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1.
Nat Commun ; 11(1): 4928, 2020 10 01.
Artigo em Inglês | MEDLINE | ID: mdl-33004791

RESUMO

High-altitude adaptation of Tibetans represents a remarkable case of natural selection during recent human evolution. Previous genome-wide scans found many non-coding variants under selection, suggesting a pressing need to understand the functional role of non-coding regulatory elements (REs). Here, we generate time courses of paired ATAC-seq and RNA-seq data on cultured HUVECs under hypoxic and normoxic conditions. We further develop a variant interpretation methodology (vPECA) to identify active selected REs (ASREs) and associated regulatory network. We discover three causal SNPs of EPAS1, the key adaptive gene for Tibetans. These SNPs decrease the accessibility of ASREs with weakened binding strength of relevant TFs, and cooperatively down-regulate EPAS1 expression. We further construct the downstream network of EPAS1, elucidating its roles in hypoxic response and angiogenesis. Collectively, we provide a systematic approach to interpret phenotype-associated noncoding variants in proper cell types and relevant dynamic conditions, to model their impact on gene regulation.


Assuntos
Aclimatação/genética , Cromatina/metabolismo , Grupos Étnicos/genética , Redes Reguladoras de Genes , Modelos Genéticos , Altitude , Doença da Altitude/etnologia , Doença da Altitude/genética , Doença da Altitude/metabolismo , Fatores de Transcrição Hélice-Alça-Hélice Básicos/genética , Hipóxia Celular/genética , Células Cultivadas , Cromatina/genética , Sequenciamento de Cromatina por Imunoprecipitação , Resistência à Doença/genética , Feminino , Regulação da Expressão Gênica , Células Endoteliais da Veia Umbilical Humana , Humanos , Hipóxia/genética , Hipóxia/metabolismo , Oxigênio/metabolismo , Polimorfismo de Nucleotídeo Único , Gravidez , Cultura Primária de Células , RNA-Seq , Elementos Reguladores de Transcrição/genética , Seleção Genética , Tibet/etnologia , Fatores de Transcrição/metabolismo , Sequenciamento Completo do Genoma
2.
Rev. cuba. pediatr ; 91(3): e687, jul.-set. 2019. tab
Artigo em Espanhol | LILACS, CUMED | ID: biblio-1093714

RESUMO

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


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


Assuntos
Humanos , Masculino , Feminino , Recém-Nascido , Triagem Neonatal/métodos , Doença da Altitude/etnologia , Peru , Nível de Oxigênio/métodos , Serviços de Saúde da Criança , Estudos Prospectivos , Estudo Observacional , Frequência Cardíaca/fisiologia
3.
Epigenetics ; 14(1): 1-15, 2019 01.
Artigo em Inglês | MEDLINE | ID: mdl-30574831

RESUMO

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


Assuntos
Doença da Altitude/genética , Fatores de Transcrição Hélice-Alça-Hélice Básicos/genética , Metilação de DNA , Elementos Nucleotídeos Longos e Dispersos/genética , Adaptação Fisiológica/genética , Adolescente , Adulto , Altitude , Doença da Altitude/etnologia , Epigênese Genética , Feminino , Humanos , Masculino , Polimorfismo de Nucleotídeo Único
4.
Med Hypotheses ; 104: 128-132, 2017 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-28673571

RESUMO

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


Assuntos
Adaptação Fisiológica , Doença da Altitude/complicações , Altitude , Pré-Eclâmpsia/genética , Complicações na Gravidez/genética , Alelos , Doença da Altitude/etnologia , Doença da Altitude/fisiopatologia , Líquido Amniótico/metabolismo , Feminino , Frequência do Gene , Genótipo , Humanos , Hipóxia , Prolina Dioxigenases do Fator Induzível por Hipóxia/genética , Polimorfismo de Nucleotídeo Único , Pré-Eclâmpsia/etnologia , Gravidez , Complicações na Gravidez/etnologia , Análise de Sequência de RNA
5.
High Alt Med Biol ; 18(1): 27-36, 2017 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-27740865

RESUMO

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


Assuntos
Altitude , Proteínas Sanguíneas/análise , Proteínas Quinases Dependentes de GMP Cíclico/sangue , Óxido Nítrico Sintase Tipo III/sangue , Proteômica/métodos , Sistema Renina-Angiotensina/genética , Aclimatação/genética , Adulto , Doença da Altitude/sangue , Doença da Altitude/etnologia , Doença da Altitude/genética , Fatores de Coagulação Sanguínea/análise , Ativação do Complemento , Voluntários Saudáveis , Humanos , Índia/etnologia , Masculino , Grupos Populacionais/etnologia , Grupos Populacionais/genética , Transdução de Sinais/genética , Adulto Jovem
6.
Oncotarget ; 7(47): 77117-77123, 2016 11 22.
Artigo em Inglês | MEDLINE | ID: mdl-27732943

RESUMO

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


Assuntos
Doença da Altitude/genética , Estudos de Associação Genética/métodos , Polimorfismo de Nucleotídeo Único , Edema Pulmonar/genética , Receptor Tipo 1 de Angiotensina/genética , Adulto , Fatores Etários , Doença da Altitude/etnologia , Grupo com Ancestrais do Continente Asiático/etnologia , Grupo com Ancestrais do Continente Asiático/genética , Estudos de Casos e Controles , China/etnologia , Feminino , Predisposição Genética para Doença , Haplótipos , Humanos , Masculino , Edema Pulmonar/etnologia , Fatores Sexuais , Adulto Jovem
7.
J Gene Med ; 18(9): 244-9, 2016 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-27552709

RESUMO

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


Assuntos
Hidrolases Anidrido Ácido/genética , Doença da Altitude/genética , Predisposição Genética para Doença/genética , Hipertensão Pulmonar/genética , Polimorfismo de Nucleotídeo Único , Telômero/genética , Adulto , Alelos , Doença da Altitude/etnologia , Grupo com Ancestrais do Continente Asiático/genética , Estudos de Casos e Controles , Distribuição de Qui-Quadrado , China , Feminino , Frequência do Gene , Predisposição Genética para Doença/etnologia , Genótipo , Humanos , Hipertensão Pulmonar/etnologia , Masculino , Fatores de Risco , Adulto Jovem
8.
J Travel Med ; 23(1)2016 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-27006981
9.
Blood Cells Mol Dis ; 57: 13-22, 2016 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-26852650

RESUMO

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.


Assuntos
Doença da Altitude/genética , Proteínas Adaptadoras de Sinalização CARD/genética , Endopeptidases/genética , Epistasia Genética , Guanilato Ciclase/genética , Proteínas de Membrana/genética , Policitemia/genética , Polimorfismo de Nucleotídeo Único , Fator A de Crescimento do Endotélio Vascular/genética , Adulto , Alelos , Altitude , Doença da Altitude/complicações , Doença da Altitude/diagnóstico , Doença da Altitude/etnologia , Grupo com Ancestrais do Continente Asiático , Estudos de Casos e Controles , Cisteína Endopeptidases , Expressão Gênica , Predisposição Genética para Doença , Proteínas de Choque Térmico HSP70/genética , Hepcidinas/genética , Humanos , Subunidade alfa do Fator 1 Induzível por Hipóxia/genética , Desequilíbrio de Ligação , Masculino , Razão de Chances , Peptidil Dipeptidase A/genética , Policitemia/complicações , Policitemia/diagnóstico , Policitemia/etnologia , Tibet
11.
PLoS One ; 10(9): e0137956, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-26368009

RESUMO

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.


Assuntos
Doença da Altitude/genética , Fatores de Transcrição Hélice-Alça-Hélice Básicos/genética , Hipóxia/genética , Polimorfismo de Nucleotídeo Único , Seleção Genética , Adolescente , Adulto , Doença da Altitude/etnologia , Humanos , Hipóxia/etnologia , Tibet/etnologia
12.
Asia Pac J Public Health ; 27(2): NP116-31, 2015 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-22186404

RESUMO

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


Assuntos
Doença da Altitude/etnologia , Grupo com Ancestrais do Continente Asiático , Militares/estatística & dados numéricos , Doença Aguda , Adolescente , Adulto , China/epidemiologia , Humanos , Incidência , Masculino , Razão de Chances , Curva ROC , Estudos Retrospectivos , Fatores de Risco , Estações do Ano , Adulto Jovem
13.
Physiology (Bethesda) ; 29(6): 403-12, 2014 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-25362634

RESUMO

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.


Assuntos
Doença da Altitude/genética , Altitude , Hipóxia/fisiopatologia , Aclimatação , Doença da Altitude/etnologia , Doença da Altitude/fisiopatologia , Doença da Altitude/terapia , Etiópia/epidemiologia , Interação Gene-Ambiente , Marcadores Genéticos , Predisposição Genética para Doença , Humanos , Hipóxia/etnologia , Hipóxia/genética , Fenótipo , Prevalência , Fatores de Proteção , Fatores de Risco , Tibet/epidemiologia
14.
PLoS One ; 8(8): e71993, 2013.
Artigo em Inglês | MEDLINE | ID: mdl-23991023

RESUMO

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


Assuntos
Doença da Altitude/genética , Predisposição Genética para Doença/genética , Hipertensão Pulmonar/genética , Polimorfismo de Nucleotídeo Único , Inibidor Tecidual de Metaloproteinase-3/genética , Adolescente , Adulto , Idoso , Alelos , Doença da Altitude/etnologia , Grupo com Ancestrais do Continente Asiático/genética , Estudos de Casos e Controles , Feminino , Frequência do Gene , Predisposição Genética para Doença/etnologia , Estudo de Associação Genômica Ampla , Genótipo , Haplótipos , Humanos , Hipertensão Pulmonar/etnologia , Japão , Desequilíbrio de Ligação , Masculino , Repetições de Microssatélites/genética , Pessoa de Meia-Idade , Adulto Jovem
15.
J Travel Med ; 20(4): 247-55, 2013.
Artigo em Inglês | MEDLINE | ID: mdl-23809076

RESUMO

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


Assuntos
Doença da Altitude/etnologia , Viagem , Aclimatação , Humanos , Incidência , Fatores de Risco
16.
Tohoku J Exp Med ; 229(4): 255-66, 2013 04.
Artigo em Inglês | MEDLINE | ID: mdl-23603420

RESUMO

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


Assuntos
Doença da Altitude/genética , Hipertensão Pulmonar/genética , Óxido Nítrico Sintase Tipo III/genética , Peptidil Dipeptidase A/genética , Polimorfismo de Nucleotídeo Único/genética , Doença da Altitude/etnologia , Grupo com Ancestrais do Continente Asiático/genética , Estudos de Casos e Controles , China , Primers do DNA/genética , Estudos de Associação Genética , Genótipo , Humanos , Hipertensão Pulmonar/etnologia , Modelos Genéticos , Razão de Chances , Reação em Cadeia da Polimerase , Espectrometria de Massas por Ionização e Dessorção a Laser Assistida por Matriz
17.
Yi Chuan ; 35(11): 1291-9, 2013 Nov.
Artigo em Chinês | MEDLINE | ID: mdl-24579312

RESUMO

High-altitude pulmonary edema (HAPE) is a non-cardiogenic pulmonary edema that is always found among unacclimatized persons after rapid ascent to high altitude, and HAPE is caused by the interaction of genetic and environmental factors. To screen and analyze the susceptibility genes and single nucleotide polymorphisms (SNPs) of HAPE in Han Chinese, the DNA samples of 40 patients with HAPE and 33 healthy controls, who performed the reconstruction tasks from the plain region in Yushu area of Qinghai province during May of 2010 to July of 2012, were scanned by Affymetrix SNP Array 6.0 Chips in this study. Genome-wide association study (GWAS, by PLINK software) was used to screen the susceptibility genes and genetic markers, and a total of 57 SNPs were found to be significantly different between case and control groups (adjust P < 0.05). GO and Pathway enrichment analysis of 74 genes around the 57 SNPs indicated that these genes were significantly correlated with prostanoid metabolic process, arachidonic acid metabolism and nitrogen metabolism (adjust P < 0.05), which were involved in the physiopathologic mechanism of HAPE. Our studies suggest that these genetic polymorphisms and genes were associated with HAPE.


Assuntos
Doença da Altitude/genética , Grupo com Ancestrais do Continente Asiático/genética , Estudo de Associação Genômica Ampla , Hipertensão Pulmonar/genética , Adulto , Altitude , Doença da Altitude/etnologia , Grupo com Ancestrais do Continente Asiático/etnologia , Estudos de Casos e Controles , China , Feminino , Predisposição Genética para Doença , Humanos , Hipertensão Pulmonar/etnologia , Masculino , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único
18.
Wilderness Environ Med ; 24(1): 32-6, 2013 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-23062320

RESUMO

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


Assuntos
Doença da Altitude/terapia , Hipertensão Pulmonar/terapia , Oxigenoterapia , Vasodilatadores/uso terapêutico , Acetazolamida/uso terapêutico , Doença da Altitude/etnologia , Dexametasona/uso terapêutico , Tratamento de Emergência/métodos , Feminino , Humanos , Hipertensão Pulmonar/etnologia , Masculino , Montanhismo , Nepal , Nifedipino/uso terapêutico , Piperazinas/uso terapêutico , Purinas/uso terapêutico , Estudos Retrospectivos , Estações do Ano , Citrato de Sildenafila , Sulfonas/uso terapêutico , Resultado do Tratamento
19.
Am J Respir Crit Care Med ; 186(12): 1229-37, 2012 Dec 15.
Artigo em Inglês | MEDLINE | ID: mdl-23103737

RESUMO

Medical problems occur at high altitude because of the low inspired Po(2), which is caused by the reduced barometric pressure. The classical physiological responses to high altitude include hyperventilation, polycythemia, hypoxic pulmonary vasoconstriction-increased intracellular oxidative enzymes, and increased capillary density in muscle. However, with the discovery of hypoxia-inducible factors (HIFs), it is apparent that there is a multitude of responses to cellular hypoxia. HIFs constitute a master switch determining the general response of the body to oxygen deprivation. The recent discovery of genetic changes in Tibetans has opened up an exciting area of research. The two major human populations that have adapted well to high altitude, the Tibetans and Andeans, have strikingly different phenotypes. Diseases of lowlanders going to high altitude include acute mountain sickness, high-altitude pulmonary edema, and high-altitude cerebral edema. Diseases affecting permanent residents or highlanders include chronic mountain sickness and high-altitude pulmonary hypertension. Important recent advances have been made on mitigation of the effects of the hypoxic environment. Oxygen enrichment of room air is very powerful. Every 1% increase in oxygen concentration reduces the equivalent altitude by about 300 m. This procedure is used in numerous facilities at high altitude and in a Chinese train to Lhasa. An alternative strategy is to increase the barometric pressure as in aircraft cabins. A hybrid approach combining both strategies shows promise but has never been used. Mines that are being developed at increasingly high altitudes pose great medical problems.


Assuntos
Aclimatação/genética , Doença da Altitude/genética , Altitude , Fatores de Transcrição Hélice-Alça-Hélice Básicos/genética , Hipóxia/genética , Aclimatação/fisiologia , Doença da Altitude/etnologia , Doença da Altitude/fisiopatologia , Fatores de Transcrição Hélice-Alça-Hélice Básicos/fisiologia , Humanos , Hipóxia/fisiopatologia , América do Sul/etnologia , Tibet/etnologia
20.
Wilderness Environ Med ; 23(2): 128-32, 2012 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-22656658

RESUMO

BACKGROUND: The role of genetics in determining an individual's susceptibility to high altitude pulmonary edema (HAPE) is unclear. However a number of genetic polymorphisms have recently been found to be overrepresented in patients with HAPE. Changes at the mitochondrial level may play an important role in the human body's adaptation to hypoxia. Polymorphisms of mitochondrial DNA (mtDNA) have been shown to be responsible for differences in organelle function. Therefore, the frequency of mtDNA 3397A/G and 3552T/A polymorphisms were studied to determine their potential role in HAPE. OBJECTIVES: To further study the role of mtDNA 3397A/G and 3552T/A variations of reduced nicotinamide adenosine dinucleotide dehydrogenase 1 in HAPE susceptibility. METHODS: The single-nucleotide polymorphisms of mtDNA 3397 and 3552 in patients with HAPE (n = 132) and their matched control subjects (n = 233) were studied using polymerase chain reaction sequencing. RESULTS: The frequency of mtDNA 3397G in the HAPE group (2.3%) was significantly higher than that of the control group (0%; P = .021; odds ratio, 2.806; 95% confidence interval, 2.443 to 3.223). The frequency of mtDNA 3552A in the HAPE group (6.8%) also was significantly higher than in the control group (1.7%; P = .012; odds ratio, 4.198; 95% confidence interval, 1.264 to 13.880). CONCLUSIONS: In this study, we present the first evidence of differences in mtDNA polymorphism frequencies between HAPE victims and healthy Han Chinese. Genotypes of mtDNA 3397G and 3552A were correlated with HAPE susceptibility. This result could contribute to defining the role of the mitochondrial genome in the pathogenesis of HAPE.


Assuntos
Doença da Altitude/genética , Grupo com Ancestrais do Continente Asiático/genética , DNA Mitocondrial/genética , Hipertensão Pulmonar/genética , Polimorfismo de Nucleotídeo Único , Adulto , Doença da Altitude/etnologia , Estudos de Casos e Controles , China , Feminino , Frequência do Gene , Predisposição Genética para Doença , Genótipo , Humanos , Hipertensão Pulmonar/etnologia , Masculino , Reação em Cadeia da Polimerase
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