natives, which was further validated in the HAPE rat model. The addition of TNF-α and RPLP0 knockdown activated apoptosis signaling in endothelial cells (ECs) and enhanced endothelial permeability. In conclusion, TNF-α and RPLP0 are shared biomarkers and molecular bases for HAPE susceptibility during the acclimatization/adaptation/maladaptation processes in sojourners and natives, inspiring new ideas for predicting and treating HAPE.

Identification and Validation of STC1 Act as a Biomarker for High-Altitude Diseases and Its Pan-Cancer Analysis.

High-altitude diseases, including acute mountain sickness (AMS), high-altitude cerebral edema (HACE), and high-altitude pulmonary edema (HAPE), are closely related to an individual's ability to adapt to hypoxic environments. However, specific research in this field is relatively limited, and further biomarker research and clinical trials are needed to clarify the exact role and potential therapeutic applications of key genes in high-altitude diseases. This study focuses on the role of the STC1 gene in high-altitude diseases and explores its expression patterns in different types of cancer. By using gene expression data analysis and functional experiments, we identified STC1 as a key gene affecting the development of altitude sickness. In addition, we also conducted expression and mutation analysis on STC1 in various cancer samples and found significant differences in the expression of this gene in 13 types of malignant tumors, which is associated with the hypoxic state in the tumor microenvironment. In addition, STC1 is significantly associated with patient prognosis and influences tumor immunity by mediating six types of immune cells (CD8+T cells, CD4+T cells, neutrophils, macrophages, monocytes, and B cells) in the tumor microenvironment. The expression and diagnostic value of STC1 were confirmed through GEO datasets and qPCR testing, indicating consistency with the results of bioinformatics analysis. These results indicate that STC1 is not only an important factor in the adaptive response to high-altitude diseases but may also play a role in the adaptation of cancer to low-oxygen environments. Our research provides a new perspective and potential targets for the discovery of biomarkers for high-altitude diseases and cancer treatment.

Whole-exome sequencing in searching for novel variants associated with the development of high altitude pulmonary edema.

BACKGROUND: High altitude pulmonary edema (HAPE) is a high-altitude idiopathic disease with serious consequences due to hypoxia at high altitude, and there is individual genetic susceptibility. Whole-exome sequencing (WES) is an effective tool for studying the genetic etiology of HAPE and can identify potentially novel mutations that may cause protein instability and may contribute to the development of HAPE. MATERIALS AND METHODS: A total of 50 unrelated HAPE patients were examined using WES, and the available bioinformatics tools were used to perform an analysis of exonic regions. Using the Phenolyzer program, disease candidate gene analysis was carried out. SIFT, PolyPhen-2, Mutation Taster, CADD, DANN, and I-Mutant software were used to assess the effects of genetic variations on protein function. RESULTS: The results showed that rs368502694 (p. R1022Q) located in NOS3, rs1595850639 (p. G61S) located in MYBPC3, and rs1367895529 (p. R333H) located in ITGAV were correlated with a high risk of HAPE, and thus could be regarded as potential genetic variations associated with HAPE. CONCLUSION: WES was used in this study for the first time to directly screen genetic variations related to HAPE. Notably, our study offers fresh information for the subsequent investigation into the etiology of HAPE.

Genetic and immune changes in Tibetan high-altitude populations contribute to biological adaptation to hypoxia.

BACKGROUND: Tibetans have lived at very high altitudes for thousands of years, and have a distinctive suite of physiological traits that enable them to tolerate environmental hypoxia. Expanding awareness and knowledge of the differences in hematology, hypoxia-associated genes, immune system of people living at different altitudes and from different ethnic groups may provide evidence for the prevention of mountain sickness. METHOD: Ninety-five Han people at mid-altitude, ninety-five Tibetan people at high-altitude and ninety-eight Han people at high-altitude were recruited. Red blood cell parameters, immune cells, the contents of cytokines, hypoxia-associated gene single nucleotide polymorphisms (SNPs) were measured. RESULTS: The values of Hematocrit (HCT), Mean cell volume (MCV) and Mean cell hemoglobin (MCH) in red blood cell, immune cell CD19+ B cell number, the levels of cytokines Erb-B2 receptor tyrosine kinase 3 (ErbB3) and Tumor necrosis factor receptor II (TNF-RII) and the levels of hypoxia-associated factors Hypoxia inducible factor-1α (HIF-1α), Hypoxia inducible factor-2α (HIF-2α) and HIF prolyl 4-hydroxylase 2 (PHD2) were decreased, while the frequencies of SNPs in twenty-six Endothelial PAS domain protein 1 (EPAS1) and Egl-9 family hypoxia inducible factor 1 (EGLN1) were increased in Tibetan people at high-altitude compared with that of Han peoples at high-altitude. Furthermore, compared with mid-altitude individuals, high-altitude individuals showed lower blood cell parameters including Hemoglobin concentration (HGB), HCT, MCV and MCH, higher Mean cell hemoglobin concentration (MCHC), lower immune cells including CD19+ B cells, CD4+ T cells and CD4/CD8 ratio, higher immune cells containing CD8+ T cells and CD16/56NK cells, decreased Growth regulated oncogene alpha (GROa), Macrophage inflammatory protein 1 beta (MIP-1b), Interleukin-8 (IL-8), and increased Thrombomodulin, downregulated hypoxia-associated factors including HIF1α, HIF2α and PHD2, and higher frequency of EGLN1 rs2275279. CONCLUSIONS: These results indicated that biological adaption to hypoxia at high altitude might have been mediated by changes in immune cells, cytokines, and hypoxia-associated genes during the evolutionary history of Tibetan populations. Furthermore, different responses to high altitude were observed in different ethnic groups, which may provide a useful knowledge to improve the protection of high-altitude populations from mountain sickness.

The blunted vascular endothelial growth factor-A (VEGF-A) response to high-altitude hypoxia and genetic variants in the promoter region of the VEGFA gene in Sherpa highlanders.

Background: Sherpa highlanders demonstrate extraordinary tolerance to hypoxia at high altitudes, which may be achieved by mechanisms promoting microcirculatory blood flow and capillary density at high altitudes for restoring oxygen supply to tissues. Vascular endothelial growth factors (VEGFs) are important signaling proteins involved in vasculogenesis and angiogenesis which are stimulated by hypoxia. We hypothesize that the VEGF-A, the major member of the VEGF family, and the gene encoding VEGF-A (VEGFA) play a part in the adaptation to high-altitude hypoxia in Sherpa highlanders. Methods: Fifty-one Sherpa highlanders in Namche Bazaar village at a high altitude of 3,440 meters (m) above sea level and 76 non-Sherpa lowlanders in Kathmandu city at 1,300 m in Nepal were recruited for the study. Venous blood was sampled to obtain plasma and extract DNA from each subject. The plasma VEGF-A concentrations were measured and five single-nucleotide polymorphisms (SNPs, rs699947, rs833061, rs1570360, rs2010963, and rs3025039) in the VEGFA were genotyped. The VEGF-A levels and allelic frequencies of the SNPs were compared between the two populations. Results: A significant difference in oxygen saturation (SpO2) was observed between the two ethnic groups locating at different elevations (93.7 ± 0.2% in Sherpas at 3,440 m vs. 96.7 ± 0.2% in non-Sherpas at 1,300 m, P < 0.05). The plasma VEGF-A concentration in the Sherpas at high altitude was on the same level as that in the non-Sherpas at low altitude (262.8 ± 17.9 pg/ml vs. 266.8 ± 21.8 pg/ml, P = 0.88). This result suggested that the plasma VEGF-A concentration in Sherpa highlanders was stable despite a high-altitude hypoxic stimulus and that therefore the Sherpas exhibited a phenotype of blunted response to hypoxic stress. Moreover, the allele frequencies of the SNPs rs699947, rs833061, and rs2010963 in the promoter region of the VEGFA were different between the Sherpa highlanders and non-Sherpa lowlanders (corrected P values = 3.30 ×10-5, 4.95 ×10-4, and 1.19 ×10-7, respectively). Conclusions: Sherpa highlanders exhibited a blunted VEGF-A response to hypoxia at high altitudes, which was speculated to be associated with the distinctive genetic variations of the SNPs and haplotype in the promoter region of VEGFA in Sherpa highlanders.

ARID1B, a molecular suppressor of erythropoiesis, is essential for the prevention of Monge's disease.

At high altitude Andean region, hypoxia-induced excessive erythrocytosis (EE) is the defining feature of Monge's disease or chronic mountain sickness (CMS). At the same altitude, resides a population that has developed adaptive mechanism(s) to constrain this hypoxic response (non-CMS). In this study, we utilized an in vitro induced pluripotent stem cell model system to study both populations using genomic and molecular approaches. Our whole genome analysis of the two groups identified differential SNPs between the CMS and non-CMS subjects in the ARID1B region. Under hypoxia, the expression levels of ARID1B significantly increased in the non-CMS cells but decreased in the CMS cells. At the molecular level, ARID1B knockdown (KD) in non-CMS cells increased the levels of the transcriptional regulator GATA1 by 3-fold and RBC levels by 100-fold under hypoxia. ARID1B KD in non-CMS cells led to increased proliferation and EPO sensitivity by lowering p53 levels and decreasing apoptosis through GATA1 mediation. Interestingly, under hypoxia ARID1B showed an epigenetic role, altering the chromatin states of erythroid genes. Indeed, combined Real-time PCR and ATAC-Seq results showed that ARID1B modulates the expression of GATA1 and p53 and chromatin accessibility at GATA1/p53 target genes. We conclude that ARID1B is a novel erythroid regulator under hypoxia that controls various aspects of erythropoiesis in high-altitude dwellers.

Serum Inflammatory Factor Profiles in the Pathogenesis of High-Altitude Polycythemia and Mechanisms of Acclimation to High Altitudes.

High-altitude polycythemia (HAPC) is a common aspect of chronic mountain sickness (CMS) caused by hypoxia and is the main cause of other symptoms associated with CMS. However, its pathogenesis and the mechanisms of high-altitude acclimation have not been fully elucidated. Exposure to high altitude is associated with elevated inflammatory mediators. In this study, the subjects were recruited and placed into a plain control (PC) group, plateau control (PUC) group, early HAPC (eHAPC) group, or a confirmed HAPC (cHAPC) group. Serum samples were collected, and inflammatory factors were measured by a novel antibody array methodology. The serum levels of interleukin-2 (IL-2), interleukin-3 (IL-3), and macrophage chemoattractant protein-1 (MCP-1) in the eHAPC group and the levels of interleukin-1 beta (IL-1 beta), IL-2, IL-3, tumor necrosis factor-alpha (TNF-alpha), MCP-1, and interleukin-16 (IL-16) in the cHAPC group were higher than those in the PUC group. More interestingly, the expression of IL-1 beta, IL-2, IL-3, TNF-alpha, MCP-1, and IL-16 in the PUC group showed a remarkable lower value than that in the PC group. These results suggest that these six factors might be involved in the pathogenesis of HAPC as well as acclimation to high altitudes. Altered inflammatory factors might be new biomarkers for HAPC and for high-altitude acclimation.

Chromatin accessibility landscape and regulatory network of high-altitude hypoxia adaptation.

High-altitude adaptation of Tibetans represents a remarkable case of natural selection during recent human evolution. Previous genome-wide scans found many non-coding variants under selection, suggesting a pressing need to understand the functional role of non-coding regulatory elements (REs). Here, we generate time courses of paired ATAC-seq and RNA-seq data on cultured HUVECs under hypoxic and normoxic conditions. We further develop a variant interpretation methodology (vPECA) to identify active selected REs (ASREs) and associated regulatory network. We discover three causal SNPs of EPAS1, the key adaptive gene for Tibetans. These SNPs decrease the accessibility of ASREs with weakened binding strength of relevant TFs, and cooperatively down-regulate EPAS1 expression. We further construct the downstream network of EPAS1, elucidating its roles in hypoxic response and angiogenesis. Collectively, we provide a systematic approach to interpret phenotype-associated noncoding variants in proper cell types and relevant dynamic conditions, to model their impact on gene regulation.

EPAS1 and VEGFA gene variants are related to the symptoms of acute mountain sickness in Chinese Han population: a cross-sectional study.

BACKGROUND: More people ascend to high altitude (HA) for various activities, and some individuals are susceptible to HA illness after rapidly ascending from plains. Acute mountain sickness (AMS) is a general complaint that affects activities of daily living at HA. Although genomic association analyses suggest that single nucleotide polymorphisms (SNPs) are involved in the genesis of AMS, no major gene variants associated with AMS-related symptoms have been identified. METHODS: In this cross-sectional study, 604 young, healthy Chinese Han men were recruited in June and July of 2012 in Chengdu, and rapidly taken to above 3700 m by plane. Basic demographic parameters were collected at sea level, and heart rate, pulse oxygen saturation (SpO2), systolic and diastolic blood pressure and AMS-related symptoms were determined within 18-24 h after arriving in Lhasa. AMS patients were identified according to the latest Lake Louise scoring system (LLSS). Potential associations between variant genotypes and AMS/AMS-related symptoms were identified by logistic regression after adjusting for potential confounders (age, body mass index and smoking status). RESULTS: In total, 320 subjects (53.0%) were diagnosed with AMS, with no cases of high-altitude pulmonary edema or high-altitude cerebral edema. SpO2 was significantly lower in the AMS group than that in the non-AMS group (P = 0.003). Four SNPs in hypoxia-inducible factor-related genes were found to be associated with AMS before multiple hypothesis testing correction. The rs6756667 (EPAS1) was associated with mild gastrointestinal symptoms (P = 0.013), while rs3025039 (VEGFA) was related to mild headache (P = 0.0007). The combination of rs6756667 GG and rs3025039 CT/TT further increased the risk of developing AMS (OR = 2.70, P < 0.001). CONCLUSIONS: Under the latest LLSS, we find that EPAS1 and VEGFA gene variants are related to AMS susceptibility through different AMS-related symptoms in the Chinese Han population; this tool might be useful for screening susceptible populations and predicting clinical symptoms leading to AMS before an individual reaches HA. TRIAL REGISTRATION: Chinese Clinical Trial Registration, ChiCTR-RCS-12002232 . Registered 31 May 2012.

Downregulation of lung miR-203a-3p expression by high-altitude hypoxia enhances VEGF/Notch signaling.

Hypoxia-related microRNAs (miRNAs) are involved in the pathogenesis of various diseases. Because potential variations in miRNA expression mediated by hypoxic lung injury at high altitude remain incompletely characterized, we used a rat model to investigate the biochemical and miRNA changes induced by high-altitude hypoxia. After 24, 48, or 72 h of hypoxic exposure, expression of VEGF/Notch pathway-related proteins were increased in rat lung tissues. Microarray screening of hypoxic lung samples revealed 57 differentially expressed miRNAs, 19 of which were related to the VEGF/Notch signaling pathway. We verified that the top downregulated miRNA (miR-203a-3p) suppresses VEGF-A translation through direct binding and also indirectly reduces Notch1, VEGFR2, and Hes1 levels, which restricts the angiogenic capacity of pulmonary microvascular endothelial cells in vitro. These findings may aid in the development of new therapeutic strategies for the prevention and treatment of hypoxic lung injury at high altitude.

Cysteine becomes conditionally essential during hypobaric hypoxia and regulates adaptive neuro-physiological responses through CBS/H2S pathway.

Brain is well known for its disproportionate oxygen consumption and high energy-budget for optimal functioning. The decrease in oxygen supply to brain, thus, necessitates rapid activation of adaptive pathways - the absence of which manifest into vivid pathological conditions. Amongst these, oxygen sensing in glio-vascular milieu and H2S-dependent compensatory increase in cerebral blood flow (CBF) is a major adaptive response. We had recently demonstrated that the levels of H2S were significantly decreased during chronic hypobaric hypoxia (HH)-induced neuro-pathological effects. The mechanistic basis of this phenomenon, however, remained to be deciphered. We, here, describe experimental evidence for marked limitation of cysteine during HH - both in animal model as well as human volunteers ascending to high altitude. We show that the preservation of brain cysteine level, employing cysteine pro-drug (N-acetyl-L-cysteine, NAC), markedly curtailed effects of HH - not only on endogenous H2S levels but also, impairment of spatial reference memory in our animal model. We, further, present multiple lines of experimental evidence that the limitation of cysteine was causally governed by physiological propensity of brain to utilize cysteine, in cystathionine beta synthase (CBS)-dependent manner, past its endogenous replenishment potential. Notably, decrease in the levels of brain cysteine manifested despite positive effect (up-regulation) of HH on endogenous cysteine maintenance pathways and thus, qualifying cysteine as a conditionally essential nutrient (CEN) during HH. In brief, our data supports an adaptive, physiological role of CBS-mediated cysteine-utilization pathway - activated to increase endogenous levels of H2S - for optimal responses of brain to hypobaric hypoxia.

Gene Expression Profile Reveals Hematopoietic-Related Molecule Changes in Response to Hypoxic Exposure.

The Qing-Tibet Plateau is characterized by low oxygen pressure, which is an important biomedical and ecological stressor. However, the variation in gene expression during periods of stay on the plateau has not been well studied. We recruited eight volunteers to stay on the plateau for 3, 7, and 30 days. Human Clariom D arrays were used to measure transcriptome changes in the mRNA expression profiles in these volunteers' blood. Analysis of variance (ANOVA) indicated that 699 genes were significantly differentially expressed in response to entering the plateau during hypoxic exposure. The genes with changes in transcript abundance were involved in the terms phosphoprotein, acetylation, protein binding, and protein transport. Furthermore, numerous genes involved in hematopoietic functions, including erythropoiesis and immunoregulation, were differentially expressed in response to hypoxia. This phenomenon may be one of reasons why the majority of people entering the plateau do not have excessive erythrocyte proliferation and are susceptible to infection.

A case-control study of the genetic polymorphism of IL6 and HAPE risk in a Chinese Han population.

AIMS: The role of inflammatory cytokines in High-altitude pulmonary edema (HAPE) remains unclear. The purpose of this study was to evaluate the role of IL4 and IL6 gene polymorphism in the development of HAPE in Chinese people. METHODS: In the present study, we screened ten polymorphisms of IL4 and IL6 gene in 265 HAPE and 303 healthy volunteers. Genotypes were determined using the Sequenom MassARRAY method. Odds ratios (ORs) and 95% confidence intervals (CIs) were calculated by unconditional logistic regression. RESULTS: Two single-nucleotide polymorphisms (SNPs) in the IL6 gene were significantly associated with HAPE. Rs1800796 and rs1524107 (G vs C, OR = 1.31, 95%CI = 1.01-1.69, P = .041 and T vs C, OR = 1.35, 95%CI = 1.05-1.74, P = .020, respectively). However, there did not found any association for IL4 gene. CONCLUSION: Inflammatory cytokines may play a role in the progress of HAPE. These polymorphisms could be genetic markers for predicting the susceptibility to HAPE.

Overexpression of genes associated with hypoxia in cattle adapted to Trans Himalayan region of Ladakh.

Ladakh is an important part of the Trans-Himalayan region located between the Kunlun mountain range in the north and the main Great Himalayas to the south in the state of Jammu and Kashmir of India. The local cattle from Leh and Ladakh region, known as "Ladakhi cattle" is a unique germplasm having an excellent adaptation potential to high altitude hypobaric stress. In the present study, an effort was made to evaluate the transcriptional pattern of hypoxia inducing factor-1 (HIF-1) and several of its regulated genes in PBMCs of local Ladakhi cattle, Holstein Frisian crosses, Jersey (exotic) maintained at high altitude region and Sahiwal (Bos indicus) and Karan Fries (cross bred) cattle maintained in tropical environment. The combined data set indicated increased expression of HIF-1 and its regulated genes viz., glucose transporter 1 (GLUT1), vascular endothelial growth factor (VEGF), and hexokinase (HK2) in high altitude cattle indicating their importance in maintaining cellular homeostasis during high altitude hypoxia. The data indicated that hypoxia associated genes accumulated under hypoxic conditions are part of an essential adaptive component for adaptation to the high altitude of the trans-Himalayan region. In contrary, higher expression of molecular chaperons' viz., HSP70 and HSP90 in tropically adapted cattle give tolerance to high ambient temperature prevalent in tropical condition. In conclusion, HIF-1 and its regulatory genes could be termed as important candidates for producing homeostatic responses to hypoxia in cattle populations reared in higher altitudes of the Trans-Himalayan region.

Tibial dyschondroplasia is highly associated with suppression of tibial angiogenesis through regulating the HIF-1α/VEGF/VEGFR signaling pathway in chickens.

Tibial dyschondroplasia (TD) is an intractable poultry problem that is characterized by the appearance of non-vascularized and non-mineralized cartilage masses in tibial growth plates (TGPs). However, the role of angiogenesis inhibition in the occurrence of TD remains unknown. In this study, we found that, compared to low-altitude Arbor Acres chickens (AACs), high-altitude Tibetan chickens showed higher tibial vascular distributions that were accompanied by up-regulation of hypoxia-inducible factor-1α (HIF-1α), vascular endothelial growth factor A (VEGFA) and VEGF receptors. These observations provide insights into hypoxia-induced angiogenesis, which may be related to the absence of TD in high-altitude native Tibetan chickens. Importantly, hypoxia experiments also showed that during hypoxia, tibial angiogenesis was enhanced, which was due to pro-angiogenic factor up-regulation (including VEGFA, VEGFR1, VEGFR2, and IL-8), in AACs. Moreover, we observed that thiram-induced TD could strongly inhibit tibial angiogenesis in the hypertrophic zone through coordinated down-regulation of HIF-1α and pro-angiogenic factors, leading to a disruption in the blood supply to the TGP. Taken together, these findings reveal that the occurrence of TD is highly associated with inhibition of tibial angiogenesis through down-regulated expression of HIF-1α, VEGFA and VEGF receptors, which results in suppression of TGP development.

The susceptibility gene screening in a Chinese high-altitude pulmonary edema family by whole-exome sequencing.

High-altitude pulmonary edema (HAPE) is one of idiopathic mountain sicknesses that occur in healthy lowlanders when they quickly ascend to altitudes exceeding 2500 m above sea levels within 1-7 days. Growing evidence suggests that genetics plays an important role in the risk of HAPE. In this study, we recruited a Chinese HAPE family and screened genetic variations in the 7 family members (including 6 family members with a medical history of HAPE and the propositus's mother) by whole-exome sequencing. The results showed 18 genetic variations (9 SNVs and 9 Indels) were related to HAPE. Two SNV sites (CFHR4 (p.L85F) and OXER1 (p.R176C)) were predicted to be damaging and alter protein functions by SIFT, PolyPhen-2 and PROVEAN software. The biological function of OXER1 was highly related to the hypoxia-inducible factor pathway. Therefore, those two sites were identified as candidate pathological variations. Moreover, other SNVs (NMB p.S150P, APOB p.I4194T, EIF4ENIF1 p.Q763P) and Indels (KCNJ12 p.EE333-334E, ANKRD31 p.LMN251-253LN, OR2A14 p.HFFC175-178HFC) were also predicted to be damaging as well, which also might be considered as potential candidate pathological variations related to HAPE. Collectively we firstly screened the susceptibility genes in a Chinese HAPE family by whole-exome sequencing, which will provide new clues for further mechanistic studies of HAPE.

Interaction of CARD14, SENP1 and VEGFA polymorphisms on susceptibility to high altitude polycythemia in the Han Chinese population at the Qinghai-Tibetan Plateau.

High altitude polycythemia (HAPC) is a serious public health problem among Han Chinese immigrants to the Qinghai-Tibetan Plateau. This study aims to explore the genetic basis of HAPC in the Han Chinese population. 484 male subjects (234 patients and 250 controls) were enrolled in this study. Genotyping was performed for polymorphisms of I/D in ACE, C1772T and G1790A in exon 12 of HIF-1α, rs2567206 in CYP1B1, rs726354 in SENP1, rs3025033 in VEGFA, rs7251432 in HAMP, rs2075800 in HSPA1L and rs8065364 in CARD14. Gene-gene interaction was assessed by multifactor dimensionality reduction. A significant association was seen between CARD14 polymorphism rs8065364 and risk of HAPC development in male Han Chinese, and the C allele of rs8065364 was a risk factor (odds ratio (OR)=1.59, 95% confidence interval (95% CI)=1.21-2.08). Gene-gene interaction analysis indicated that a synergistic relationship existed between rs3025033 and rs8065364 (1.00%), rs3025033 and rs726354 (0.18%), and rs726354 and rs8065364 (0.17%). The combination of rs8065364 in CARD14, rs3025033 in VEGFA and rs726354 in SENP1 was the best model to predict HAPC development in this study (testing accuracy=0.6183, p=0.0010, cross-validated consistency=10/10). Genetic interactions of SNPs in CARD14, SENP1 and VEGFA might represent a functional mechanism in the pathogenesis of HAPC.

Genetic factors associated with exercise performance in atmospheric hypoxia.

BACKGROUND AND OBJECTIVE: 'Natural selection' has been shown to have enriched the genomes of high-altitude native populations with genetic variants of advantage in this hostile hypoxic environment. In lowlanders who ascend to altitude, genetic factors may also contribute to the substantial interindividual variation in exercise performance noted at altitude. We performed a systematic literature review to identify genetic variants of possible influence on human hypoxic exercise performance, commenting on the strength of any identified associations. CRITERIA FOR CONSIDERING STUDIES FOR THIS REVIEW: All studies of the association of genetic factors with human hypoxic exercise performance, whether at sea level using 'nitrogen dilution of oxygen' (normobaric hypoxia), or at altitude or in low-pressure chambers (field or chamber hypobaric hypoxia, respectively) were sought for review. SEARCH STRATEGY FOR IDENTIFICATION OF STUDIES: Two electronic databases were searched (Ovid MEDLINE, Embase) up to 31 January 2014. We also searched the reference lists of relevant articles for eligible studies. All studies published in English were included, as were studies in any language for which the abstract was available in English. DATA COLLECTION AND ANALYSIS: Studies were selected and data extracted independently by two reviewers. Differences regarding study inclusion were resolved through discussion. The quality of each study was assessed using a scoring system based on published guidelines for conducting and reporting genetic association studies. RESULTS: A total of 11 studies met all inclusion criteria and were included in the review. Subject numbers ranged from 20 to 1,931 and consisted of healthy individuals in all cases. The maximum altitude of exposure ranged from 2,690 to 8,848 m. The exercise performance phenotypes assessed were mountaineering performance (n = 5), running performance (n = 2), and maximum oxygen consumption ([Formula: see text]O2max) (n = 4). In total, 13 genetic polymorphisms were studied, four of which were associated with hypoxic exercise performance. The adenosine monophosphate deaminase (AMPD1) C34T (rs17602729), beta2-adrenergic receptor (ADRB2) Gly16Arg single nucleotide polymorphism (SNP) (rs1042713), and androgen receptor CAG repeat polymorphisms were associated with altitude performance in one study, and the angiotensin I-converting enzyme (ACE) insertion/deletion (I/D) (rs4646994) polymorphism was associated with performance in three studies. The median score achieved in the study quality analysis was 6 out of 10 for case-control studies, 8 out of 10 for cohort studies with a discrete outcome, 6 out of 9 for cohort studies with a continuous outcome, and 4.5 out of 8 for genetic admixture studies. CONCLUSION: The small number of articles identified in the current review and the limited number of polymorphisms studied in total highlights that the influence of genetic factors on exercise performance in hypoxia has not been studied in depth, which precludes firm conclusions being drawn. Support for the association between the ACE-I allele and improved high-altitude performance was the strongest, with three studies identifying a relationship. Analysis of study quality highlights the need for future studies in this field to improve the conduct and reporting of genetic association studies.

Variants of the low oxygen sensors EGLN1 and HIF-1AN associated with acute mountain sickness.

Two low oxygen sensors, Egl nine homolog 1 (EGLN1) and hypoxia-inducible factor 1-α inhibitor (HIF-1AN), play pivotal roles in the regulation of HIF-1α, and high altitude adaption may be involved in the pathology of acute mountain sickness (AMS). Here, we aimed to analyze single nucleotide polymorphisms (SNPs) in the untranslated regions of the EGLN1 and HIF-1AN genes and SNPs chosen from a genome-wide adaptation study of the Han Chinese population. To assess the association between EGLN1 and HIF-1AN SNPs and AMS in a Han Chinese population, a case-control study was performed including 190 patients and 190 controls. In total, thirteen SNPs were genotyped using the MassARRAY® MALDI-TOF system. Multiple genetic models were tested; The Akaike's information criterion (AIC) and Bayesian information criterion (BIC) values indicated that the dominant model may serve as the best-fit model for rs12406290 and rs2153364 of significant difference. However, these data were not significant after Bonferroni correction. No significant association was noted between AMS and rs12757362, rs1339894, rs1361384, rs2009873, rs2739513 or rs2486729 before and after Bonferroni correction. Further haplotype analyses indicated the presence of two blocks in EGLN1; one block consists of rs12406290-rs2153364, located upstream of the EGLN1 gene. Carriers of the "GG" haplotype of rs12406290-rs2153364 exhibited an increased risk of AMS after adjustments for age and smoking status. However, no significant association was observed among HIF-1AN 3'-untranslated region (3'-UTR) polymorphisms, haplotype and AMS. Our study indicates that variants in the EGLN1 5'-UTR influence the susceptibility to AMS in a Han Chinese population.