GCH1 plays a role in the high-altitude adaptation of Tibetans.

Tibetans are well adapted to high-altitude hypoxia. Previous genome-wide scans have reported many candidate genes for this adaptation, but only a few have been studied. Here we report on a hypoxia gene ( GCH1, GTP-cyclohydrolase I), involved in maintaining nitric oxide synthetase (NOS) function and normal blood pressure, that harbors many potentially adaptive variants in Tibetans. We resequenced an 80.8 kb fragment covering the entire gene region of GCH1 in 50 unrelated Tibetans. Combined with previously published data, we demonstrated many GCH1 variants showing deep divergence between highlander Tibetans and lowlander Han Chinese. Neutrality tests confirmed a signal of positive Darwinian selection on GCH1 in Tibetans. Moreover, association analysis indicated that the Tibetan version of GCH1 was significantly associated with multiple physiological traits in Tibetans, including blood nitric oxide concentration, blood oxygen saturation, and hemoglobin concentration. Taken together, we propose that GCH1 plays a role in the genetic adaptation of Tibetans to high altitude hypoxia.

EP300 contributes to high-altitude adaptation in Tibetans by regulating nitric oxide production.

The genetic adaptation of Tibetans to high altitude hypoxia likely involves a group of genes in the hypoxic pathway, as suggested by earlier studies. To test the adaptive role of the previously reported candidate gene EP300 (histone acetyltransferase p300), we conducted resequencing of a 108.9 kb gene region of EP300 in 80 unrelated Tibetans. The allele-frequency and haplotype-based neutrality tests detected signals of positive Darwinian selection on EP300 in Tibetans, with a group of variants showing allelic divergence between Tibetans and lowland reference populations, including Han Chinese, Europeans, and Africans. Functional prediction suggested the involvement of multiple EP300 variants in gene expression regulation. More importantly, genetic association tests in 226 Tibetans indicated significant correlation of the adaptive EP300 variants with blood nitric oxide (NO) concentration. Collectively, we propose that EP300 harbors adaptive variants in Tibetans, which might contribute to high-altitude adaptation through regulating NO production.

Physiological responses and evaluation of effects of BMI, smoking and drinking in high altitude acclimatization: a cohort study in Chinese Han young males.

High altitude acclimatization is a series of physiological responses taking places when subjects go to altitude. Many factors could influence these processes, such as altitude, ascending speed and individual characteristics. In this study, based on a repeated measurement design of three sequential measurements at baseline, acute phase and chronic phase, we evaluated the effect of BMI, smoking and drinking on a number of physiological responses in high altitude acclimatization by using mixed model and partial least square path model on a sample of 755 Han Chinese young males. We found that subjects with higher BMI responses were reluctant to hypoxia. The effect of smoking was not significant at acute phase. But at chronic phase, red blood cell volume increased less while respiratory function increased more for smoking subjects compared with nonsmokers. For drinking subjects, red blood cell volume increased less than nondrinkers at both acute and chronic phases, while blood pressures increased more than nondrinkers at acute phase and respiratory function, red blood cell volume and oxygen saturation increased more than nondrinkers at chronic phase. The heavy and long-term effect of smoking, drinking and other factors in high altitude acclimatization needed to be further studied.

A genetic adaptive pattern-low hemoglobin concentration in the Himalayan highlanders.

Mean hemoglobin (Hb) concentration of about 3 500 subjects derived from 17 studies of Himalayan highlanders (Tibetans, Sherpas, and Ladakhis) was compared with lowlanders (Chinese Han, Indian Tamils) lived in the Himalayas, and European climbers during Everest expeditions as well as Andean natives. The results found that Hb concentration in Himalayan highlanders was systemically lower than those reported for Andean natives and lowland immigrants. These comparative data demonstrated that a healthy native population may successfully reside at high altitude without a significant elevation in Hb, and the lower Hb levels of Himalayan highlanders than those of migrated lowlanders and Andean natives are an example of favourable adaptation over the generations. In addition, excessive polycythemia has frequently been used as a marker of chronic mountain sickness (CMS). Altitude populations who have a higher Hb concentration also have a higher incidence of CMS. The low Hb in Himalayans suggested as showing adaptation over many generations in Tibetan stock. Recent work in Tibet, suggested that Tibetans there may have adapted to high altitude as a result of evolutionary pressure selecting for genes which give an advantage at altitude. All of the population genomic and statistical analysis indicated that EPAS1 and EGLN1 are mostly likely responsible for high altitude adaptation and closely related to low Hb concentration in Tibetans. These data supported the hypothesis that Himalayan highlanders have evolved a genetically different erythropoietic response to chronic hypoxia by virtue of their much longer exposure to high altitude.

Studies on separating the impedance change components of blood vessels and ventricles in thorax from mixed impedance signals on chest surface.

PURPOSE: The aim of the present study is to separate the impedance change components of the blood vessels and ventricles in thorax from the mixed impedance signals detected on the chest surface. METHODS: The mixed impedance signals on the chest surface are measured with a 15 electrode lead system. The thoracic impedance equations are established and solved iteratively with the algebraic reconstructed technique. Experiments were performed on 80 healthy, otherwise normal, adults. RESULTS: Five impedance change components for the aorta (AO), blood vessel in left lung (PL), blood vessel in right lung (PR), left ventricle (LV), and right ventricle (RV) are separated from the mixed impedance signals. The experiments show that the main waveform of the ventricular components LV and RV is contrary to that of the vascular components AO, PL, and PR, and the negative peak point of the waveform graphs of LV and RV are in phase with the second cardiac sound (S2). The waveform graphs of various components correspond with the physiological activities of the heart and blood vessels in a cardiac cycle. The statistical results for 80 normal adults show that the amplitude of AO is the largest and that of PL and PR is the next, while that of LV and RV is the smallest. There are significant differences between them (P < 0.01). CONCLUSIONS: The mathematical model and the measurement method for the separation in the present paper are feasible.

[Integripetal rhodiola herb attenuates high altitude-induced pulmonary arterial remodeling and expression of vascular endothelial growth factor in rats].

The aim of this study was to investigate the effect of integripetal rhodiola herb on pulmonary arterial remodeling and expression of vascular endothelial growth factor (VEGF) in high altitude pulmonary hypertension in rats. Fifty healthy male Wistar rats were divided into five groups randomly: Plain control group (LC group), 10-day plateau group (H(10) group), 30-day plateau group (H(30) group), 10-day rhodiola-treated plateau group (R(10) group), and 30-day rhodiola-treated plateau group (R(30) group). Each group included 10 rats. The rats in LC group were kept in Chengdu (500 meters above sea level), and rats in H and R groups were kept in Lhasa (3 700 meters above sea level). The rats in R group were daily treated with integripetal rhodiola herb extract (24%, 10 mL/kg) intragastrically for 10 d or 30 d, while rats in LC and H groups were treated with the same volume of saline. Mean pulmonary arterial pressure (mPAP) was detected via a catheter in the pulmonary artery by pressure waveform monitoring. The ratio value of right ventricle weight to left ventricle plus septum weight [RV/(LV + S)] was measured. The microstructure of pulmonary arterioles was examined by electron microscopy. The expression of VEGF in the lung was investigated using immunohistochemistry. The results showed that mPAP and [RV/(LV + S)] in H(10) group and H(30) group were higher than those in LC group (P < 0.05); but there was no significant difference between H(10) group and R(10) group (P < 0.05); and mPAP and [RV/(LV + S)] in H(30) group were lower than those in H(30) group (P < 0.05). Electron microscopy showed that compared to LC group, arteriolar endothelial cells were arranged in a columnar or palisading form, protruding into the lumen, accompanied with luminal stenosis, irregular internal elastic membrane, and proliferation of vascular smooth muscle cells in H groups, which was more obvious in H(30) group than in H(10) group; while these pathological changes were attenuated in the R groups compared to H groups. The levels of VEGF protein in H groups were also higher than those in LC group (P < 0.05); while the expression of VEGF in R(30) group was lower than that in H(30) group. In summary, the results show that the integripetal rhodiola herb can attenuate high altitude-induced pulmonary arterial remodeling in rats, and the inhibition of VEGF protein expression by rhodiola may be one of the mechanisms.

Mechanism of the formation for thoracic impedance change.

The purpose of this study is to investigate the mechanism of the formation for thoracic impedance change. On the basis of Ohm's law and the electrical field distribution in the cylindrical volume conductor, the formula about the thoracic impedance change are deduced, and they are demonstrated with the model experiment. The results indicate that the thoracic impedance change caused by single blood vessel is directly proportional to the ratio of the impedance change to the basal impedance of the blood vessel itself, to the length of the blood vessel appearing between the current electrodes, and to the basal impedance between two detective electrodes on the chest surface, while it is inversely proportional to the distance between the blood vessel and the line joining two detective electrodes. The thoracic impedance change caused by multiple blood vessels together is equal to the algebraic addition of all thoracic impedance changes resulting from the individual blood vessels. That is, the impedance changes obey the principle of adding scalars in the measurement of the electrical impedance graph. The present study can offer the theoretical basis for the waveform reconstruction of Impedance cardiography (ICG).

Polymorphisms of renin-angiotensin system in essential hypertension in Chinese Tibetans.

OBJECTIVE: To evaluate the potential implications of the genetic variability of angiotensin converting enzyme, angiotensinogen and angiotensin II type 1 receptor gene for essential hypertension in Tibetan. METHODS: A case-control study was conducted in 173 hypertensive individuals and 193 individuals with normal blood pressure. Multiple logistic regression analyses were used to estimate the risks of developing hypertension for different genotypes, and haplotype analyses of the angiotensinogen gene were used to determine the association between two-locus angiotensinogen gene polymorphisms and hypertension. RESULTS: As to the risk to high blood pressure and high systolic pressure, women with MM genotype were 7.7 (95% CI: 1.3-20.5) and 8.7 (95% CI: 1.8-20.1) times higher than those with TT genotype after adjustment for age and body mass index. Haplotype frequencies for M235T and G-6A were significantly different between hypertensive individuals and controls, which indicated an association of angiotensinogen gene haplotypes with hypertension, and a significant association of 235T/-6A haplotype with hypotensive effect. CONCLUSION: Our results suggest that angiotensinogen gene 235MM is a predictor for hypertension development in Tibetan women but not in men, and may exert its hypertensive effect on linkage disequilibrum with a possible function locus of G-6A.

[A1166C polymorphism of the angiotensin II type 1 receptor gene and essential hypertension in Han, Tibetan and Yi populations].

OBJECTIVE: To clarify whether A1166C polymorphism of the angiotensin II type 1 receptor (AT(1)R) gene is associated with susceptibility to essential hypertension in Han, Tibetan and Yi populations in China. METHODS: This study involved 302 normotensive and 446 hypertensive subjects. The polymorphism was detected by polymerase chain reaction-restriction fragment length polymorphism in genomic DNA. The data were analyzed by ANCOVA, chi-square test, and multiple logistic regression. RESULTS: In normotensive controls, the A1166 allele frequencies were 0.979, 0.939 and 0.965 in Han, Tibetan and Yi participants, respectively. There was no significant intergroup variation in frequency of the allele in normotensives (chi-square=4.166, P=0.125). The frequency of the A1166 allele in Tibetan male hypertensives was significantly higher than that in normotensives (chi-square=11.46, P=0.001). There was no significant difference in A1166C genotype distribution and allele frequency between normotensives and hypertensives either in the Han (P=0.465) or Yi (P=0.357) populations. Body mass index in the Han and Yi populations (P=0.0001), age in the Tibetan and Yi populations (P=0.0001), and AA genotype in the Tibetan male population (P=0.0034) all were independent risk factors for hypertension. Diastolic blood pressure levels were significantly higher in Tibetan male subjects with the AA genotype than in those with the AC+CC genotype (P=0.0040). CONCLUSION: The A1166 allele is very common in Han, Tibetan and Yi populations, approximately 1.35-fold more common than in Caucasians. The A1166 allele of the AT(1)R gene may be a predisposing factor for essential hypertension in Tibetan males. A1166C polymorphism of the AT(1)R gene is probably not involved in the pathogenesis of essential hypertension in Han and Yi populations.