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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., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Background: Hemoglobin concentration at high altitude is considered an important marker of high altitude adaptation, and native Tibetans in the Qinghai-Tibetan plateau show lower hemoglobin concentrations than Han people who have emigrated from plains areas. Genetic studies revealed that EPAS1 plays a key role in high altitude adaptation and is associated with the low hemoglobin concentration in Tibetans. Three single nucleotide polymorphisms (rs13419896, rs4953354, rs1868092) of noncoding regions in EPAS1 exhibited significantly different allele frequencies in the Tibetan and Han populations and were associated with low hemoglobin concentrations in Tibetans., Methods: To explore the hereditary basis of high altitude polycythemia (HAPC) and investigate the association between EPAS1 and HAPC in the Han population, these 3 single nucleotide polymorphisms were assessed in 318 male Han Chinese HAPC patients and 316 control subjects. Genotyping was performed by high resolution melting curve analysis., Results: The G-G-G haplotype of rs13419896, rs4953354, and rs1868092 was significantly more frequent in HAPC patients than in control subjects, whereas no differences in the allele or genotype frequencies of the 3 single nucleotide polymorphisms were found between HAPC patients and control subjects. Moreover, genotypes of rs1868092 (AA) and rs4953354 (GG) that were not observed in the Chinese Han in the Beijing population were found at frequencies of 1.6% and 0.9%, respectively, in our study population of HAPC patients and control subjects., Conclusions: Carriers of this EPAS1 haplotype (G-G-G, rs13419896, rs4953354, and rs1868092) may have a higher risk for HAPC. These results may contribute to a better understanding of the pathogenesis of HAPC in the Han population., (Copyright © 2014 Wilderness Medical Society. Published by Elsevier Inc. All rights reserved.)

Background: Excessive erythrocytosis (EE) is a prevalent condition in populations living at high altitudes (> 2,500 m above sea level). Few large population-based studies have explored the association between EE and multiple subject-specific traits including oxygen saturation, iron status indicators, and pulmonary function., Methods: We enrolled a sex-stratified and age-stratified sample of 1,065 high-altitude residents aged ≥ 35 years from Puno, Peru (3,825 m above sea level) and conducted a standardized questionnaire and physical examination that included spirometry, pulse oximetry, and a blood sample for multiple clinical markers. Our primary objectives were to estimate the prevalence of EE, characterize the clinical profile and iron status indicators of subjects with EE, and describe subject-specific traits associated with EE., Results: Overall prevalence of EE was 4.5% (95% CI, 3.3%-6.0%). Oxygen saturation was significantly lower among EE than non-EE group subjects (85.3% vs 90.1%, P < .001) but no difference was found in iron status indicators between both groups (P > .09 for all values). In multivariable logistic regression, we found that age ≥ 65 years (OR = 2.45, 95% CI, 1.16-5.09), male sex (3.86, 1.78-9.08), having metabolic syndrome (2.66, 1.27-5.75) or being overweight (5.20, 1.95-16.77), pulse oximetry < 85% (14.90, 6.43-34.90), and % predicted FVC < 80% (13.62, 4.40-41.80) were strongly associated with EE. Attributable fractions for EE were greatest for being overweight (26.7%), followed by male sex (21.5%), pulse oximetry < 85% (16.4%), having metabolic syndrome (14.4%), and % predicted FVC < 80% (9.3%)., Conclusions: We found a lower prevalence of EE than in previous reports in the Peruvian Andes. Although the presence of hypoxemia and decreased vital capacity were strongly associated with excessive erythrocytosis, being overweight or having metabolic syndrome were associated with an important fraction of cases in our study population.

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.

About 30 million people live above 2500 m in the Andean Mountains of South America. Among them are 5.5 million Aymaras, an ethnic group with its own language, living on the altiplano of Bolivia, Peru, and northern Chile at altitudes of up to 4400 m. In this high altitude region traces of human population go back for more than 2000 years with constant evolutionary pressure on its residents for genetic adaptation to high altitude. Aymaras as the assumed direct descendents of the ancient cultures living in this region were the focus of much research interest during the last decades and several distinctive adaptation patterns to life at high altitude have been described in this ethnic group. The aim of this article was to review the physiology and pathophysiology of circulatory adaptation and maladaptation to longtime altitude exposure in Aymaras and Caucasians.

Aim: The objective of this study is to disclose the association of polycythemia with lifestyle-related diseases (hypertension, obesity and glucose intolerance) among the three ethnicities in Qinghai, China., Methods: The subjects were 393 elderly people (247 Han, 97 Tibetan and 49 Mongolian) aged 60 years and more living in Qinghai (3000 m a.s.l.) in China. The associated factors with polycythemia were analyzed in the subjects. Excessive polycythemia was defined as hemoglobin concentration over 20 mg/dL., Results: Polycythemia was associated with men, hypoxemia, obesity and high diastolic blood pressure (DBP) in the elderly in Qinghai. Male sex was associated with polycythemia in all ethnicities. Obesity was associated with Han and Tibetan men. Glucose intolerance and activities of daily living were not directly associated with polycythemia after adjustment for sex. There were 7.9% with excessive polycythemia. Independently-associated factors for excessive polycythemia were male sex, body mass index of 25 or more, SpO(2) of less than 85%, DBP of 85 mmHg or more and Han ethnicity (vs Tibetan) by multiple logistic regression., Conclusion: There was a close association of polycythemia with diastolic hypertension and obesity in lifestyle-related diseases in high-altitude elderly people. Han people had a higher hemoglobin concentration after adjustment of lifestyle-related diseases compared with Tibetan people. The difference of hemoglobin concentration may be due to Tibetans undergoing a much longer period of adaptation than Han people. Further study is needed to disclose the association between the difference of hypoxic adaptation, lifestyle-related diseases and chronic mountain sickness for their prevention.

Chuvash polycythemia results from a homozygous 598C>T mutation in exon 3 of the von Hippel-Lindau (VHL) gene. This disrupts the normoxia pathway for degrading hypoxia inducible factor (HIF)-1alpha and HIF-2alpha causing altered expression of HIF-1 and HIF-2 inducible genes. As hypoxia induces expression of pro-inflammatory cytokines, we hypothesized that there might be an elevation of Th1 cytokines in the setting of Chuvash polycythemia. We analyzed plasma concentrations of Th1 (interleukins-2 and 12, interferon-gamma, granulocyte-monocyte colony-stimulating factor, tumor necrosis factor-alpha) and Th2 cytokines (interleukins-4, 5, 10, and 13) using the Bio-Plex multiplex suspension array system in 34 VHL598C>T homozygotes and 32 VHL wild-type participants from Chuvashia. Concentrations of all the Th1 and Th2 cytokines measured were elevated in the VHL598C>T homozygotes compared with the control wild-type participants, but the ratios of Th1 to Th2 cytokines did not differ by genotype. In parallel, peripheral blood concentrations of CD4 positive T-helper cells and CD4/CD8 ratio were lower in the VHL598C>T homozygotes. In conclusion, the up-regulated hypoxic response in Chuvash polycythemia is associated with increased plasma products of both the Th1 and Th2 pathways, but the balance between the two pathways seems to be preserved.

This review will focus on the molecular basis of certain polycythemic disorders. Primary polycythemias are characterized by acquired somatic or inherited germ-line mutations expressed within hematopoietic progenitors that cause increased accumulation of red blood cells. Polycythemia vera (PV), an acquired condition, is the most common primary polycythemia; although some progress has been made in the understanding of PV, its molecular basis remains unknown. In contrast, recent advances in delineating the molecular defects of some inherited polycythemias have greatly furthered our knowledge of the regulation of erythropoiesis and hypoxia sensing; however, more work needs to be done.

Congenital polycythemias may result from inherited defects in hypoxia sensing, from inherited intrinsic defects in red blood cell precursors, or from inherited conditions that cause low tissue oxygen tension and secondary polycythemia. Conditions of defective hypoxia sensing feature inappropriately normal or elevated serum erythropoietin (Epo) concentrations in the setting of normoxia and erythrocytosis. They are often due to homozygous or compound heterozygous germline mutations in the von Hippel Lindau tumor suppressor gene (VHL) but without increased incidence of tumors. Affected persons have a high risk of arterial thrombosis and early mortality. The molecular biology of rare polycythemic patients with a single mutated VHL allele remains obscure. Primary congenital and familial polycythemias are characterized by low Epo levels and increased erythroid precursor responsiveness to Epo. They are often due to heterozygous gain-of function mutations in the gene for erythropoietin receptor (EPOR). Secondary congenital polycythemias have low tissue oxygen tension due to hemoglobins with high affinity for oxygen, low erythrocyte 2,3 biphosphoglycerate levels, methemoglobinemia or cyanotic heart or lung disease. Whether phlebotomy therapy reduces complications and prolongs survival in congenital polycythemia is not known.

Diabetes complicating pregnancy has not yet been properly evaluated in Guam and the prevalence and morbidity of infants of diabetic mothers (IDM) in Micronesian population on Guam is described. The prevalence of IDM among the Micronesian population is 5.0% vs non-Micronesian's 3.7%. 82.5% were gestational diabetic mothers (GDM) diet controlled, 10.2% were GDM insulin controlled and 6.9% had Insulin Dependent Diabetes Mellitus. LGAs were 11% of IDMs in contrast to 6.4% of total births. Ten infants (NICU) spent total of 29 days on ventilator. Cesarean delivery, LGA, oxygen and ventilatory requirements were higher in Micronesian IDMs than in the non-Micronesian IDMs. The incidence is also higher in the Micronesian population (5.0%) compared to non Micronesian population (3.7%) on Guam. Micronesian IDMs were at higher risk for cesarean delivery, recurrent hypoglycemia, oxygen and ventilatory requirements than their non-Micronesian counterparts were. There is also a higher incidence of LGA among the Micronesian population and Chuukese had the highest incidence probably because they seek late or no prenatal care. We report 5.0% prevalence of diabetes during pregnancy in Micronesian population on Guam which imposes a significant economic burden on the local government's hospital resources. Micronesian IDMs were at higher risk for cesarean delivery, LGA, recurrent hypoglycemia, oxygen and ventilatory requirements than their non-Micronesian counterparts were. Chuukese had the highest LGA incidence in the study group. About 2/3rd of the IDM stayed 1110 extra days in hospital. IDMs accounted for the majority of expensive off-island transports.

An abnormal hemoglobin with increased oxygen affinity, Hb Malmö [alpha 2 beta 297(FG4)His-->Gln], was found to cause erythrocytosis in two apparently unrelated Swedish families. Direct nucleotide sequencing of amplified DNA demonstrated a CAC-->CAA substitution in one family and a CAC-->CAG substitution in the other. Both mutations resulted in a His-->Gln substitution in codon 97. This finding prompted us to examine the possible point mutations underlying the different hemoglobin variants reported in the literature.

Blood oxygen balance and acid-base equilibrium were studied in 22 Chuvash patients with hereditary erythrocytosis. Despite the lack of the anomalous types of hemoglobin in the given type of erythrocytosis a number of the patients showed secondary tissue hypoxia associated with hyperoxia of the peripheral venous blood. It is shown that tissues are capable of extracting oxygen from the blood. It is assumed that the development of tissue hypoxia in the patients is determined by a fall in the rate of oxygen diffussion from the capillaries to the tissues or by blood shunting via the arteriolo-venular anastomoses because of microcirculatory disorders. The lowering of hematocrit to the level close to normal with the aid of bloodlettings makes oxygen balance return to normal and reduces tissue hypoxia.