Analysis of MTHFR C677T genotype and related factors in H-type hypertension in Tibet, China.

BACKGROUND AND AIMS: H-type hypertension is essential hypertension combined with high homocysteine, and both synergistically increase the risk of cardiovascular and cerebrovascular events. The aim of this study was to investigate the risk factors of H-type hypertension in Tibetan plateau population and correlation with MTHFR C677T gene. METHODS AND RESULTS: A multi-stage cluster random sampling method was used to select the research subjects in Tibet Autonomous Region from June 2020 to November 2021. Among Tibetans, the incidence of H-type hypertension accounted for 84.31% of hypertensive patients. The logistic regression analysis demonstrated that age, uric acid (UA), triglyceride (TG) and low-density lipoprotein cholesterol (LDL-C) were risk factors for the prevalence of H-type hypertension, the OR (95% CI) was 1.083(1.073-1.094), 1.002(1.001-1.004), 1.240(1.050-1.464) and 2.274(1.432-3.611), respectively. MTHFR C677T TT genotype patients with H-type hypertension OR (95% CI) was 1.629(1.004-2.643). Based on this, a nomogram model was established, and the reliability of the model was proved by area under ROC curve, Brier score and average absolute error. The model's results indicate that for every five years of age, the score increases by 6 points; for a 2mmol/L increase in TG, the score increases by 5.5 points; for a 1mmol/L increase in LDL-C, the score increases by 10 points; and individuals with the TT genotype receive 8 points. The higher the score, the greater the risk of disease. CONCLUSION: The MTHFR C677T TT genotype is a risk locus for Tibetan patients with H-type hypertension, with age, TG, and LDL-C were identified as risk factors for the disease.

Analysis of the current status and associated risk factors of cognitive function in Tibetan hypertensive patients at various altitudes.

OBJECTIVE: This study aims to explore the current cognitive status and identify risk factors associated with cognitive function in Tibetan hypertensive patients living at various altitudes. METHODS: The Simple Mental Status Scale (MMSE) was used to evaluate the cognitive function of 611 Tibetan hypertensive patients at various altitudes in Gannan Tibetan Autonomous Prefecture. Afterward, we conducted an analysis to identify the factors influencing their cognitive function. RESULTS: The study found that the prevalence of cognitive dysfunction was 22.3%, with a higher incidence at high altitude (group D 29.0%) compared to low altitude (group A 16.0%). The study conducted a binary logistic regression analysis to identify the risk factors for cognitive dysfunction. The analysis revealed that altitude, age, body mass index, marital status, education, income level, and blood pressure control level were all significant risk factors. After controlling for age, body mass index, marital status, educational level, income level, and blood pressure control level, the risk of developing cognitive dysfunction was 2.773 times higher (p < .05) for individuals in group C at high altitude and 2.381 times higher (p < .05) for individuals in group D at high altitude compared to those in group A at low altitude. CONCLUSIONS: Altitude plays a role in the development of cognitive dysfunction in hypertensive patients. Tibetan hypertensive patients living at high altitudes may be at a higher risk of cognitive dysfunction compared to those living at lower altitudes. Therefore, interventions should be targeted to prevent or mitigate potential cognitive impairment.

Oral health status of 916 children in Tibetan settlement (Bylakuppe, India): A cross-sectional descriptive study.

BACKGROUND: Dietary and oral hygiene habits among integrated migrant cultural minorities can vary and could impact susceptibility to caries. AIM: This study aimed to assess and compare the oral health status of Tibetan schoolchildren living in the Tibetan settlement of Bylakuppe, India, stratified by type of residence. DESIGN: A descriptive cross-sectional study was conducted among Tibetan schoolchildren attending nine schools in the Bylakuppe region. RESULTS: The study population consisted of 916 children aged 5-17: 702 (76.6%) living in secular houses (LSH) and 214 (23.4%) living in monasteries (LM). The prevalence of dental caries was 70.9%, and the mean value of decayed, missing, filled teeth for mixed and primary dentition (DMFT*; dmft) of LSH children (1.56 ± 2.34/1.74 ± 2.66) was higher than of LM ones (1.14 ± 2.34/0.83 ± 2.80; p < .001). DMFT for LM children (1.46 ± 2.04) was slightly higher than for LSH children (1.38 ± 1.96; p > .05). Among the sample, 99.1% had a good simplified Oral Hygiene Index (OHI) and LM children showed higher rates of good values (99.5% vs. 98.2% in LSH children). Most children needed preventive/routine dental treatment, whereas 16.6% needed urgent dental treatment. In 4.5% of children, oral mucosal lesions were present. CONCLUSION: This study confirms the high need for dental treatment in the children of the Tibetan settlement investigated.

[Distribution of ABO and Rh Blood Groups in Tibetan and Han Populations With Cleft Lip and Palate in a Tertiary Hospital in Western China]. / ä¸­å›½è¥¿éƒ¨æŸä¸‰ç”²åŒ»é™¢è—æ—ä¸Žæ±‰æ—å”‡è ­è£‚æ‚£è€ ABO血型及Rhè¡€åž‹åˆ†å¸ƒç ”ç©¶.

Objective: Congenital cleft lip and palate is a common birth defect that seriously affects the lives of the afflicted children and their families. Previously, no research has been done to investigate the pathogenic characteristics of cleft lip and palate among ethnic minorities, for example, Tibetans, a minority ethnic group with a large population in China. This study aims to investigate the relationship between the occurrence of cleft lip and palate in Tibetans and Han Chinese in western China and the distribution of ABO blood groups and Rh blood groups to provide a theoretical basis for the precise prevention and treatment of cleft lip and palate. Methods: In this study, statistics on Tibetan patients with cleft lip and palate, some Han patients with cleft lip and palate, and normal controls from western China were retrospectively collected. All participants were patients from West China Stomatology Hospital, Sichuan University. All patients with cleft lip and palate received treatment at the hospital between January 2016 and September 2023. The normal controls were outpatients or inpatients who did not have cleft lip and palate, and who received treatment at the hospital between January 2020 and October 2023. Information on the A, B, O, and AB blood groups and Rh positive and negative blood groups of the patients was collected and compared with that of the normal controls. The incidence of different phenotypes, including cleft lip alone, cleft palate alone, and cleft lip with cleft palate, in patients of blood groups A, B, O and AB were statistically analyzed by Chi-square test. Results: A total of 1227 Tibetan patients with cleft lip and palate, 4064 Han patients with cleft lip and palate, and 5360 normal controls were included in the study. Among all the patients with cleft lip and palate, 1863 had cleft lip alone, 1425 had cleft palate alone, and 2003 had cleft lip with cleft palate. The ABO blood group distribution of Tibetan patients with cleft lip and palate was characterized as O>B>A>AB, with Rh positive blood group accounting for 100%, blood type O accounting for 41.15%, and blood type B accounting for 30.64%. The blood group distribution of the Han patients with cleft lip and palate was characterized as O>A>B>AB, with Rh positive blood group accounting for 99.58%, blood type O accounting for 35.78%, and type A accounting for 30.54%. There was a significant difference in ABO blood groups between Tibetan and Han patients with cleft lip and palate (P<0.005), but no significant difference in Rh blood groups. The ABO blood group distribution of the Tibetan patients with cleft lip and palate showed an obvious difference from that of the control group, while those of the Han patients with cleft lip and cleft palate and the control group did not show obvious differences. In the analysis of the subtypes, it was found that the blood group distribution in the subtypes of cleft lip alone, cleft palate alone, and cleft lip with cleft palate in the Tibetan population was O>B>A>AB, while that in the Han Chinese population was O>A>B>AB. There were differences in blood group distribution between Tibetans and Hans of the subtypes of cleft lip alone and cleft lip with cleft palate (P<0.001), but there was no difference in blood group distribution in the population of cleft palate-only subtype. The proportion of blood type O in Tibetan patients with cleft lip and palate was significantly higher than that in the Han patients with cleft lip and palate. The blood group distribution of Tibetan patients with cleft lip and palate in Sichuan Province, Xizang Autonomous Region, and Qinghai Province was always O>B>A>AB. Tibetan patients from Shiqu County and Baiyu County, Ganzi Tibetan Autonomous Prefecture and Chaya County, Qamdo City were predominantly of blood type B, and those from other regions were mainly of blood type O. Conclusion: There were significant differences in the phenotype composition and ABO blood group distribution between the Tibetan and Han populations with cleft lip and palate in western China. The distribution of blood group O in the population with cleft lip and palate was higher than that in the normal population, and the same trend was observed for different phenotypes. However, differences between Tibetan and Han populations in ABO blood group distribution were only found in the phenotypes of cleft lip only and cleft lip with palate. Tibetans with blood type O are more prone to cleft lip deformity than Han people, and the effect in the phenotype of cleft lip with palate is less pronounced than that in the phenotype of cleft lip only.

How Placenta Promotes the Successful Reproduction in High-Altitude Populations: A Transcriptome Comparison between Adaptation and Acclimatization.

As the best adapted high altitude population, Tibetans feature a relatively high offspring survival rate. Genome-wide studies have identified hundreds of candidate SNPs related to high altitude adaptation of Tibetans, although most of them have unknown functional relevance. To explore the mechanisms behind successful reproduction at high altitudes, we compared the placental transcriptomes of Tibetans, sea level Hans (SLHan), and Han immigrants (ImHan). Among the three populations, placentas from ImHan showed a hyperactive gene expression pattern. Their increased activation demonstrates a hypoxic stress response similar to sea level individuals experiencing hypoxic conditions. Unlike ImHan, Tibetan placentas were characterized by the significant up-regulation of placenta-specific genes, and the activation of autophagy and the tricarboxylic acid (TCA) cycle. Certain conserved hypoxia response functions, including the antioxidant system and angiogenesis, were activated in both ImHan and Tibetans, but mediated by different genes. The coherence of specific transcriptome features linked to possible genetic contribution was observed in Tibetans. Furthermore, we identified a novel Tibetan-specific EPAS1 isoform with a partial deletion at exon six, which may be involved in the adaption to hypoxia through the EPAS1-centred gene network in the placenta. Overall, our results show that the placenta grants successful pregnancies in Tibetans by strengthening the natural functions of the placenta itself. On the other hand, the placenta of ImHan was in an inhabiting time-dependent acclimatization process representing a common hypoxic stress response pattern.

Transcriptome analysis reveals molecular pathways in the iron-overloaded Tibetan population.

Iron overload can lead to chronic complications, serious organ dysfunction or death in the body. Under hypoxic conditions, the body needs more iron to produce red blood cells to adapt to the hypoxic environment. The prevalence of iron overload in the Tibetan population is higher than that in the Han population. To explore the molecular mechanism of iron-overload in the Tibetan population, this study investigated the transcriptome of the Tibetan iron overload population to obtain differentially expressed genes (DEGs) between the iron-overloaded population and the normal iron population. Functional enrichment analysis identified key related pathways, gene modules and coexpression networks under iron-overload conditions, and the 4 genes screened out have the potential to become target genes for studying the development of iron overload. A total of 28 pathways were screened to be closely related to the occurrence and development of iron overload, showing that iron overload is extremely related to erythrocyte homeostasis, cell cycle, oxidative phosphorylation, immunity, and transcriptional repression.

[Distribution Characteristics and the Influencing Factors of High Altitude Deterioration in People Working in Tibet]. / è¥¿è—è‡ªæ²»åŒºåœ¨èŒèŒå·¥é«˜åŽŸè¡°é€€ç—‡çš„åˆ†å¸ƒç‰¹å¾åŠå½±å“å› ç´ .

Objective: To comprehensively investigate and analyze the distribution characteristics of high altitude deterioration (HADT) among people working in 7 cities of Tibet Autonomous Region, to examine the relevant influencing factors, and to provide baseline survey data for further research on HADT. Methods: A self-designed questionnaire was used to conduct a self-administered survey among employees in seven prefectures or cities (Lhasa City, Qamdo City, Shigatse City, Nyingchi City, Shannan City, Naqu City, and Ngari Prefecture) in Tibet. The respondents were selected through random cluster sampling. The survey covered 21 symptoms involving 4 systems of the human body, including the respiratory, nervous, circulatory, and digestive systems. The distributive characteristics of HADT (as manifested by maladaptation to high altitude) were described and Spearman's correlation was used to examine the influencing factors of maladaptation to high altitude. Results: A total of 3 901 respondents were included in the sample analyzed in the study, including 2 107 (54%) native Tibetans and 1 794 (46%) immigrant Han people. There were 1 994 males (51%) and 1 907 females (49%). Their age ranged from 20 to 57 years, averaging (34.45±8.11) years. The subjects lived at a high altitude for a duration of 0.5 to 54 years, averaging (19.51±13.84) years. The overall rates of maladaptation for the 21 symptoms among native Tibetans and immigrant Han people were 60.10% (26 578/44 247) and 73.20% (27 565/37 674), respectively. The maladaptation rates of the native Tibetan population for the respiratory, nervous, circulatory, and digestive systems of the human body were all lower than those of the immigrant Han population (P<0.001). There were no significant differences in the maladaptation rates of employees from different regions of Tibet (66.21% for Ngari Prefecture, 65.02% for Qamdo City, 66.67% for Lhasa City, 62.29% for Shigatse City, 65.03% for Shannan City, 64.42% for Nyingchi City, and 61.65% for Naqu City). The type of high-altitude residents (i.e., being native Tibetan or immigrant Han) was the main influencing factor for high-altitude maladaptation of the respiratory, nervous, circulatory, and digestive systems (P<0.001). According to the findings of the correlation analysis, age, type of high-altitude residents, and the duration of residence at a high altitude were associated with high-altitude maladaptation of the respiratory system, while type of high-altitude residents was the only factor associated with maladaptation of the nervous system, circulatory system, and digestive systems. Age and duration of living at at high altitude had significant effect on self-perceived dyspnea, a type of maladaptation of the respiratory system (P<0.001). Duration of high-altitude residence had significant effect on cyanotic lips or redness in the cheeks, a type of maladaptation of the circulatory system, and self-perceived loss of appetite, a type of maladaptation of the digestive system (P<0.05). Conclusion: More attention should be given to the HADT among employees of public institutions and enterprises who are living in Tibet Autonomous Region and immigrant Han people, in particular, should pay special attention to the protection of their respiratory, nervous, circulatory, and digestive systems.

Correlation analysis between vitamin A, D, and E status with altitude, seasonal variation, and other factors, among children aged 0-6 years in a Chinese population living in the Tibetan plateau of Ganzi prefecture.

OBJECTIVE: We attempted to understand the status of vitamin (Vit) A, D, and E in children aged 0-6 living in the Tibetan plateau areas of Ganzi prefecture, to provide the basis for relevant government departments to carry out physical examinations of these children and to prevent and cure four key diseases (Infantile diarrhea, nutritional anemia, rickets, and infantile pneumonia). METHODS: Serum retinol and tocopherol levels were detected using high-performance liquid chromatography (HPLC). Serum levels of 25-(OH)D were detected by high-performance liquid chromatography-tandem mass spectrometry (LC-MS). The polynomial logistic regression was used to analyze the effects of age, season, altitude, and gender on Vit A, D, and E levels. RESULTS: Vit A and D had the lowest mean serum levels before the age of 1 year and with the most significant deficiency rates. The lowest Vit E levels were seen in the Toddlerhood group. The rates of deficiency and insufficiency were the highest. Vit A, D, and E levels were significantly affected by seasonal changes and were significantly higher in the summer than in any other season. Vit A and D were significantly affected by altitude, and their levels were lowest above 4 km. CONCLUSION: The overall levels of Vit A, D, and E in children aged 0-6 in the Tibetan plateau areas of Ganzi prefecture were lower than those in the plain's areas.

The overlooked significance of plasma volume for successful adaptation to high altitude in Sherpa and Andean natives.

In contrast to Andean natives, high-altitude Tibetans present with a lower hemoglobin concentration that correlates with reproductive success and exercise capacity. Decades of physiological and genomic research have assumed that the lower hemoglobin concentration in Himalayan natives results from a blunted erythropoietic response to hypoxia (i.e., no increase in total hemoglobin mass). In contrast, herein we test the hypothesis that the lower hemoglobin concentration is the result of greater plasma volume, rather than an absence of increased hemoglobin production. We assessed hemoglobin mass, plasma volume and blood volume in lowlanders at sea level, lowlanders acclimatized to high altitude, Himalayan Sherpa, and Andean Quechua, and explored the functional relevance of volumetric hematological measures to exercise capacity. Hemoglobin mass was highest in Andeans, but also was elevated in Sherpa compared with lowlanders. Sherpa demonstrated a larger plasma volume than Andeans, resulting in a comparable total blood volume at a lower hemoglobin concentration. Hemoglobin mass was positively related to exercise capacity in lowlanders at sea level and in Sherpa at high altitude, but not in Andean natives. Collectively, our findings demonstrate a unique adaptation in Sherpa that reorientates attention away from hemoglobin concentration and toward a paradigm where hemoglobin mass and plasma volume may represent phenotypes with adaptive significance at high altitude.

Association of Daytime Napping with chronic diseases among Tibetan people in China: a cross-sectional study.

BACKGROUND: Obesity, diabetes, and hypertension, as three of the most prevalent chronic diseases, remain a daunting health challenge. However, to our knowledge, no study has made a thorough examination of the association between the three chronic diseases and daytime napping, a widely accepted behavior in many countries. This is especially necessary among Tibetan populations, whose lifestyles and health outcomes may be unique, yet patterns of chronic diseases and napping are under-examined. Thus, we sought to explore the aforementioned association in the Tibetan population of China. METHODS: A total of 2902 participants aged 45-79 in 2019 were included. Multivariate logistic regressions were conducted in 2020. The sex disparity was examined through interaction and stratified analyses. RESULTS: Hypertension (40.7%) was more prevalent than obesity (20.2%) and diabetes (21.6%). Comparing to non-nappers, those who napped were more likely to have any conditions (OR = 1.30, 95% CI = 1.04-1.62 for 1-59 min/day group and OR = 1.40, 95% CI = 1.10-1.80 for ≥60 min/day group). Participants who had 1-59 min/day of napping were more likely to develop obesity (OR = 1.37, 95% CI = 1.07-1.75), and ≥ 60 min/day of napping was associated with diabetes (OR = 1.33, 95% CI = 1.01-1.74). The interactions between napping and sex were not statistically significant in the models. CONCLUSIONS: The study revealed napping was unfavorably associated with obesity, diabetes, and any conditions in Tibetan people living on the Tibetan Plateau. Future interventions regarding the three chronic diseases may pay more attention to napping. TRIAL REGISTRATION: Not applicable.

Neural network correlates of high-altitude adaptive genetic variants in Tibetans: A pilot, exploratory study.

Although substantial progress has been made in the identification of genetic substrates underlying physiology, neuropsychology, and brain organization, the genotype-phenotype associations remain largely unknown in the context of high-altitude (HA) adaptation. Here, we related HA adaptive genetic variants in three gene loci (EGLN1, EPAS1, and PPARA) to interindividual variance in a set of physiological characteristics, neuropsychological tests, and topological attributes of large-scale structural and functional brain networks in 135 indigenous Tibetan highlanders. Analyses of individual HA adaptive single-nucleotide polymorphisms (SNPs) revealed that specific SNPs selectively modulated physiological characteristics (erythrocyte level, ratio between forced expiratory volume in the first second to forced vital capacity, arterial oxygen saturation, and heart rate) and structural network centrality (the left anterior orbital gyrus) with no effects on neuropsychology or functional brain networks. Further analyses of genetic adaptive scores, which summarized the overall degree of genetic adaptation to HA, revealed significant correlations only with structural brain networks with respect to local interconnectivity of the whole networks, intermodule communication between the right frontal and parietal module and the left occipital module, nodal centrality in several frontal regions, and connectivity strength of a subnetwork predominantly involving in intramodule edges in the right temporal and occipital module. Moreover, the associations were dependent on gene loci, weight types, or topological scales. Together, these findings shed new light on genotype-phenotype interactions under HA hypoxia and have important implications for developing new strategies to optimize organism and tissue responses to chronic hypoxia induced by extreme environments or diseases.

Genetic signatures of high-altitude adaptation in Tibetans.

Indigenous Tibetan people have lived on the Tibetan Plateau for millennia. There is a long-standing question about the genetic basis of high-altitude adaptation in Tibetans. We conduct a genome-wide study of 7.3 million genotyped and imputed SNPs of 3,008 Tibetans and 7,287 non-Tibetan individuals of Eastern Asian ancestry. Using this large dataset, we detect signals of high-altitude adaptation at nine genomic loci, of which seven are unique. The alleles under natural selection at two of these loci [methylenetetrahydrofolate reductase (MTHFR) and EPAS1] are strongly associated with blood-related phenotypes, such as hemoglobin, homocysteine, and folate in Tibetans. The folate-increasing allele of rs1801133 at the MTHFR locus has an increased frequency in Tibetans more than expected under a drift model, which is probably a consequence of adaptation to high UV radiation. These findings provide important insights into understanding the genomic consequences of high-altitude adaptation in Tibetans.

Down-Regulation of EPAS1 Transcription and Genetic Adaptation of Tibetans to High-Altitude Hypoxia.

Tibetans are well adapted to the hypoxic environments at high altitude, yet the molecular mechanism of this adaptation remains elusive. We reported comprehensive genetic and functional analyses of EPAS1, a gene encoding hypoxia inducible factor 2α (HIF-2α) with the strongest signal of selection in previous genome-wide scans of Tibetans. We showed that the Tibetan-enriched EPAS1 variants down-regulate expression in human umbilical endothelial cells and placentas. Heterozygous EPAS1 knockout mice display blunted physiological responses to chronic hypoxia, mirroring the situation in Tibetans. Furthermore, we found that the Tibetan version of EPAS1 is not only associated with the relatively low hemoglobin level as a polycythemia protectant, but also is associated with a low pulmonary vasoconstriction response in Tibetans. We propose that the down-regulation of EPAS1 contributes to the molecular basis of Tibetans' adaption to high-altitude hypoxia.

Differentiation analysis for estimating individual ancestry from the Tibetan Plateau by an archaic altitude adaptation EPAS1 haplotype among East Asian populations.

Tibetans have adapted to the extreme environment of high altitude for hundreds of generations. A highly differentiated 5-SNP (Single Nucleotide Polymorphism) haplotype motif (AGGAA) on a hypoxic pathway gene, EPAS1, is observed in Tibetans and lowlanders. To evaluate the potential usage of the 5-SNP haplotype in ancestry inference for Tibetan or Tibetan-related populations, we analyzed this haplotype in 1053 individuals of 12 Chinese populations residing on the Tibetan Plateau, peripheral regions of Tibet, and plain regions. These data were integrated with the genotypes from the 1000 Genome populations and populations in a previously reported paper for population structure analyses. We found that populations representing highland and lowland groups have different dominant ancestry components. The core Denisovan haplotype (AGGAA) was observed at a frequency of 72.32% in the Tibetan Plateau, with a frequency range from 9.48 to 21.05% in the peripheral regions and < 2.5% in the plains area. From the individual perspective, 87.57% of the individuals from the Tibetan Plateau carried the archaic haplotype, while < 5% of the Chinese Han people carried the haplotype. Our findings indicate that the 5-SNP haplotype has a special distribution pattern in populations of Tibet and peripheral regions and could be integrated into AISNP (Ancestry Informative Single Nucleotide Polymorphism) panels to enhance ancestry resolution.

Frequency of Polycythemia and Other Abnormalities in a Tibetan Herdsmen Population Residing in the Kham Area of Sichuan Province, China.

INTRODUCTION: The Kham Tibetans are one of several Tibetan ethnic subgroups living in the Kham area of China. Because studies on the high-altitude adaptation of the Kham people are scant, the main aim of this study is to investigate whether the response to hypoxia, especially polycythemia status, in the Kham Tibetans is different from other Tibetan ethnic subgroups. METHODS: The primary investigation was conducted on 346 native Kham Tibetan adults (268 men and 78 women) from 3 herdsmen villages located in Hongyuan County situated at an altitude of greater than 3600 m. The participants were aged 46.2±14.1 (21-82; mean±SD with range) years. Anthropometric measurements such as weight, height, waist circumference, body mass index, and blood pressure, as well as laboratory blood tests such as glycosylated hemoglobin, hemoglobin, total cholesterol, triglycerides, high-density lipoprotein cholesterol, low-density lipoprotein cholesterol, and uric acid were analyzed. RESULTS: The concentrations of hemoglobin were 171.3±12.9 (66-229) mg·L-1 and 151.4±16.4 (86-190) mg·L-1 in men and women, respectively. The frequency of polycythemia was found to be 25.5 and 21.8% in men and women, respectively. Polycythemia was found to be significantly associated with glycosylated hemoglobin concentrations, hypertension, and hyperuricemia (P=0.002, 0.023, and 0.009, respectively). CONCLUSIONS: There is a higher frequency of polycythemia in the Kham Tibetans when compared with reported studies from other Tibetan ethnic subgroups living on the Qinghai-Tibet plateau.

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.

Closing the Womb Door: Contraception Use and Fertility Transition Among Culturally Tibetan Women in Highland Nepal.

Objectives Whether in metropoles or remote mountain communities, the availability and adoption of contraceptive technologies prompt serious and wide-ranging biological, social, and political-economic questions. The potential shifts in women's capacities to create spaces between pregnancies or to prevent future pregnancies have profound and often positive biological, demographic, and socioeconomic implications. Less acknowledged, however, are the ambivalences that women experience around contraception use-vacillations between moral frameworks, generational difference, and gendered forms of labor that have implications well beyond the boundaries of an individual's reproductive biology. This paper hones in on contraceptive use of culturally Tibetan women in two regions of highland Nepal whose reproductive lives occurred from 1943 to 2012. Methods We describe the experiences of the 296 women (out of a study of more than 1000 women's reproductive histories) who used contraception, and under what circumstances, examining socioeconomic, geographic, and age differences as well as points of access and patterns of use. We also provide a longitudinal perspective on fertility. Results Our results relate contraception usage to fertility decline, as well as to differences in access between the two communities of women. Conclusions We argue that despite seemingly similar social ecologies of these two study sites-including stated reasons for the adoption of contraception and expressed ambivalence around its use, some of which are linked to moral and cosmological understandings that emerge from Buddhism-the dynamics of contraception uptake in these two regions are distinct, as are, therefore, patterns of fertility transition.

[Association of Gene Polymorphisms in Wnt Signal Pathway with Tuberculosis in Chinese Tibetan Population.]

OBJECTIVES: To determine the correlation between gene polymorphisms in Wnt signal pathway and susceptibility of Chinese Tibetan people to tuberculosis. METHODS: A total of 488 active tuberculosis patients and 454 healthy subjects(control) were enrolled in this case-control study.Five single nucleotide polymorphisms (SNPs) in Wnt signal pathway (rs4135385 in CTNNB1 gene,rs11001553 in DKK1 gene,rs56900803 in WIF1 gene,rs7832767 in SFRP1 gene and rs11079571 in AXIN2 gene) were genotyped using MassARRAY method.The genotype and allele distributions of these loci were determined using SPSS19.0 and SNP stats software.Significant SNPs were measured in the co-dominant,dominant and recessive genetic models.The polymorphism distributions of Chinese Tibetans were compared with those of Chinese Han populations. RESULTS: The genotype distributions of all SNPs coincided with the Hardy-Weinberg equilibrium in the 2 groups.The frequencies of genotype and allele of rs7832767 in SFRP1 gene were significantly different (P=0.004,0.002,respectively) between the Tibetan patients with tuberculosis and the Tibetan healthy controls.Compared with C allele carriers,those carrying T allele of rs7832767 showed increased risk of tuberculosis [odds ratio (OR)=1.260,95% confidence interval (CI):1.086-1.471,P=0.002].The co-dominant,dominant and recessive models of this locus were also associated with higher risk of tuberculosis.No significant differences in genotype and allele distributions were observed for the other four SNP loci (P all>0.05).The distribution of rs4135385 in CTNNB1 gene in the Chinese Tibetan population differed from the Han population (P=0.035 for genotype,0.021 for allele).There were no obvious differences in genotype and allele distributions for the other four SNPs between the Tibetan and Han populations (P all >0.05). CONCLUSIONS: SFRP1 gene polymorphism in Wnt signal pathway is associated with tuberculosis susceptibility in Chinese Tibetan population.The distribution of CTNNB1 gene polymorphism differs between Chinese Tibetan and Han populations.

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

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

Identification of a Tibetan-specific mutation in the hypoxic gene EGLN1 and its contribution to high-altitude adaptation.

Tibetans are well adapted to high-altitude hypoxic conditions, and in recent genome-wide scans, many candidate genes have been reported involved in the physiological response to hypoxic conditions. However, the limited sequence variations analyzed in previous studies would not be sufficient to identify causal mutations. Here we conducted resequencing of the entire genomic region (59.4 kb) of the hypoxic gene EGLN1 (one of the top candidates from the genome-wide scans) in Tibetans and identified 185 sequence variations, including 13 novel variations (12 substitutions and 1 insertion or deletion). There is a nonsynonymous mutation (rs186996510, D4E) showing surprisingly deep divergence between Tibetans and lowlander populations (Fst = 0.709 between Tibetans and Han Chinese). It is highly prevalent in Tibetans (70.9% on average) but extremely rare in Han Chinese, Japanese, Europeans, and Africans (0.56-2.27%), suggesting that it might be the causal mutation of EGLN1 contributing to high-altitude hypoxic adaptation. Neutrality test confirmed the signal of Darwinian positive selection on EGLN1 in Tibetans. Haplotype network analysis revealed a Tibetan-specific haplotype, which is absent in other world populations. The estimated selective intensity (0.029 for the C allele of rs186996510) puts EGLN1 among the known genes that have undergone the strongest selection in human populations, and the onset of selection was estimated to have started at the early Neolithic (∼8,400 years ago). Finally, we detected a significant association between rs186996510 and hemoglobin levels in Tibetans, suggesting that EGLN1 contributes to the adaptively low hemoglobin level of Tibetans compared with acclimatized lowlanders at high altitude.