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.

Disparities in Hypoxemia Detection by Pulse Oximetry Across Self-Identified Racial Groups and Associations With Clinical Outcomes.

OBJECTIVES: To assess disparities in hypoxemia detection by pulse oximetry across self-identified racial groups and associations with clinical outcomes. DESIGN: Observational cohort study from May 5, 2018, to December 31, 2020. SETTING: Three academic medical centers in the United States. PATIENTS: Adults greater than or equal to 18 years who self-identified as White, Black, Asian, or American Indian admitted to the ICU or undergoing surgery during inpatient hospitalization with simultaneous measurements of pulse oximetry-estimated oxygen saturation and arterial blood gas-derived oxygen saturation. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Multivariable models were employed to assess the relationships between race, occult hypoxemia (i.e., arterial blood gas-derived oxygen saturation < 88% despite pulse oximetry-estimated oxygen saturation ≥ 92%), and clinical outcomes of hospital mortality and hospital-free days. One-hundred twenty-eight-thousand two-hundred eighty-five paired pulse oximetry-estimated oxygen saturation-arterial blood gas-derived oxygen saturation measurements were included from 26,603 patients. Pulse oximetry-estimated oxygen saturation on average overestimated arterial blood gas-derived oxygen saturation by 1.57% (1.54-1.61%). Black, Asian, and American Indian patients were more likely to experience occult hypoxemia during hospitalization (estimated probability 6.2% [5.1-7.6%], 6.6% [4.9-8.8%], and 6.6% [4.4-10.0%], respectively) compared with White patients (3.6% [3.4-3.8%]). Black patients had increased odds of occult hypoxemia compared with White patients after adjustment (odds ratio, 1.65; 1.28-2.14; p < 0.001). Differences in occult hypoxemia between Asian and American Indian patients compared with White patients were not significant after adjustment (odds ratio, 1.53; 0.95-2.47; p = 0.077 and odds ratio, 1.31; 0.80-2.16; p = 0.288, respectively). Occult hypoxemia was associated with increased odds of mortality in surgical (odds ratio, 2.96; 1.20-7.28; p = 0.019) and ICU patients (1.36; 1.03-1.80; p = 0.033). Occult hypoxemia was associated with fewer hospital-free days in surgical (-2.5 d [-3.9 to -1.2 d]; p < 0.001) but not ICU patients (0.4 d [-0.7 to 1.4 d]; p = 0.500). CONCLUSIONS: Occult hypoxemia is more common in Black patients compared with White patients and is associated with increased mortality, suggesting potentially important outcome implications for undetected hypoxemia. It is imperative to validate pulse oximetry with expanded racial inclusion.

Analysis of Discrepancies Between Pulse Oximetry and Arterial Oxygen Saturation Measurements by Race and Ethnicity and Association With Organ Dysfunction and Mortality.

Importance: Discrepancies in oxygen saturation measured by pulse oximetry (Spo2), when compared with arterial oxygen saturation (Sao2) measured by arterial blood gas (ABG), may differentially affect patients according to race and ethnicity. However, the association of these disparities with health outcomes is unknown. Objective: To examine racial and ethnic discrepancies between Sao2 and Spo2 measures and their associations with clinical outcomes. Design, Setting, and Participants: This multicenter, retrospective, cross-sectional study included 3 publicly available electronic health record (EHR) databases (ie, the Electronic Intensive Care Unit-Clinical Research Database and Medical Information Mart for Intensive Care III and IV) as well as Emory Healthcare (2014-2021) and Grady Memorial (2014-2020) databases, spanning 215 hospitals and 382 ICUs. From 141 600 hospital encounters with recorded ABG measurements, 87 971 participants with first ABG measurements and an Spo2 of at least 88% within 5 minutes before the ABG test were included. Exposures: Patients with hidden hypoxemia (ie, Spo2 ≥88% but Sao2 <88%). Main Outcomes and Measures: Outcomes, stratified by race and ethnicity, were Sao2 for each Spo2, hidden hypoxemia prevalence, initial demographic characteristics (age, sex), clinical outcomes (in-hospital mortality, length of stay), organ dysfunction by scores (Sequential Organ Failure Assessment [SOFA]), and laboratory values (lactate and creatinine levels) before and 24 hours after the ABG measurement. Results: The first Spo2-Sao2 pairs from 87 971 patient encounters (27 713 [42.9%] women; mean [SE] age, 62.2 [17.0] years; 1919 [2.3%] Asian patients; 26 032 [29.6%] Black patients; 2397 [2.7%] Hispanic patients, and 57 632 [65.5%] White patients) were analyzed, with 4859 (5.5%) having hidden hypoxemia. Hidden hypoxemia was observed in all subgroups with varying incidence (Black: 1785 [6.8%]; Hispanic: 160 [6.0%]; Asian: 92 [4.8%]; White: 2822 [4.9%]) and was associated with greater organ dysfunction 24 hours after the ABG measurement, as evidenced by higher mean (SE) SOFA scores (7.2 [0.1] vs 6.29 [0.02]) and higher in-hospital mortality (eg, among Black patients: 369 [21.1%] vs 3557 [15.0%]; P < .001). Furthermore, patients with hidden hypoxemia had higher mean (SE) lactate levels before (3.15 [0.09] mg/dL vs 2.66 [0.02] mg/dL) and 24 hours after (2.83 [0.14] mg/dL vs 2.27 [0.02] mg/dL) the ABG test, with less lactate clearance (-0.54 [0.12] mg/dL vs -0.79 [0.03] mg/dL). Conclusions and Relevance: In this study, there was greater variability in oxygen saturation levels for a given Spo2 level in patients who self-identified as Black, followed by Hispanic, Asian, and White. Patients with and without hidden hypoxemia were demographically and clinically similar at baseline ABG measurement by SOFA scores, but those with hidden hypoxemia subsequently experienced higher organ dysfunction scores and higher in-hospital mortality.

Sleep Characteristics and Measures of Glucose Metabolism in Blacks: The Jackson Heart Study.

Background Characterizing associations of sleep characteristics with blood-glucose-level factors among blacks may clarify the underlying mechanisms of impaired glucose metabolism and help identify treatment targets to prevent diabetes mellitus in blacks. Methods and Results Cross-sectional analyses were conducted in 789 blacks who completed home sleep apnea testing and 7-day wrist actigraphy in 2012-2016. Sleep-disordered breathing measurements included respiratory event index associated with 4% oxygen desaturation and minimum oxygen saturation. Sleep patterns on actigraphy included fragmented sleep indices. Associations between sleep characteristics (8 exposures) and measures of glucose metabolism (3 outcomes) were determined using multivariable linear regression. Mean (SD) age of the participants was 63 (11) years; 581 (74%) were women; 198 (25%) were diabetes mellitus, and 158 (20%) were taking antihyperglycemic medication. After multivariable adjustment, including antihyperglycemic medication use, the betas (95% CI) for fasting glucose and hemoglobin A1c, respectively, for each SD higher level were 0.13 (0.02, 0.24) mmol/L and 1.11 (0.42, 1.79) mmol/mol for respiratory event index associated with 4% oxygen desaturation and 0.16 (0.05, 0.27) mmol/L and 0.77 (0.10, 1.43) mmol/mol for fragmented sleep indices. Among 589 participants without diabetes mellitus, the betas (95% CI) for homeostatic model assessment of insulin resistance for each SD higher level were 1.09 (1.03, 1.16) for respiratory event index associated with 4% oxygen desaturation, 0.90 (0.85, 0.96) for minimum oxygen saturation, and 1.07 (1.01, 1.13) for fragmented sleep indices. Conclusions Sleep-disordered breathing, overnight hypoxemia, and sleep fragmentation were associated with higher blood glucose levels among blacks.

Effects of oxytocin and carbetocin on farrowing performance.

During sow parturition, there is need for an alternative uterotonic to oxytocin with less potency so piglets are not at risk of hypoxia and stillbirth. In this study, there was examination of carbetocin, a longer lasting analogue of oxytocin, and whether the lesser contractile force and duration resulting as a consequence of this treatment would improve piglet survivability. Following delivery of the first piglet, sows were serially assigned by parity to receive injections of 10 IU oxytocin (n = 35), 0.07 mg carbetocin (n = 36), or serve as a non-injected control (n = 30). The incidence of dystocia and stillbirths was recorded. To estimate liveborn piglet viability, umbilical cord blood samples were obtained from pigs 1, 2, 3 and 8, 9, 10, and lactate content was quantified to assess hypoxia during delivery. A blood sample collected at 24 h was assayed for total protein in plasma (%) as an indicator of colostrum intake. Treatment with oxytocin and carbetocin reduced farrowing duration (P = 0.023) and sows treated with carbetocin had piglets with the least umbilical cord blood lactate (P = 0.008) and plasma protein (P = 0.005) concentrations. These data indicate carbetocin has the efficacy to accelerate piglet delivery and reduce piglet hypoxia, although the reason for reduced plasma protein with this treatment remains unexplained.

UBC-Nepal expedition: phenotypical evidence for evolutionary adaptation in the control of cerebral blood flow and oxygen delivery at high altitude.

KEY POINTS: Sherpa have lived in the Nepal Himalaya for 25-40 thousand years and display positive physiological adaptations to hypoxia. Sherpa have previously been demonstrated to suffer less negative cerebral side effects of ascent to extreme altitude, yet little is known as to whether or not they display differential regulation of oxygen delivery to the brain compared to lowland natives. We demonstrate that Sherpa have lower brain blood flow during ascent to and acclimatization at high altitude compared to lowlanders and that this difference in flow is not attributable to factors such as mean arterial pressure, blood viscosity and pH. The observed lower cerebral oxygen delivery in Sherpa likely represents a positive adaptation that may indicate a cerebral hypometabolic conservation of energy at altitude and/or decreased risk of other cerebral consequences such as vasogenic oedema. ABSTRACT: Debilitating side effects of hypoxia manifest within the central nervous system; however, high-altitude natives of the Tibetan plateau, the Sherpa, experience negligible cerebral effects compared to lowland natives at extreme altitude. Phenotypical optimization of the oxygen cascade has been demonstrated in the systemic circulation of Tibetans and Sherpa, likely underscoring their adapted capacity to thrive at altitude. Yet, little is known as to how the cerebral circulation of Sherpa may be adapted. To examine potential differences in cerebral oxygen delivery in Sherpa compared to lowlanders we measured arterial blood gases and global cerebral blood flow (duplex ultrasound) during a 9 day ascent to 5050 m. Although cerebral oxygen delivery was maintained during ascent in lowlanders, it was significantly reduced in the Sherpa at 3400 m (-30.3 ± 21.6%; P < 0.01) and 4371 m (-14.2 ± 10.7%; P = 0.03). Furthermore, linear mixed effects modelling indicated that independent of differences in mean arterial pressure, pH and blood viscosity, race accounts for an approximately 100 mL min-1 (∼17-34%) lower cerebral blood flow in Sherpa compared to lowlanders across ascent to altitude (P = 0.046). To ascertain the role of chronic hypoxia independent of the ascent, Sherpa who had not recently descended were also examined at 5050 m. In these Sherpa, cerebral oxygen delivery was also lower compared to lowlanders (∼22% lower; P < 0.01). We highlight new information about the influence of race and genetic adaptation in the regulation of cerebral oxygen delivery. The lower cerebral oxygen delivery in the Sherpa potentially represents a positive adaptation considering Sherpa endure less deleterious cerebral consequences than lowlanders at altitude.

Global expression profiling and pathway analysis in two different population groups in relation to high altitude.

High altitude (HA) is associated with number of stresses. Response of these stresses may vary in different populations depending upon altitude, duration of residency, ancestry, geographical variation, lifestyle, and ethnicities. For understanding population variability in transcriptome, array-based global gene expression profiling was performed on extracted RNA of male volunteers of two different lowland population groups, i.e., Indians and Kyrgyz, at baseline and day 7 of HA exposure (3200 m). A total of 97 genes were differentially expressed at basal in Kyrgyz as compared to Indians (82 downregulated and 15 upregulated), and 196 were differentially expressed on day 7 of HA (118 downregulated and 78 upregulated). Ingenuity Pathway Analysis and gene ontology highlighted eIF2 signaling with most significant negative activation z score at basal in Kyrgyz compared to Indians with downregulation of various L- and S-ribosomal proteins indicating marked translational repression. On day 7, cAMP-mediated signaling is most enriched with positive activation z score in Kyrgyz compared to Indians. Plasma cAMP levels were higher in Kyrgyz on day 7 compared to Indians. Extracellular adenosine levels were elevated in both the groups upon HA, but higher in Kyrgyz compared to Indians. Valedictory qRT-PCR showed upregulation of ADORA2B and CD73 along with downregulation of ENTs in Kyrgyz compared to Indians indicating elevated levels of extracellular nucleotides mainly adenosine and activation of extracellular cAMP-adenosine pathway which as per literature triggers endogenous protective mechanisms under stress conditions like hypoxia. Thus, transcriptome changes at HA are population-specific, and it may be necessary to take care while interposing similar results in different populations.

Analysis of Hypoxic and Hypercapnic Ventilatory Response in Healthy Volunteers.

INTRODUCTION: A previous study has suggested that the Human Leukocyte Antigen (HLA) allele DQB1*06:02 affects hypoxic ventilatory response (HVR) but not hypercapnic ventilatory response (HCVR) in an Asian population. The current study evaluated the relationship in Caucasians and Asians. In addition we assessed whether gender or polymorphisms in genes participating in the control of breathing affect HVR and HCVR. METHODS: A re-breathing system was used to measure HVR and HCVR in 551 young adults (56.8% Caucasians, 30% Asians). HLA-DQB1*06:02 and tagged polymorphisms and coding variants in genes participating in breathing (PHOX2B, GPR4 and TASK2/KCNK5) were analyzed. The associations between HVR/HCVR and HLA-DQB1*06:02, genetic polymorphisms, and gender were evaluated using ANOVA or frequentist association testing with SNPTEST. RESULTS: HVR and gender are strongly correlated. HCVR and gender are not. Mean HVR in women was 0.276±0.168 (liter/minute/%SpO2) compared to 0.429±0.266 (liter/minute/%SpO2) in men, p<0.001 (55.4% higher HVR in men). Women had lower baseline minute ventilation (8.08±2.36 l/m vs. 10.00±3.43l/m, p<0.001), higher SpO2 (98.0±1.3% vs. 96.6±1.7%, p<0.001), and lower EtCO2 (4.65±0.68% vs. 4.82±1.02%, p = 0.025). One hundred and two (18.5%) of the participants had HLA-DQB1*06:02. No association was seen between HLA-DQB1*06:02 and HVR or HCVR. Genetic analysis revealed point wise, uncorrected significant associations between two TASK2/KCNK5 variants (rs2815118 and rs150380866) and HCVR. CONCLUSIONS: This is the largest study to date reporting the relationship between gender and HVR/ HCVR and the first study assessing the association between genetic polymorphisms in humans and HVR/HCVR. The data suggest that gender has a large effect on hypoxic breathing response.

HMOX2 Functions as a Modifier Gene for High-Altitude Adaptation in Tibetans.

Tibetans are well adapted to high-altitude environments. Among the adaptive traits in Tibetans, the relatively low hemoglobin level is considered a blunted erythropoietic response to hypoxic challenge. Previously, EPAS1 and EGLN1, the major upstream regulators in the hypoxic pathway, were reportedly involved in the hemoglobin regulation in Tibetans. In this study, we report a downstream gene (HMOX2) involved in heme catabolism, which harbors potentially adaptive variants in Tibetans. We first resequenced the entire genomic region (45.6 kb) of HMOX2 in Tibetans, which confirmed the previously suspected signal of positive selection on HMOX2 in Tibetans. Subsequent association analyses of hemoglobin levels in two independent Tibetan populations (a total of 1,250 individuals) showed a male-specific association between the HMOX2 variants and hemoglobin levels. Tibetan males with the derived C allele at rs4786504:T>C displayed lower hemoglobin level as compared with the T allele carriers. Furthermore, our in vitro experiments indicated that the C allele of rs4786504 could increase the expression of HMOX2, presumably leading to a more efficient breakdown of heme that may help maintain a relatively low hemoglobin level at high altitude. Collectively, we propose that HMOX2 contributes to high-altitude adaptation in Tibetans by functioning as a modifier in the regulation of hemoglobin metabolism.

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.

King of the mountains: Tibetan and Sherpa physiological adaptations for life at high altitude.

Anecdotal evidence surrounding Tibetans' and Sherpas' exceptional tolerance to hypobaric hypoxia has been recorded since the beginning of high-altitude exploration. These populations have successfully lived and reproduced at high altitude for hundreds of generations with hypoxia as a constant evolutionary pressure. Consequently, they are likely to have undergone natural selection toward a genotype (and phenotype) tending to offer beneficial adaptation to sustained hypoxia. With the advent of translational human hypoxic research, in which genotype/phenotype studies of healthy individuals at high altitude may be of benefit to hypoxemic critically ill patients in a hospital setting, high-altitude natives may provide a valuable and intriguing model. The aim of this review is to provide a comprehensive summary of the scientific literature encompassing Tibetan and Sherpa physiological adaptations to a high-altitude residence. The review demonstrates the extent to which evolutionary pressure has refined the physiology of this high-altitude population. Furthermore, although many physiological differences between highlanders and lowlanders have been found, it also suggests many more potential avenues of investigation.

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.

The effect of 'sleep high and train low' on weight loss in overweight Chinese adolescents: study protocol for a randomized controlled trial.

BACKGROUND: Exercise and diet are the cornerstones for the treatment of obesity in obese children and adolescents. However, compensatory changes in appetite and energy expenditure elicited by exercise and dieting make it hard to maintain a reduced weight over the longterm. The anorexic effect of hypoxia can be potentially utilized to counteract this compensatory increase, thereby enhancing the success of weight loss. The purpose of the study is to assess the effectiveness of four week intermittent hypoxia exposure added to a traditional exercise and diet intervention on inducing short- and longterm weight loss in obese adolescents. METHODS/DESIGN: In this randomized parallel group controlled clinical trial, 40 obese adolescents (20 boys and 20 girls, 11 to 15-years-old), will be recruited from a summer weight loss camp at the Shanghai University of Sport, China. Participants will be stratified by gender and randomly assigned to either the control group or the hypoxia group. During the four-week intervention period, both groups will exercise and eat a balanced diet. Additionally, the control group will sleep in normal conditions, while the hypoxia group will sleep in a normobaric hypoxia chamber (sleep high and train low). The primary outcome will be body composition and the main secondary outcomes will be the circulating levels of appetite regulatory gastrointestinal hormones. All the outcome measures will be assessed at baseline, after the four-week intervention, and at two months follow-up. DISCUSSION: Our study will be the first to evaluate the effectiveness of 'sleep high and train low' on short- and longterm weight loss among obese adolescents. A potential mechanism for the appetite regulatory effect of hypoxia will also be explored. The results of the study will provide an evidence-based recommendation for the use of hypoxia in a weight loss intervention among obese children and adolescents. Furthermore, the clarification of mechanisms leading to weight loss in 'sleep high and train low' might provide information for the development of new strategies in combating obesity. TRIAL REGISTRATION: This trial was registered on 10 January 2014 at the Chinese Clinical Trial Registry with the registration number: ChiCTR-TRC-14004106.

Shared and unique signals of high-altitude adaptation in geographically distinct Tibetan populations.

Recent studies have used a variety of analytical methods to identify genes targeted by selection in high-altitude populations located throughout the Tibetan Plateau. Despite differences in analytic strategies and sample location, hypoxia-related genes, including EPAS1 and EGLN1, were identified in multiple studies. By applying the same analytic methods to genome-wide SNP information used in our previous study of a Tibetan population (n = 31) from the township of Maduo, located in the northeastern corner of the Qinghai-Tibetan Plateau (4200 m), we have identified common targets of natural selection in a second geographically and linguistically distinct Tibetan population (n = 46) in the Tuo Tuo River township (4500 m). Our analyses provide evidence for natural selection based on iHS and XP-EHH signals in both populations at the p<0.02 significance level for EPAS1, EGLN1, HMOX2, and CYP17A1 and for PKLR, HFE, and HBB and HBG2, which have also been reported in other studies. We highlight differences (i.e., stratification and admixture) in the two distinct Tibetan groups examined here and report selection candidate genes common to both groups. These findings should be considered in the prioritization of selection candidate genes in future genetic studies in Tibet.

Hematological parameters in high altitude residents: Tibetan natives versus Han migrants.

OBJECTIVE: Aim of our study was to compare hematological parameters in Tibetan natives with those in Han migrants living on the Tibet plateau in order to determine the potential effects of age, gender, and ethnicity on hematological response to hypoxia. METHODS: Blood hemoglobin (Hb, g/dl), hematocrit (Hct, %), red blood cells (RBC,10(6)/mm3) were measured in 3 588 healthy Tibetan natives and 3 371 Han migrants ranging in age from 5 to 72 years, living at a mean altitudes of 2 664 m, 3 813 m, 4 525m and 5 226 m. RESULTS: Hemoglobin (Hb) concentration analysis was made by multiple regression equations relating hemoglobin to altitude and age. For 2 093 Han males, Hb = 9.612+ 0.001440xaltitude+ 0.06148xage. For 1 948 Tibetan males, Hb =12.202+ 0.000462xaltitude+ 0.02893xage. For 1 278 Han females, Hb = 10.858+ 0.000939xaltitude+ 0.02632xage. For 1 640 Tibetan females, Hb = 11.402+ 0.000626xaltitude+ 0.00412xage. Each of the four equations was statistically significant (P < 0.001), and had variance (r2) of 0.86 or more, indicating that altitude and age accounted for at least 85% of the variation in hemoglobin levels. The coefficients for altitude and for age were higher (P < 0.05) in Han males than in Tibetan males and higher (P < 0.05) in Han females than in Tibetan females. The Tibetan postmenopausal females had higher Hb values than premenopausal females only presented at altitude above 4 000 m while this phenomenon was beginning at altitude of 2 664 m among Han females. CONCLUSION: We conclude that gender and increasing age in Tibetans are associated with lower hemoglobin values than those in Han at high altitude, and we speculate that genetic factors seems to be important.

Tibetans living at sea level have a hyporesponsive hypoxia-inducible factor system and blunted physiological responses to hypoxia.

Tibetan natives have lived on the Tibetan plateau (altitude ∼ 4,000 m) for at least 25,000 years, and as such they are adapted to life and reproduction in a hypoxic environment. Recent studies have identified two genetic loci, EGLN1 and EPAS1, that have undergone natural selection in Tibetans, and further demonstrated an association of EGLN1/EPAS1 genotype with hemoglobin concentration. Both genes encode major components of the hypoxia-inducible factor (HIF) transcriptional pathway, which coordinates an organism's response to hypoxia. Patients living at sea level with genetic disease of the HIF pathway have characteristic phenotypes at both the integrative-physiology and cellular level. We sought to test the hypothesis that natural selection to hypoxia within Tibetans results in related phenotypic differences. We compared Tibetans living at sea level with Han Chinese, who are Tibetans' most closely related major ethnic group. We found that Tibetans had a lower hemoglobin concentration, a higher pulmonary ventilation relative to metabolism, and blunted pulmonary vascular responses to both acute (minutes) and sustained (8 h) hypoxia. At the cellular level, the relative expression and hypoxic induction of HIF-regulated genes were significantly lower in peripheral blood lymphocytes from Tibetans compared with Han Chinese. Within the Tibetans, we found a significant correlation between both EPAS1 and EGLN1 genotype and the induction of erythropoietin by hypoxia. In conclusion, this study provides further evidence that Tibetans respond less vigorously to hypoxic challenge. This is evident at sea level and, at least in part, appears to arise from a hyporesponsive HIF transcriptional system.

Pulmonary circulation and gas exchange at exercise in Sherpas at high altitude.

Tibetans have been reported to present with a unique phenotypic adaptation to high altitude characterized by higher resting ventilation and arterial oxygen saturation, no excessive polycythemia, and lower pulmonary arterial pressures (Ppa) compared with other high-altitude populations. How this affects exercise capacity is not exactly known. We measured aerobic exercise capacity during an incremental cardiopulmonary exercise test, lung diffusing capacity for carbon monoxide (DL(CO)) and nitric oxide (DL(NO)) at rest, and mean Ppa (mPpa) and cardiac output by echocardiography at rest and at exercise in 13 Sherpas and in 13 acclimatized lowlander controls at the altitude of 5,050 m in Nepal. In Sherpas vs. lowlanders, arterial oxygen saturation was 86 ± 1 vs. 83 ± 2% (mean ± SE; P = nonsignificant), mPpa at rest 19 ± 1 vs. 23 ± 1 mmHg (P < 0.05), DL(CO) corrected for hemoglobin 61 ± 4 vs. 37 ± 2 ml · min(-1) · mmHg(-1) (P < 0.001), DL(NO) 226 ± 18 vs. 153 ± 9 ml · min(-1) · mmHg(-1) (P < 0.001), maximum oxygen uptake 32 ± 3 vs. 28 ± 1 ml · kg(-1) · min(-1) (P = nonsignificant), and ventilatory equivalent for carbon dioxide at anaerobic threshold 40 ± 2 vs. 48 ± 2 (P < 0.001). Maximum oxygen uptake was correlated directly to DL(CO) and inversely to the slope of mPpa-cardiac index relationships in both Sherpas and acclimatized lowlanders. We conclude that Sherpas compared with acclimatized lowlanders have an unremarkable aerobic exercise capacity, but with less pronounced pulmonary hypertension, lower ventilatory responses, and higher lung diffusing capacity.

[Clinical characteristics and changes in blood electrolyte and renal function of neonates with polycythemia at high altitude].

OBJECTIVE: To analyze the relationship between neonatal hypoxia and polycythemia and to study clinical characteristics of Tibetan neonates whose family lived in Tibetan plateau for generations and Han neonates whose family moved to the plateau. METHOD: From Jan. 2005 to Oct. 2006, totally 739 patients were hospitalized in the ward of neonatology of the hospital. Of these patients, 40 (20 were Tibetan and the other 20 were Han) with neonatal polycythemia. The clinical features, transcutaneous oxygen saturation (TcSO2), peripheral routine tests and myocardial enzyme profile were studied. RESULT: The values of hemoglobin (Hb), hematocrit (HCT), and erythrocyte count (RBC) of the Han neonates were significantly higher than those of the Tibetan newborns. Han neonates with polycythemia had lower TcSPO2 than Tibetan neonates (P < 0.01). Comparison of myocardial enzymes showed that Han neonates had higher CKMB than that of Tibetan groups before treatment (P < 0.01), troponin was not significantly different between the Han and Tibetan groups before treatment (P > 0.05). The major common clinical manifestations of the Han and Tibetan newborns were tachypnea, cyanosis, irritability, weak reflexes and hypoxemia. The Han neonates additionally had poor responses, apnea, lower muscle tone, confusion and asphyxia. CONCLUSION: The clinical characteristics, TcSO2, peripheral blood routine tests and myocardial enzyme profile are helpful in diagnosis and treatment of neonatal polycythemia. Newborn infants born to mothers who moved to the plateau area may be more susceptible to neonatal polycythemia and are prone to impairments of other organs, esp. the functions of the heart and brain.

[Study of nine single nucleotide polymorphism loci of human HIF1A gene in three Tibetan groups].

OBJECTIVE: To investigate the effect of hypoxia environment induced by altitude on hypoxia inducible factor 1α (HIF1A) gene. METHODS: Nine single nucleotide polymorphism (SNP) loci of the HIF1A gene from three Tibetan groups (Tibet, Qinghai Province and Yunnan Province) were genotyped using PCR-restriction fragment length polymorphism (PCR-RFLP) method. RESULTS: For non-synonymous mutation SNP site, there was no significant difference among the three Tibetan groups, except for SNP rs11549465 between Tibet Tibetan and Yunnan Tibetan, as well as between Qinghai Tibetan and Yunnan Tibetan. Frequencies of genotypes and alleles in rs4899056, rs1957757, rs10873142 and rs3783752 had significant differences between Tibet Tibetan and Yunnan Tibetan, and between Qinghai Tibetan and Yunnan Tibetan (all P<0.05). We also observed that the difference was negatively correlated with the altitude. CONCLUSION: The results suggested that the HIF1A gene might be under hypoxic selection induced by high altitude in the three groups.