Associations between NKX2-5 gene polymorphisms and congenital heart disease in the Chinese Tibetan population.

BACKGROUND: The pathogenesis of congenital heart disease (CHD) has not been fully elucidated, and this study considers the interaction between inheritance and the environment as the main cause of CHD. Previous studies have found that the incidence of CHD in the Tibetan plateau population is significantly higher than in low-altitude populations. Numerous reports have confirmed that NKX2-5 gene mutations can lead to coronary heart disease, but the relationship between NKX2-5 and Tibetan nationality has not yet been reported. OBJECTIVE: To explore the relationship between NKX2-5 gene polymorphisms and CHD in Tibetan people. METHODS: Blood samples were collected retrospectively from Tibetan patients diagnosed with CHD as well as healthy Tibetans, and the exons of NKX2-5 were sequenced. The MassARRAY technique was used to detect and genotype candidate tag single nucleotide polymorphisms (SNPs) in the non-coding regions of NKX2-5. RESULTS: Exon sequencing revealed no difference in the coding regions of the NKX2-5 gene between the CHD and control groups. In the non-coding regions of NKX2-5, rs6882776 and rs2546741 differed significantly between the two groups. Strong linkage disequilibrium was found between the selected sites of NKX2-5. CONCLUSIONS: The NKX2-5 exons do not associate with CHD in Tibetans. Rs6882776 and rs2546741 in the non-coding regions of NKX2-5 may protect against CHD in Tibetans. The NKX2-5 haplotype associated with CHD occurrence in the Tibetan population.

Comparative genomic analysis of high-altitude adaptation for Mongolia Mastiff, Tibetan Mastiff, and Canis Lupus.

Tibetan Mastiff has adapted to the extreme environment of the Qinghai-Tibetan Plateau. Yet, the underlying mechanisms of its high-altitude-adaptation and origin remains elusive. Here, we generated the draft genomes of Mongolia Mastiff, Tibetan Mastiff, and Canis Lupus. The phylogenetic tree uncovered that Tibetan Mastiff and Mongolia Mastiff were derived from Canis Lupus species. The comparative genomic analyses identified that the expansion of gene families related to DNA repair and damage response, and contraction related to ATPase activity revealed the genetic adaptations of Tibetan Mastiff and Canis Lupus to high altitude. In addition, the Tibetan Mastiff and Canis Lupus had signals of positive selection for genes involved in fatty-acid α/ß- oxidation for highland adaptation. Notably, the positively selected TERT of Tibetan Mastiff should be an adaptive trait for correcting DNA damage. These findings suggested that the Tibetan Mastiff and Canis Lupus evolves basic strategies for adaptation to high altitude.

Association Between the Polymorphism of Steroid Hormone Metabolism Genes and High-Altitude Pulmonary Edema in the Chinese Han Population.

PURPOSE: Steroid hormone metabolism plays an essential role in high-altitude pulmonary edema (HAPE) progression. This study aimed to investigate the association between polymorphism in seven steroid hormone metabolism genes (STAR, HSD3B1, HSD3B2, CYP17A1, CYP21A2, CYP11B1, and CYP11B2) and HAPE susceptibility among Han Chinese. PATIENTS AND METHODS: A total of 41 tagSNPs in the seven genes were genotyped using Sequenom MassARRAY SNP assays from 169 HAPE patients (HAPE-p) and 309 matched Han Chinese individuals resistant to HAPE (HAPE-r). The genotypic and allele frequencies, odds ratios (ORs), and 95% confidence intervals (95% CIs) were calculated. RESULTS: Four SNPs, including the allele C of rs6203 (p = 0.034, OR [95% CI] = 1.344 [1.022-1.767]) in HSD3B1, allele G of rs3740397 (p = 0.044, OR [95% CI] = 1.314 [1.007-1.714]) and allele C of rs10786712 (p = 0.039, OR [95% CI] = 0.751 [0.572-0.986]) in CYP17A1, and allele T of rs6402 (p = 0.006, OR [95% CI] = 0.504 [0.306-0.830]) in CYP11B1, were significantly associated with HAPE. The distribution of the genotypes of these SNPs also significantly differed between the HAPE-p and HAPE-r groups. Moreover, six haplotypes (the linkage disequilibrium block including rs10883783, rs4919686, rs3740397, rs3824755, and rs10786712) of CYP17A1 were also significantly associated with HAPE. CONCLUSION: The four SNPs located in HSD3B1 (rs6203), CYP17A1 (rs3740397 and rs10786712), and CYP11B1 (rs6402) and the six haplotypes of CYP17A1 are likely to have an effect on HAPE.

Novel insights into plasma biomarker candidates in patients with chronic mountain sickness based on proteomics.

Chronic mountain sickness (CMS) is a progressive incapacitating syndrome induced by lifelong exposure to hypoxia. In the present study, proteomic analysis was used to identify the differentially expressed proteins (DEPs) and then evaluate the potential plasma biomarkers between CMS and non-CMS groups. A total of 145 DEPs were detected in CMS Han Chinese people who live in the plateau (CMS-HPu), among which 89 were significantly up-regulated and 56 were significantly down-regulated. GO enrichment analysis showed that various biological processes were enriched, including the hydrogen peroxide metabolic/catabolic process, reactive oxygen species (ROS) metabolic, and acute inflammatory response. Protein-protein interaction analysis showed that antioxidant activity, the hydrogen peroxide catabolic process and peroxidase activity were primarily mapped in interaction proteins. Nine modules showed significantly clustering based on WGCNA analysis, with two being the most significant, and GO analysis showed that proteins of both modules were primarily enriched in oxidative stress-related biological processes. Four DEPs increased in CMS patients were evaluated as the candidate biomarkers, and three showed significant AUC: hemoglobin ß chain (HB-ß), thioredoxin-1 (TRX1), and phosphoglycerate kinase 1 (PGK1). The present study provides insights into the pathogenesis of CMS and further evaluates the potentially biomarkers for its prevention and treatment of it.

Exploring the Mechanism of Swertia mussotii Franch. for Hepatoprotective Effects with iTRAQ LC-MS/MS.

BACKGROUND AND OBJECTIVE: A Tibetan traditional herb named Swertia mussotii Franch., also called "Zangyinchen" by the local people of the Qinghai-Tibet area, has been used to protect the liver from injury for many years. However, the curative effect and molecular mechanism of the herb have not been demonstrated clearly. MATERIALS AND METHODS: In our study, serum alanine aminotransferase, aspartate aminotransferase, and total bilirubin levels were examined after S. mussotii Franch. treatment of the acute liver injury on the carbon tetrachloride-induced rat model. Then, proteome analysis was conducted to explore the potential mechanism of SMT for hepatoprotective effects after iTRAQLC-MS/MS analysis (isobaric tag for relative and absolute quantification-liquid chromatography-mass spectrometer with tandem mass spectrometry). RESULTS: Serum results showed that alanine aminotransferase, aspartate aminotransferase, and total bilirubin levels of rats with acute liver injury were all improved with SMT treatment. Moreover, proteome analysis suggested that, with S. mussotii Franch. treatment, the levels of lipid catabolic process and lipid homeostasis were all enhanced. Furthermore, the results of protein-protein interaction (PPI) analysis illustrated that the proteins assembled in PPI networks were found to be significantly enriched in response to lipid, negative regulation of lipase activity, and in response to lipopolysaccharides. Furthermore, the down-regulated MRP14 and MRP8 proteins were found to be involved in the lipid metabolism, which may indicate the mechanism of SMT for the protection of the liver from ALI induced by carbon tetrachloride. CONCLUSION: SMT herb could play a role in hepatoprotection and alleviating the acute liver injury by impacting the lipid metabolism associated with the biological process.

Exploration of the Hepatoprotective Effect and Mechanism of Swertia mussotii Franch in an Acute Liver Injury Rat Model.

BACKGROUND AND OBJECTIVE: Swertia mussotii Franch, also known as "Zangyinchen", is one of a Tibetan traditional herb used for treatment of liver diseases over thousands of years at Qinghai-Tibet Plateau, has been confirmed to be hepatoprotective. However, the underlying mechanism is largely unknown. MATERIALS AND METHODS: In this study, we evaluated the effect of S. mussotii treatment in a carbon tetrachloride-induced acute liver injury rat model by examining the serum alanine aminotransferase, aspartate aminotransferase, total bilirubin levels and performing histological observations of the liver tissues. Meanwhile, the metabolomics analysis was used to explore the molecular mechanism of S. mussotii treatment by high performance liquid chromatography tandem mass spectrometry. RESULTS: The results showed that S. mussotii treatment could effectively improve the serum alanine aminotransferase, aspartate aminotransferase, total bilirubin in acute liver injury rat model. Histological observation showed that S. mussotii treatment could effectively alleviate liver injury. Moreover, the metabolomics analysis showed that S. mussotii treatment could normalize the levels of many fatty acid metabolism related metabolites. And the results of pathway analysis showed that these metabolites significantly enriched in fatty acid biosynthesis pathway (myristic acid, dodecanoic acid and capric acid) and linoleic acid metabolism pathway (13-OxoODE). CONCLUSION: The results indicated that S. mussotii treatment could significantly improve acute liver injury through affecting the pathways related to lipid metabolism.

Adaptive Changes in Hemoglobin Function in High-Altitude Tibetan Canids Were Derived via Gene Conversion and Introgression.

A key question in evolutionary biology concerns the relative importance of different sources of adaptive genetic variation, such as de novo mutations, standing variation, and introgressive hybridization. A corollary question concerns how allelic variants derived from these different sources may influence the molecular basis of phenotypic adaptation. Here, we use a protein-engineering approach to examine the phenotypic effect of putatively adaptive hemoglobin (Hb) mutations in the high-altitude Tibetan wolf that were selectively introgressed into the Tibetan mastiff, a high-altitude dog breed that is renowned for its hypoxia tolerance. Experiments revealed that the introgressed coding variants confer an increased Hb-O2 affinity in conjunction with an enhanced Bohr effect. We also document that affinity-enhancing mutations in the ß-globin gene of Tibetan wolf were originally derived via interparalog gene conversion from a tandemly linked ß-globin pseudogene. Thus, affinity-enhancing mutations were introduced into the ß-globin gene of Tibetan wolf via one form of intragenomic lateral transfer (ectopic gene conversion) and were subsequently introduced into the Tibetan mastiff genome via a second form of lateral transfer (introgression). Site-directed mutagenesis experiments revealed that the increased Hb-O2 affinity requires a specific two-site combination of amino acid replacements, suggesting that the molecular underpinnings of Hb adaptation in Tibetan mastiff (involving mutations that arose in a nonexpressed gene and which originally fixed in Tibetan wolf) may be qualitatively distinct from functionally similar changes in protein function that could have evolved via sequential fixation of de novo mutations during the breed's relatively short duration of residency at high altitude.

NR3C1 gene polymorphisms are associated with high-altitude pulmonary edema in Han Chinese.

BACKGROUND: High-altitude pulmonary edema (HAPE) is a life-threatening form of non-cardiogenic edema which occurs in unacclimatized individuals after rapid ascent to high altitude. NR3C1 gene encodes for glucocorticoid receptor (GR) which plays an important role in stress and inflammation. This study aimed to investigate the association of NR3C1 polymorphisms with the susceptibility to HAPE in Han Chinese. METHODS: The 30 SNPs in the NR3C1 gene were genotyped by the Sequenom MassARRAY SNP assay in 133 HAPE patients (HAPE-p) and 135 matched Han Chinese resistant to HAPE (HAPE-r). The genotypic and allele frequencies, odds ratios (ORs), and 95% confidence intervals (95% CIs) were calculated, respectively. RESULTS: The 12 SNPs showed a significant difference between the HAPE-p and HAPE-r groups. In allelic model analysis, we found that the allele "A" of rs17287745, rs17209237, rs17209251, rs6877893, and rs1866388; the allele "C" of rs6191, rs6188, and rs2918417; the allele "T" of rs33388 and rs4634384; and the allele "G" of rs41423247 and rs10052957 were associated with increased the risk of HAPE. In the genetic model analysis, we found that rs17287745, rs6191, rs6188, rs33388, rs2918417, rs6877893, rs1866388, rs41423247, rs4634384, and rs10052957 were relevant to the increased HAPE risk under the dominant model. In addition, the haplotype AACACTCAAGTG of the 12 SNPs was detected to be significantly associated with HAPE risk (OR = 2.044, 95%CI = 1.339~3.120, P = 0.0008), while the haplotype GGAGCACGACCG was associated with the decreased risk of HAPE (OR = 0.573, 95% CI = 0.333~0.985, P = 0.0422). CONCLUSIONS: Our findings provide new evidence for the association between SNPs in NR3C1 and an increased risk of HAPE in the Chinese population. NR3C1 polymorphisms are associated with the susceptibility to HAPE in Han Chinese.

NR3C2 Gene is Associated with Susceptibility to High-Altitude Pulmonary Edema in Han Chinese.

INTRODUCTION: The mineralocorticoid receptor is encoded by the NR3C2 gene and plays an important role in regulating vascular tone in high-altitude pulmonary edema (HAPE). This study aimed to investigate the association of the polymorphisms in the NR3C2 gene with HAPE susceptibility in Han Chinese. METHODS: We enrolled 133 HAPE patients and 131 matched healthy Han Chinese from the Yushu area in Qinghai, where the altitude is greater than 3500 m. Two single nucleotide polymorphisms (SNPs) of the NR3C2 gene, rs2070951 and rs5522, were genotyped by the Sequenom MassARRAY SNP assay. RESULTS: The genotypic distributions and allele frequencies of NR3C2 SNP rs5522 were significantly different between the HAPE and control groups (P<0.05). The frequency of the A allele of rs5522 was significantly higher in the HAPE group than in the control group (P<0.05) with an odds ratio of 1.7 (95% CI: 1.0-2.8). There were no significant differences in the genotypic distributions and allele frequencies of NR3C2 SNP rs2070951 between the HAPE and control groups. The frequencies of the C-A and C-G haplotypes were significantly higher in the HAPE group than in control group. CONCLUSIONS: The rs5522 polymorphism of the NR3C2 gene was associated with HAPE susceptibility in Chinese subjects. The A allele may contribute to the susceptibility to HAPE. The frequency of the C-A and C-G haplotypes of rs2070951 and rs5522 in the NR3C2 gene may increase the risk of HAPE.

Sequencing the exons of human glucocorticoid receptor (NR3C1) gene in Han Chinese with high-altitude pulmonary edema.

BACKGROUND: High-altitude pulmonary edema (HAPE) is a serious acute mountain sickness that mainly occurs in non-acclimatized individuals after rapid ascent to high altitude. The precise etiology of HAPE remains unclear. This study aimed to investigate whether NR3C1 gene polymorphism is associated with the susceptibility to HAPE. METHODS: The exons of NR3C1 gene were sequenced by a ABI 3730 DNA analyzer in 133 HAPE patients and matched 135 healthy Han Chinese controls from the Yushu area in Qinghai (the altitude greater than 3500 m). RESULTS: DNA sequencing showed the heterozygous substitutions at codon 588 (rs6194) in exon 6 and 766 (rs6196) in exon 9 of NR3C1 gene. The genotypic distributions and allelic frequencies of NR3C1 SNP rs6194 showed significant differences in two groups (P < 0.05). The frequencies of the C allele were significantly higher in the HAPE group than in the control group (P < 0.05) with an odds ratio of 3.009 (95% CI = 1.250-7.244). There were no differences in genotypic and allelic frequencies in rs6196 polymorphism between the two groups. CONCLUSIONS: NR3C1 gene rs6194 polymorphism is correlated with HAPE susceptibility. CC genotype and C allele of rs6194 polymorphism might increase the risk of HAPE in Han Chinese.

The combination of crocin with cisplatin suppresses growth of gastric carcinoma cell line BGC-823 and promotes cell apoptosis.

This study aimed to investigate the efficacy of crocin alone and in combination with cisplatin in the therapy of gastric carcinoma cells. In this study, human gastric carcinoma cell line BGC-823 was purchased and maintained in standard condition. Crocin, cisplatin and crocin plus cisplatin diluted to different concentrations were added into medium, respectively. MTT assay and flow cytometry were performed to test the anti-proliferation effects and apoptosis rates of cells, respectively. In addition, quantitative RT-PCR was used to detect the mRNA expression of apoptosis-related genes, such as p53, Bax and Bcl-2. After treated with different concentrations of crocin, the inhibition ratio and apoptosis rate of BGC-823 cells were not significantly changed. However, the tumor cell inhibition ratio and apoptosis rate in crocin plus cisplatin group were significantly higher than that in cisplatin, crocin and control group (p<0.05). The treatment of crocin plus cisplatin significantly increased the expression of p53 and Bax (p< 0.05), and significantly decreased the Bcl-2 expression (p<0.05). Collectively, our data demonstrated for the first time that crocin plus cisplatin may be used as a new anticancer drug for the treatment of gastric cancer.

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.

Thymocytes maintain immune activity through telomere elongation in rats under hypoxic conditions.

The main purpose of the present study was to investigate the change in thymocyte telomere length of rats exposed to different hypoxic conditions for different periods of time, as well as its effect on the immune system. A total of 110 male Wistar rats were randomly assigned to one of the three following groups: i) Sea level (SL) group, in which 10 rats were maintained at an altitude of 10 m; ii) moderate altitude (MA) group, in which 50 rats were maintained at an altitude of 2,260 m and then randomly sacrificed on days 1, 3, 7, 15 and 30 (n=10 each); and iii) simulated high altitude (SHA) group, in which 50 rats were maintained at a simulated altitude of 5,000 m, and then randomly sacrificed on days 1, 3, 7, 15 and 30 (n=10 each). The morphological changes of the thymus were observed, while the telomere length, the mRNA and protein expression levels of telomerase reverse transcriptase (TERT), and the peripheral blood lymphocyte count were measured. The results indicated that hypoxia induced morphological changes and apoptosis in thymocytes, as well as atrophy of the thymus tissue, and resulted in a significant increase in telomere length and TERT mRNA and protein expression levels. This effect appeared to be more pronounced in the SHA group compared with that in the MA group; however, no statistically significant changes were observed in the peripheral blood lymphocyte count. Based on these findings, the hypoxia-associated loss of thymic function appears to be only quantitative and not qualitative, and the thymus may be able to maintain its immune function even under hypoxic conditions.

The Local HIF-2α/EPO Pathway in the Bone Marrow is Associated with Excessive Erythrocytosis and the Increase in Bone Marrow Microvessel Density in Chronic Mountain Sickness.

AIM: Chronic mountain sickness (CMS) is characterized by excessive erythrocytosis, and angiogenesis may be involved in the pathogenesis of this disease. The bone marrow niche is the primary site of erythropoiesis and angiogenesis. This study was aimed at investigating the associations of the levels of hypoxia-inducible factors (HIFs), erythropoietin (EPO), and erythropoietin receptor (EPOR), as well as microvessel density (MVD) in the bone marrow with CMS. RESULTS: A total of 34 patients with CMS and 30 control subjects residing in areas at altitudes of 3000-4500 m were recruited for this study. The mRNA and protein expression of HIF-2α and EPO in the bone marrow cells was significantly higher in the CMS patients than in the controls. Moreover, changes in HIF-2α expression in CMS patients were significantly correlated with EPO and hemoglobin levels. In contrast, the expression of mRNA and protein expression of HIF-1α and EPOR did not differ significantly between the CMS and control patients. Increased MVD was observed in the bone marrow of the patients with CMS and it was significantly correlated with hemoglobin. CONCLUSIONS: Bone marrow cells of CMS patients may show enhanced activity of the HIF-2α/EPO pathway, and EPO may regulate the erythropoiesis and vasculogenesis through autocrine or/and paracrine mechanisms in the bone marrow niche. The increased MVD in the bone marrow of CMS patients appears to be involved in the pathogenesis of this disease.

Effects of the aqueous extract of a Tibetan herb, Rhodiola algida var. tangutica on proliferation and HIF-1α, HIF-2α expression in MCF-7 cells under hypoxic condition in vitro.

ETHNOPHARMACOLOGICAL RELEVANCE: Rhodiola algida var. tangutica is a traditional Tibetan herb. Its root and rhizome have been successfully used as an effective clinical remedy for the prevention and treatment of cancer and high-altitude sickness. This study aimed to investigate the effect of Rhodiola algida var. tangutica on hypoxic MCF-7 breast cancer cells and the underlying mechanisms. MATERIALS AND METHODS: The antiproliferative effects of R. algida on MCF-7 breast cancer cells were compared in vitro under hypoxic and normal conditions by using MTT analysis. The influence of R. algida on cancer cell apoptosis was determined by flow cytometry. The expression levels of hypoxia-inducible factor (HIF)-1α and HIF-2α were evaluated by western blot analysis. RESULTS: R. algida inhibited the proliferation of MCF-7 breast cancer cells in a dose- and time-dependent manner. The results of flow cytometry indicated that the antiproliferative effect of R. algida was mediated by apoptosis induction. Pretreatment with R. algida significantly suppressed the hypoxia-induced proliferation and expression of HIF-1α and HIF-2α in MCF-7 breast cancer cells. CONCLUSIONS: R. algida might exert an anti-carcinogenic effect on MCF-7 breast cancer cells by decreasing the protein levels of HIF-1α and HIF-2α, which are overexpressed under hypoxic conditions. This effect might be elicited by inhibiting the hypoxia-induced proliferation of MCF-7 breast cancer cells.

[Association between genetic polymorphisms of EDNRA gene and high altitude polycythemia in Tibetans at the Qinghai-Tibetan Plateau].

OBJECTIVE: To test the hypothesis that the polymorphisms in EDNRA gene are associated with the susceptibility to high-altitude polycythemia (HAPC) in Tibetans at the Qinghai-Tibetan Plateau in China. METHODS: We enrolled 63 Tibetan HAPC patients and 131 healthy, age-and gender-matched control Tibetans. All subjects came from Yushu area of Qinghai where the altitude was over 3,500 meters. Five SNPs of EDNRA gene (rs10003447, rs1801708, rs2048894, rs5335 and rs6841581) were genotyped by the Sequenom MassARRAY SNP assays. RESULTS: None of five SNPs in EDNRA gene were associated with HAPC risk (P=0.742; P=0.733; P=0.828; P=0.417; P=0.096). CONCLUSION: EDNRA gene is likely to have adaptive benefits for high altitude environment. However, it is not protective against HAPC in Tibetans.

Vascular Endothelial Growth Factor as a Prognostic Parameter in Subjects with "Plateau Red Face".

UNLABELLED: Ma, Lan, Ying Chen, Guoen Jin, Yingzhong Yang, Qin Ga, and Ri-Li Ge. Vascular endothelial growth factor as a prognostic parameter in subjects with "plateau red face." High Alt Med Biol 16:147-153, 2015.--Some individuals living at high altitude on the Qinghai Plateau in China develop a red face called " Plateau Red Face" (PRF). It is characterized by telangiectasia of the cheeks, which become a unique ruddy color. It is more common in young females than males, subjects who have polycythemia are more susceptible to PRF, and its pathogenesis is unknown. The aim of this study was to investigate associations between PRF and levels of vascular endothelial growth factor (VEGF). METHODS: A total of 158 subjects (82 male and 76 female) residing at 4300 m and 140 subjects (73 male and 67 female) residing at 2260 m on the Qinghai Plateau, China, participated in this study. The determination and magnitude of PRF is evaluated by the dilation of veins on the face in the Qinghai chronic mountain sickness(CMS) score, established during the World Congress in 2004. Arterial O(2) saturation (Sao(2)), hemoglobin (Hb) concentration, pulmonary function tests, and serum concentration of VEGF (by ELISA) were measured in all participants. RESULTS: The occurrence of PRF was 32.9% (52/158) among subjects living at 4300 m and 15.7% (22/140) among those living at 2260 m. The levels of VEGF in PRF and non-PRF subjects were 399.9±115.6 pg/mL and 270.7±78.1 pg/mL, respectively (p<0.001) at 4300 m, and 244.4±109.0 pg/mL and 135.6±65.3 pg/mL, respectively (p<0.01) at 2260 m. However, comparing the levels of VEGF between the genders and ethnic groups at the same altitude, there were no significant differences between male and female both in Xining (p=0.12) and Maduo (p=0.18). There was also no significant difference between Tibetan and Han nationality in Xining (p=0.71), but In Maduo, the levels of VEGF in Han (351.70±122.62 pg/mL) were higher than that of Tibetan (300.20±102.89 pg/mL), and there was significant difference (p=0.01). Sao2 levels in PRF subjects (86.58±3.49) were lower than those of non-PRF subjects (88.04±3.68; p=0.018), while Hb was higher. Areas under receiver operator characteristic curve for diagnosis of PRF were 0.813, 0.679, and 0.373 for VEGF, Hb, and Sao(2), respectively. VEGF levels correlated positively with Hb levels both in Xining (r=0.367, p<0.001) and Maduo (r=0.319, p<0.001), and only negatively with Sao(2) levels in Maduo (r=-0.424, P<0.001) but not in Xining (r=0.125, p=0.141). CONCLUSION: Chronic hypoxemia may stimulate overproduction of angiogenic cytokine (VEGF), and this peptide may lead to formation of abnormal new vessels and development of congestion in mucosa and conjunctiva. Thus, VEGF may, at least in part, serve as a marker of the pathophysiologic trigger for PRF.

CYP17A1 and CYP2E1 variants associated with high altitude polycythemia in Tibetans at the Qinghai-Tibetan Plateau.

Tibetans adapt to high altitude environments through low blood hemoglobin concentrations. Previous work has identified that CYP17A1 and CYP2E1 genes exhibit evidence of local positive selection for this Tibetan high-altitude adaptation. Nevertheless, despite this apparent genetic advantage, some Tibetans still develop high altitude polycythemia (HAPC) yet the reasons for this remain unknown. We sought to determine if polymorphisms in CYP17A1 and CYP2E1 genes were associated with susceptibility to HAPC in Tibetans at the Qinghai-Tibetan Plateau in China. We enrolled 63 Tibetan HAPC patients and 131 healthy, age- and gender-matched control Tibetans. All subjects are from the Yushu area of Qinghai where the altitude is over 3500 m. Three SNPs of the CYP17A1 including rs3781287, rs11191548 and rs1004467, and four SNPs of CYP2E1 gene, including rs1536836, rs3813865, rs3813867 and rs743535, were genotyped by the Sequenom MassARRAY SNP assays. We discovered that SNP rs1004467 of the CYP17A1 gene and SNP rs3813865 of the CYP2E1 gene were significantly associated with HAPC risk. Furthermore, we identified a positive correlation between these two SNPs and plasma hemoglobin levels. Thus, taken together, our study is the first to our knowledge to show that polymorphisms in the rs1004467 SNP of CYP17A1 and rs3813865 SNP of CYP2E1 correlate with susceptibility to HAPC.

EPAS1 Gene Polymorphisms Are Associated With High Altitude Polycythemia in Tibetans at the Qinghai-Tibetan Plateau.

OBJECTIVE: To test the hypothesis that the polymorphisms in the EPAS1 gene are associated with the susceptibility to high altitude polycythemia (HAPC) in Tibetans at the Qinghai-Tibetan Plateau. METHODS: We enrolled 63 Tibetan HAPC patients and 131 matched healthy Tibetans as a control group, from the Yushu area in Qinghai where the altitude is greater than 3500 m. Eight single-nucleotide polymorphisms (SNPs) of the EPAS1 gene, including rs12619696, rs13420857, rs2881504, rs4953388, rs13419896, rs4953354, rs10187368, and rs7587138, were genotyped by the Sequenom MassARRAY SNP assay. RESULTS: The frequencies of the G allele of EPAS1 SNP rs13419896 were significantly higher in the HAPC group than in the control group (P < .05). Moreover, the A alleles of rs12619696 and rs4953354 were prevalent in the HAPC group, and their counterpart homozygotes were prevalent in the normal Tibetan group (P < .05). CONCLUSIONS: Compared with normal Tibetans, Tibetans with HAPC are maladapted and have a different haplotype in EPAS1 SNPs rs12619696, rs13419896, and rs4953354.

Sleep disturbances in long-term immigrants with chronic mountain sickness: a comparison with healthy immigrants at high altitude.

The aim of this study was to examine sleep disturbances in patients with chronic mountain sickness (CMS). The sleep of 14 patients with CMS and 11 healthy controls with or without sleep disorders (control N: without sleep disorders; control D: with sleep disorders) was studied by polysomnography. Hypopnea was the sleep disorder most commonly suffered by CMS patients and control D subjects. No major differences were observed in sleep structure between CMS and control groups, with the exception of shorter rapid eye movement latency in controls and increased deep non-rapid eye movement in the control N group. Periodic breathing was observed in only two study participants, one each in the CMS and control D groups. The level of saturated oxygen was significantly lower in the CMS group during sleep than the control groups (P<0.05). CMS scores were positively correlated with the apnea-hypopnea index, and negatively correlated with saturated oxygen levels. These results demonstrate that sleep disorders and nocturnal hypoxia are important in the development of CMS.