Establishment of a reference interval for total carbon dioxide using indirect methods in Chinese populations living in high-altitude areas: A retrospective real-world analysis.

BACKGROUND: Hypoxia leads to different concentrations of the bicarbonate buffer system in Tibetan people. Indirect methods were used to establish the reference interval (RI) for total carbon dioxide (tCO2) based on big data from the adult population of Tibet, a high-altitude area in Western China. METHODS: Anonymous tCO2 test data (n = 442,714) were collected from the People's Hospital of the Tibet Autonomous Region from January 2018, to December 2021. Multiple linear regression and variance component analyses were performed to assess the effects of sex, age, and race on tCO2 levels. Indirect methods, including Hoffmann, Bhattacharya, expectation maximization (EM), kosmic and refineR, were used to calculate the total RI and ethnicity-partitioned RI. RESULTS: A total of 230,821 real-world tCO2 test results were eligible. Sex, age, and race were significantly associated with the tCO2 levels. The total and ethnically-partitioned RIs estimated using the five indirect methods were comparable. The total RI of tCO2 was 14-24 mmol/L (calculated using Hoffmann and refineR) and 15-24 mmol/L (Bhattacharya, EM and kosmic). For Han nationality, the RIs were 14-25 mmol/L (calculated using Hoffmann and Bhattacharya), 16-23 mmol/L (EM), 15-24 mmol/L (kosmic), and 14.2-24.5 mmol/L (refineR). For the Tibetan population, the RIs were 14-24 mmol/L (calculated using Hoffmann and refineR), 15-24 mmol/L (Bhattacharya and kosmic), and 15-23 mmol/L (EM). The established RIs were significantly lower than those living at lower altitudes area (22-29 mmol/L) that was provided by the manufacturer. CONCLUSION: The tCO2 RI of the populations living on the Tibetan Plateau was significantly lower than those at the lower altitudes. The RIs established using indirect methods are suitable for clinical applications in Tibet.

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.

Case studies in physiology: Nocturnal cardiorespiratory adaptive differences between an Italian trekker and a Nepali guide.

The cardiopulmonary system is a physiological cornerstone in the adaptive response to hypobaric hypoxia. Portable devices make it feasible nowadays to precisely assess the response to high altitude (HA) expeditions. In this study, we investigated breathing and arterial blood pressure responses during a Himalayan trek from 665 m to 4,780 m altitude in a white European (Italian) sojourner and a native Nepali (Tamang) guide, both healthy males. Resting diurnal and nocturnal data were acquired by means of ambulatory blood pressure monitoring (ABPM) and sleep apnea monitoring. We found an increase in the mean diurnal arterial blood pressure. Nocturnal blood pressure dipping was confirmed at all altitudes. Oxygen saturation decreased at altitude, with its additional nocturnal fall. Sleep apneic episodes, present in the Italian only, increased with altitude. We conclude that the nocturnal, more than diurnal, cardiorespiratory function is affected by HA hypoxia. Further studies should address the role of ethnicity, medications, and sociodemographic factors in the cardiorespiratory responses to hypobaric hypoxia.

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.

Saturación de oxígeno, frecuencia cardiaca y respiratoria en recién nacidos a término en poblaciones de altura / Oxygen saturation, heart and respiratory frequency of term newborns in high-altitude populations

Introducción: La adaptación a la vida extrauterina de los recién nacidos es importante, especialmente en poblaciones de altura donde las características son diferentes a poblaciones a nivel del mar. Objetivos: Determinar la correlación entre saturación de oxígeno, frecuencia cardiaca y respiratoria durante los primeros 720 minutos de vida en recién nacidos a término a 3 400 metros sobre el nivel del mar. Métodos: Estudio observacional, prospectivo. Se incluyó a recién nacidos de parto eutócico a término del servicio de neonatología de un hospital de Cusco-Perú durante octubre y diciembre del 2016. Se evaluó la saturación de oxígeno, frecuencia cardiaca y respiratoria a los 5, 30, 120, 360, 480 y 720 minutos después del nacimiento. Se realizó un análisis descriptivo y se calcularon las correlaciones entre las variables utilizando el coeficiente de Correlación de Pearson. Se consideró significativos los valores p<0,05. Resultados: La media de saturación de oxígeno, frecuencia cardiaca y frecuencia respiratoria fue estable a las dos horas. Se obtuvo una correlación significativa entre la frecuencia cardiaca y saturación de oxígeno a los 5, 30, 120, 360 y 720 minutos. La frecuencia respiratoria y saturación de oxígeno se correlacionó significativamente a los 5, 30, 480 y 720 minutos. Conclusiones: La correlación entre la saturación de oxígeno, frecuencia cardiaca y frecuencia respiratoria es adecuada en distintos periodos. Este estudio contribuye a conocer mejor la adaptación a la vida extrauterina del recién nacido en esta población de altura(AU)

Introduction: Newborns adaptation to extrauterine life is important, especially in high altitude populations where the characteristics are different from sea level populations. Objectives: To estimate the correlation between oxygen saturation, heart and respiratory frequency during the first 720 minutes of life in term newborns at 3 400 meters above sea level. Methods: An observational, prospective study was performed. Newborns from eutocic delivery at term that were born during October and December 2016 in the neonatology service at Cusco-Peru Hospital were included in the study. Oxygen saturation, heart frequency and respiratory frequency were assessed at 5, 30, 120, 360, 480 and 720 minutes after birth. A descriptive analysis was performed and the correlations among the variables were calculated using Pearson's correlation coefficient test. Values p <0.05 were considered significant. Results: Mean oxygen saturation, heart rate and respiratory rate were stable at two hours. A significant correlation was obtained between heart rate and oxygen saturation at 5, 30, 120, 360 and 720 minutes. Respiratory frequency and oxygen saturation correlated significantly at 5, 30, 480 and 720 minutes. Conclusions: Correlation between oxygen saturation, heart rate and respiratory rate are adequate in different periods. This study contributes to better understand the adaptation of newborns in these high altitude populations(AU)

LINE-1 and EPAS1 DNA methylation associations with high-altitude exposure.

Recent discoveries indicate a genetic basis for high-altitude adaptation among human groups who have resided at high altitude for millennia, including Andeans, Tibetans, and Ethiopians. Yet, genetics alone does not explain the extent of variation in altitude-adaptive phenotypes. Current and past environments may also play a role, and one way to determine the effect of the environment is through the epigenome. To characterize if Andean adaptive responses to high altitude have an epigenetic component, we analyzed DNA methylation of the promoter region of EPAS1 and LINE-1 repetitive element among 572 Quechua individuals from high- (4,388 m) and low-altitude (0 m) in Peru. Participants recruited at high altitude had lower EPAS1 DNA methylation and higher LINE-1 methylation. Altitude of birth was associated with higher LINE-1 methylation, not with EPAS1 methylation. The number of years lived at high altitude was negatively associated with EPAS1 methylation and positively associated with LINE-1 methylation. We found four one-carbon metabolism SNPs (MTHFD1 rs2236225, TYMS rs502396, FOLH1 rs202676, GLDC rs10975681) that cumulatively explained 11.29% of the variation in average LINE-1 methylation. And identified an association between LINE-1 methylation and genome-wide SNP principal component 1 that distinguishes European from Indigenous American ancestry suggesting that European admixture decreases LINE-1 methylation. Our results indicate that both current and lifetime exposure to high-altitude hypoxia have an effect on EPAS1 and LINE-1 methylation among Andean Quechua, suggesting that epigenetic modifications may play a role in high-altitude adaptation.

High altitude and pre-eclampsia: Adaptation or protection.

Adaptive genes of high altitude can also be protective in diseases like preeclampsia, hypertension, and diabetes mellitus, Alzheimer, Parkinson Disease and Cancer, which may result from deregulation of hypoxia pathway. The example of pre-eclampsia and normal pregnancy were studied to see if the hypoxia-induced disorders can be dragged towards adaptation. Here, we analyse the genetic variants that are known to be associated with adaptation to high altitude hypoxia. Our results demonstrated that the genetic variants of EPAS1, ADAM9, and EGLN1 increased approximately three-fold in the cases of preeclampsia compared to normal pregnancy. This may suggest the ability of the hypoxic cells of preeclampsia to respond to the high selective pressure of hypoxia with a higher degree of genetic variability, which can lead to adaptation. Signs of "acclimatisation" were seen both in cases and controls but with higher frequencies in controls. This can be a new approach that follows patients' genetic selection and susceptibility of individuals for adaptability, which could be enhanced by drug development.

Plasma Proteomics of Ladakhi Natives Reveal Functional Regulation Between Renin-Angiotensin System and eNOS-cGMP Pathway.

Padhy, Gayatri, Anamika Gangwar, Manish Sharma, Kalpana Bhargava, and Niroj Kumar Sethy. Plasma proteomics of Ladakhi natives reveal functional regulation between renin-angiotensin system and eNOS-cGMP pathway. High Alt Med Biol. 18:27-36, 2017.-Humans have been living in high altitudes for more than 25,000 years but the molecular pathways promoting survival and performance in these extreme environments are not well elucidated. In an attempt to understand human adaptation to high altitudes, we used two-dimensional gel electrophoresis combined with MALDI-TOF/TOF to identify plasma proteins and associated pathways of ethnic Ladakhi natives residing at 3520 m. This resulted in the identification of 36 differential proteins compared with sea-level individuals. Proteins belonging to coagulation cascade and complement activation were found to be less abundant in Ladakhi natives. Interestingly, we observed lower abundance of angiotensinogen (ANGT) and subsequent analysis also revealed lower levels of both ANGT and angiotensin II (Ang II) in Ladakhi natives. Concomitantly, we observed elevated levels of eNOS, phosphorylated eNOS (Ser1177), and plasma biomarkers for nitric oxide (NO) production (nitrate and nitrite) and availability (cGMP). These results suggest that functional interplay between renin-angiotensin system and NO-cGMP pathway contributes to the hypoxia adaptation in Ladakhi natives. These findings will augment the present understanding of higher NO and NO-derived metabolite availability during human adaptation to high altitude.

Angiotensin II receptor 1 gene variants are associated with high-altitude pulmonary edema risk.

Previous studies demonstrated that Angiotensin II Receptor 1 (AGTR1) may play an important role in the development of high-altitude pulmonary edema. We envisaged a role for AGTR1 gene variants in the pathogenesis of HAPE and investigated their potential associations with HAPE in a Han Chinese population. We genotyped seven AGTR1 polymorphisms in 267 patients with diagnosed HAPE and 304 controls and evaluated their association with risk of HAPE. Statistically significant associations were found for the single nucleotide polymorphisms (SNPs) rs275651 (p = 0.017; odds ratio [OR] = 0.65) and rs275652 (p = 0.016; OR = 0.64). Another SNP rs10941679 showed a marginally significant association after adjusting for age and sex in the additive genetic model (adjusted OR = 1.44, 95% CI = 1.01-2.04, p = 0.040). Haplotype analysis confirmed that the haplotype "AG" was associated with a 35% reduction in the risk of developing HAPE, while the haplotype "AA" increased the risk of developing HAPE by 44%. These results provide the first evidence linking genetic variations in AGTR1 with HAPE risk in Han Chinese individuals.

Telomere length-related gene ACYP2 polymorphism is associated with the risk of HAPE in Chinese Han population.

BACKGROUND: High altitude pulmonary edema (HAPE) is a type of pneumonedema that mostly occurs under conditions such as high altitude, rapid ascent and hypoxia, amongst others. The ACYP2 polymorphism is suggested to be associated with mean telomere length, and telomere length is significantly longer at a moderate attitude than at sea-level or at simulated high attitude. The present study aimed to determine whethher there is any association between ACYP2 polymorphism and the risk of HAPE. METHODS: A total of 265 patients and 303 healthy controls were enrolled in our case-control study. Six SNPs were selected and genotyped using the Sequenom MassARRAY method. Odds ratios (ORs) and 95% confidence intervals (95% CIs) were calculated by unconditional logistic regression with adjustment for gender and age. RESULTS: Using chi-squared tests, we found that the minor allele G of rs11896604 is significantly associated with a decreased risk of HAPE [odds ratio (OR) = 0.87, 95% confidence interval (CI) = 0.65-1.16, p = 0.048]. We also found that the 'A/A' genotype of rs12615793 is associated with a decreased risk of HAPE based on the recessive model (OR =0.28; 95% CI = 0.09-0.88; p = 0.017). Additionally, the 'G/G' genotype of rs11896604 was found to be associated with a decreased risk of HAPE based on the codominant model (OR =0.26; 95% CI = 0.08-0.79; p = 0.025) and recessive model (OR =0.25; 95% CI = 0.08-0.77; p = 0.007). However, only rs11896604 remained significant after Bonferroni correction (p < 0.0083). CONCLUSIONS: The present study found that the ACYP2 gene polymorphism significantly decreased the risk of HAPE. Copyright © 2016 John Wiley & Sons, Ltd. Copyright © 2016 John Wiley & Sons, Ltd.

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.

HIF2A Variants Were Associated with Different Levels of High-Altitude Hypoxia among Native Tibetans.

Hypoxia inducible factors, including HIF1A and HIF2A, play central roles in response to high-altitude hypoxia and genetic variants of HIF1A or HIF2A were associated with high-altitude sickness or adaptation. However, it remains to determine whether they are associated with tolerance to different levels of high-altitude selection pressure among native Tibetans. We recruited 189 Tibetan subjects living at 2,700 meters (Low level of high altitude, LHA), 197 at 3,200 meters (Middle level of high altitude of high altitude, MHA), 249 at 3,700 meters (High level of high altitude, HHA) and 269 at 4,700 meters (Very high level of high altitude, VHA) and performed association analysis of twelve tSNPs (tagging SNPs) in HIF1A and HIF2A with high-altitude. We found (1) a increasing trend of HIF2A rs5621780-C(18.4%, 15.9%, 32.8% and 31.1%, respectively, in LHA, MHA, HHA and VHA)(P = 3.56E-9); (2) increasing trends of HIF2A rs6756667-A(68.7%, 73.4%, 79.9% and 89.6%), rs7589621- G(74.6%, 77.9%, 83.7%, and 92.1%) and rs1868092-A(64.1%, 67.3%, 75.1% and 84.4%) (P = 3.56E-9, 4.68E-16, 1.17E-13 and 7.09E-14, respectively); (3) a increasing trend of haplotype AG (68.7%, 73.1%, 79.9% and 89.6%) (P = 2.22E-7) which was constructed by rs6756667 and rs7589621; (4) a strong linear correlation between major alleles of rs6756667-A (R2 = 0.997, P = 0.002), rs7589621-G (R2 = 0.994, P = 0.003), rs1868092-A (R2 = 0.985, P = 0.008) and altitude by linear correlation test. The associations between HIF2A variants and different level of high altitude support that extremely high-altitude hypoxia challenge imposes selective effects on HIF2A variants among native Tibetans.

Factors associated with acute mountain sickness in young Chinese men on entering highland areas.

AIM: The aim of this study was to explore the prediction factors for incidence of acute mountain sickness (AMS) in young males newly entering highland areas. METHODS: A retrospective study of 4367 records of male highland soldiers from 2000 to 2005 was done. The factors were tested by logistic regression. RESULTS: After selection by univariate model, ethnicity, altitude, season, deployment type, and prophylaxis were inserted into a multivariate model. The adjusted odds ratio (AOR) was 0.078 for Tibetan compared with Han. AORs for altitudes 3600 to 3700, 4000 to 4300, and 4600 to 4700 m versus 2900 to 3100 m were 4.490, 4.532, and 4.964, respectively. AOR for cold season versus warm season was 1.332. AORs for emergency land deployment and air deployment versus normal land deployment were 2.261 and 1.614, respectively. The AOR was 0.741 for prophylaxis versus none. The area under receiver operating characteristic curve was 0.731 (optimal cutoff = 0.370). CONCLUSIONS: Adjusting for altitude, risk factors that contributed to AMS were being non-Tibetan, cold season, greater speed of transport, emergency conditions, and without prophylaxis. The model established is acceptable for assisting AMS prediction.

The genetic basis of chronic mountain sickness.

Chronic mountain sickness (CMS) is a disease that affects many high-altitude dwellers, particularly in the Andean Mountains in South America. The hallmark symptom of CMS is polycythemia, which causes increased risk of pulmonary hypertension and stroke (among other symptoms). A prevailing hypothesis in high-altitude medicine is that CMS results from a population-specific "maladaptation" to the hypoxic conditions at high altitude. In contrast, the prevalence of CMS is very low in other high-altitude populations (e.g., Tibetans and Ethiopians), which are seemingly well adapted to hypoxia. In recent years, concurrent with the advent of genomic technologies, several studies have investigated the genetic basis of adaptation to altitude. These studies have identified several candidate genes that may underlie the adaptation, or maladaptation. Interestingly, some of these genes are targeted by known drugs, raising the possibility of new treatments for CMS and other ischemic diseases. We review recent discoveries, alongside the methodologies used to obtain them, and outline some of the challenges remaining in the field.

Polymorphisms of the tissue inhibitor of metalloproteinase 3 gene are associated with resistance to high-altitude pulmonary edema (HAPE) in a Japanese population: a case control study using polymorphic microsatellite markers.

INTRODUCTION: High-altitude pulmonary edema (HAPE) is a hypoxia-induced, life-threatening, high permeability type of edema attributable to pulmonary capillary stress failure. Genome-wide association analysis is necessary to better understand how genetics influence the outcome of HAPE. MATERIALS AND METHODS: DNA samples were collected from 53 subjects susceptible to HAPE (HAPE-s) and 67 elite Alpinists resistant to HAPE (HAPE-r). The genome scan was carried out using 400 polymorphic microsatellite markers throughout the whole genome in all subjects. In addition, six single nucleotide polymorphisms (SNPs) of the gene encoding the tissue inhibitor of metalloproteinase 3 (TIMP3) were genotyped by Taqman® SNP Genotyping Assays. RESULTS: The results were analyzed using case-control comparisons. Whole genome scanning revealed that allele frequencies in nine markers were statistically different between HAPE-s and HAPE-r subjects. The SNP genotyping of the TIMP3 gene revealed that the derived allele C of rs130293 was associated with resistance to HAPE [odds ratio (OR) = 0.21, P = 0.0012) and recessive inheritance of the phenotype of HAPE-s (P = 0.0012). A haplotype CAC carrying allele C of rs130293 was associated with resistance to HAPE. DISCUSSION: This genome-wide association study revealed several novel candidate genes associated with susceptibility or resistance to HAPE in a Japanese population. Among those, the minor allele C of rs130293 (C/T) in the TIMP3 gene was linked to resistance to HAPE; while, the ancestral allele T was associated with susceptibility to HAPE.

Hypoxia-related altitude illnesses.

BACKGROUND: Millions of tourists and climbers visit high altitudes annually. Many unsuspecting and otherwise healthy individuals may get sick when sojourning to these high regions. Acute mountain sickness represents the most common illness, which is usually benign but can rapidly progress to the more severe and potentially fatal forms of high-altitude cerebral edema and high-altitude pulmonary edema. METHODS: Data were identified by searches of Medline (1965 to May 2012) and references from relevant articles and books. Studies, reviews, and books specifically pertaining to the epidemiology, prevention, and treatment of high-altitude illnesses in travelers were selected. RESULTS: This review provides information on geographical aspects, physiology/pathophysiology, clinical features, risk factors, and the prevalence of high-altitude illnesses and also state-of-the art recommendations for prevention and treatment of such illnesses. CONCLUSION: Given an increasing number of recreational activities at high and extreme altitudes, the general practitioner and specialist are in higher demand for medical recommendations regarding the prevention and treatment of altitude illness. Despite an ongoing scientific discussion and controversies about the pathophysiological causes of altitude illness, treatment and prevention recommendations are clearer with increased experience over the last two decades.

Polymorphisms of angiotensin converting enzyme and nitric oxide synthase 3 genes as risk factors of high-altitude pulmonary edema: a case-control study and meta-analysis.

High-altitude pulmonary edema (HAPE) is a non-cardiogenic type of pulmonary edema developing altitudes > 2,500 m. Angiotensin converting enzyme (ACE) and nitric oxide synthase 3 (NOS3) play important roles in regulating pulmonary vascular tone. To assess associations between genetic variants in the ACE and NOS3 genes and HAPE risk, 27 HAPE patients and 108 matched controls were genotyped and analyzed. The indicated HAPE association of the NOS3 G894T (Glu298Asp) single nucleotide polymorphism (SNP), which may change NO production, was further evaluated by a meta-analysis of six studies involving 399 HAPE patients and 495 controls. Odds ratios (ORs) and 95% confidence intervals (CIs) were determined with fixed-effects models. Stratification analyses of ethnicity and geographic location were performed. Significant associations were observed for the dominant model in two ACE tag SNPs influencing serum ACE concentrations (rs8066114 polymorphism: GG+CG vs. CC; rs4461142 polymorphism: TT+CT vs. CC). Furthermore, Single-locus analysis indicated significantly different distributions of G allele frequency between the cases (29.63%) and controls (17.13%) for the ACE rs8066114 polymorphism. The case-control distributions of genotype frequencies and T allele frequency of NOS3 G894T (Glu298Asp) polymorphism were significantly higher in the cases than controls, and the NOS3 G894T (Glu298Asp) SNP showed elevated HAPE risk under the dominant model (TT+GT vs. GG). Meta-analysis showed overall association of NOS3 G894T SNP with HAPE risk under the allele contrast and dominant genetic models, which remained significant for Asians. In conclusion, ACE rs8066114 and rs4461142 and NOS3 rs1799983 (G894T) polymorphisms may be associated with increased HAPE risk in Asians.

Management of high altitude pulmonary edema in the Himalaya: a review of 56 cases presenting at Pheriche medical aid post (4240 m).

OBJECTIVE: The purpose of this study was to review the patient characteristics and management of 56 cases of high altitude pulmonary edema at the Pheriche Himalayan Rescue Association Medical Aid Post, and to measure the use of medications in addition to descent and oxygen. METHODS: In a retrospective case series, we reviewed all patients diagnosed clinically with high altitude pulmonary edema during the 2010 Spring and Fall seasons. Nationality, altitude at onset of symptoms, physical examination findings, therapies administered, and evacuation methods were evaluated. RESULTS: Of all patients, 23% were Nepalese, with no difference in clinical features compared with non-Nepalese patients; 28% of all patients were also suspected of having high altitude cerebral edema. Symptoms developed in 91% of all patients at an altitude higher than the aid post (median altitude of onset of 4834 m); 83% received oxygen therapy, and 87% received nifedipine, 44% sildenafil, 32% dexamethasone, and 39% acetazolamide. Patients who were administered sildenafil, dexamethasone, or acetazolamide had presented with significantly lower initial oxygen saturations (P ≤ .05). After treatment, 93% of all patients descended; 38% descended on foot without a supply of oxygen. CONCLUSIONS: A significant number of patients presenting to the Pheriche medical aid post with high altitude pulmonary edema were given dexamethasone, sildenafil, or acetazolamide in addition to oxygen, nifedipine, and descent. This finding may be related to perceived severity of illness and evacuation limitations. Although no adverse effects were observed, the use of multiple medications is not supported by current evidence and should not be widely adopted without further study.