Heterogeneity in Hematological Parameters of High and Low Altitude Tibetan Populations.

INTRODUCTION: High altitude hypoxia is believed to be experienced at elevations of more than 2500 meters above sea level. Several studies have shed light on the biochemical aspects of high altitude acclimatization, where participants were sojourners to the high altitude from low altitude areas. However, information regarding the difference between the high altitude adapted Tibetans living at high altitude and their counterparts who reside at low altitude are lacking. To understand this, we have measured various hematological parameters in the Tibetan populations, who are residing in both high and low altitudes in India. METHODS: A total of 168 individuals (79 from high altitude (≥4500 meters) and 89 from low altitude (~850 meters) were recruited for this study. Hematological parameters such as red blood cells (RBC) count, hematocrit (HCT), hemoglobin concentration (Hb), mean corpuscular volume (MCV), mean corpuscular hemoglobin (MCH) and mean corpuscular hemoglobin concentration (MCHC) were measured from the individuals from high and low altitudes. Serum erythropoietin (EPO) was measured by ELISA. Statistical analyses were performed to compare data from both of the altitudes. Gender-wise comparison of data was reported. Correlation analysis was performed within relevant parameters. RESULTS: Highly significant differences (p <0.0001) between high and low altitude Tibetans were detected in RBC count, HCT, Hb, MCHC in both males and females and in MCV in females. In the case of MCHC, however, age and BMI were potential confounders. Nominally significant differences (p <0.05) were detected in MCV and MCH within males. No significant difference in serum EPO level was found between altitude groups, in any gender. No significant correlation was found between serum EPO with Hb as well as serum EPO with HCT. DISCUSSION: Our study explores significantly lower RBC count, HCT, Hb, MCH, MCHC and higher MCV in long-term Tibetan residents living at low altitude compared to their high altitude counterparts, which is likely due to the outcome of hematological adaptation to a relatively hyperoxic environment in low altitude areas.

High altitude with monotonous environment has significant impact on mood and cognitive performance of acclimatized lowlanders: Possible role of altered serum BDNF and plasma homocysteine level.

BACKGROUND: Monotony resulting due to the wilderness, sparse population and isolation from society could adversely affect human physiology and cause mood alterations. Thus, observations need to be conducted in order to elucidate the possible role of circulating biomarkers in inducing altered mood and cognitive performance following prolonged exposure to high altitude (HA) with persistent monotonous environment. OBJECTIVE: The present study aimed towards investigating the impact of monotonous environment in remote HA on mood and cognitive performance of human volunteers and its correlation with serum brain derived neurotrophic factor (BDNF) and plasma homocysteine level. METHODS: The present study was conducted on male lowlander participants who had normal social life prior to induction in HA environment. Baseline data was acquired at altitude ≤240 m mean sea level (MSL). Thereafter, the participants were inducted to an altitude of 4500-4800 m MSL. After acclimatization to HA, the participants were assigned as acclimatized low landers (ALL). Longitudinal follow up was conducted after 8 months of high altitude induction on acclimatized low landers (8ALL). Further, to study the effect of monotony, the participants were randomly assigned into different group sizes during their further stay of 4 months in HA viz. ≤5 (12ALL ≤ 5) and ≥10 (12ALL ≥ 10). Mood and cognitive performance of the participants were assessed by standard self-administered questionnaires. Serum BDNF and plasma homocysteine were estimated and their correlation with mood and cognition were determined. RESULTS: The findings showed significantly low serum BDNF in 12ALL ≤ 5 group when compared to baseline, 8ALL and 12AL ≥ 10 groups. Alleviated serum BDNF was associated with increased prevalence of mood alterations in HA with persistent monotonous environment. Participants of 12ALL ≥ 10 group showed significantly higher cognitive performance as compared to 12ALL ≤ 5 group which was associated with reduced plasma homocysteine level. LIMITATIONS: Total registered volunteers during baseline study were not available during the entire period of this study. The second limitation was exclusion of participants with medical history of severe head injuries, chronic diseases in family and extreme baseline serum profile. Third limitation of the study was to exclude the participants detected with MCI after 8 months of HA induction for negating the role of hypobaric hypoxia on mood and cognition. CONCLUSION: The study advocated that ALLs of 12ALL ≤ 5 group have increased prevalence of depressive trait and cognitive impairment which was correlated with reduced serum BDNF and augmented plasma homocysteine level as compared to participants of 12ALL ≥ 10 group having better social interaction with improved cognition and mood. The basic findings of the present study revealed that prolonged HA stay after physiological acclimatization should be regulated by proper social interaction involving normal group size to avoid detrimental effect of monotony and its significant impact on circulatory biomarkers.

Prevalence and risk factors of hypertension in acclimatized lowlanders staying at high altitude for different durations.

Hypoxic exposure at high-altitude (HA) modulates blood pressure (BP). High prevalence of hypertension among native highlanders (NH) has been reported. However, information on prevalence and determinants of hypertension in acclimatized young lowlanders (ALL) staying at HA for different durations is sparse. We aimed to determine the prevalence of hypertension in ALL staying at HA for different durations and its association with cardiovascular risk factors. Male volunteers were categorized on the basis of their duration of stay at HA; Lowlanders (LL) (0 months; n = 151), ALL (1-24 months; n = 519) and NH (n = 103). ALL were sub grouped into ALL 1 (1-6 months; n = 165), ALL 2 (6-12 months; n = 181), and ALL 3 (12-24 months; n = 173). BP, sympathetic activity, arterial stiffness, lipid profile, and homocysteine were estimated. Regression analysis was performed to determine association of risk factors with hypertension. Prevalence of hypertension among ALL was highest with 17.53% followed by NH (11.6%) and LL (9.27%). Prevalence of hypertension in ALL sub group was in order ALL 1 < ALL 2 < ALL 3. Hypertension was significantly associated with sympathetic dominance (p < 0.001) in ALL 1. Hypertension in ALL 2 was associated with dyslipidemia (p < 0.01) while in ALL 3 hypertension was associated with hyperhomocysteinemia (hHCY, p < 0.001), arterial stiffness and dyslipidemia (p < 0.01). In conclusion, our report suggests higher prevalence of hypertension in ALL. The association of studied risk factors and hypertension in different ALL sub groups varied significantly. Our findings suggest the need for a differential clinical approach to control hypertension in ALL considering their duration of stay at HA.

Sleep quality among elderly high-altitude dwellers in Ladakh.

It has been already known that people who temporarily stay at high altitude may develop insomnia as a symptom of acute mountain sickness. However, much less is known about people living at high altitude. The aim of this study was to determine the effect of high altitude environment on sleep quality for the elderly who have been living at high altitude for their whole lives. A cross-sectional study was conducted in Domkhar valley at altitudes of 2800-4200m, Ladakh. Sleep quality was assessed using Insomnia Severity Index (ISI). Measurement items include body mass index, blood pressure, blood sugar, hemoglobin, timed Up and Go test, oxygen saturation during wakefulness, respiratory function test, Oxford Knee Score (OKS), and Geriatric Depression Scale (GDS), and so on. The participants were Ladakhi older adults aged 60 years or over (n=112) in Domkhar valley. The participation rate was 65.1% (male: female=47:65, mean age: 71.3 years and 67.9 years, respectively). The prevalence of the high score of ISI (8 or more) was 15.2% (17 out of 112). Altitude of residence was significantly correlated with ISI. Stepwise multiple regression analysis showed that OKS and altitude of residence were significantly related with ISI.

Health and happiness among community-dwelling older adults in Domkhar valley, Ladakh, India.

AIM: The aim of the present study was to show the status of objective geriatric functions and subjective quality of life in Ladakh, India, compared with Japanese controls. METHODS: We analyzed data of 117 people aged 60 years or older in Domkhar, and age- and sex-specific Japanese controls. Variables measured included blood pressure, hemoglobin, timed up & go test, basic activities of daily living, Geriatric Depression Scale and the Visual Analog Scale for subjective quality of life. RESULTS: People in Domkhar were more likely to have difficulties in basic activities of daily living compared with Japanese controls. However, they were significantly more likely to maintain social roles. The Visual Analog Scale scores in subjective friendship, economic satisfaction and happiness were higher in Domkhar compared with Japanese controls. Living alone (OR 9.92, 95% CI 2.13-46.26), high Geriatric Depression Scale score (6 or more; OR 8.45, 95% CI 1.65-43.35) and timed up & go test (17 s or more; OR 21.00, 95% CI 1.69-260.87) were significantly associated with a low score of subjective happiness (less than 50). Residence in Domkhar (OR 0.17, 95% CI 0.04-0.77) was a significant factor for low prevalence of a low score of subjective happiness by multivariate logistic regression analysis. CONCLUSIONS: Subjective quality of life among older adults in Domkhar was higher than Japanese controls despite a higher rate of difficulty in basic activities of daily living. We have to consider prevention, treatment, and care of not only diseases and disabilities, but also loneliness for the older adults. Geriatr Gerontol Int 2017; 17: 480-486.

Glucose intolerance associated with hypoxia in people living at high altitudes in the Tibetan highland.

OBJECTIVES: To clarify the association between glucose intolerance and high altitudes (2900-4800 m) in a hypoxic environment in Tibetan highlanders and to verify the hypothesis that high altitude dwelling increases vulnerability to diabetes mellitus (DM) accelerated by lifestyle change or ageing. DESIGN: Cross-sectional epidemiological study on Tibetan highlanders. PARTICIPANTS: We enrolled 1258 participants aged 40-87 years. The rural population comprised farmers in Domkhar (altitude 2900-3800 m) and nomads in Haiyan (3000-3100 m), Ryuho (4400 m) and Changthang (4300-4800 m). Urban area participants were from Leh (3300 m) and Jiegu (3700 m). MAIN OUTCOME MEASURE: Participants were classified into six glucose tolerance-based groups: DM, intermediate hyperglycaemia (IHG), normoglycaemia (NG), fasting DM, fasting IHG and fasting NG. Prevalence of glucose intolerance was compared in farmers, nomads and urban dwellers. Effects of dwelling at high altitude or hypoxia on glucose intolerance were analysed with the confounding factors of age, sex, obesity, lipids, haemoglobin, hypertension and lifestyle, using multiple logistic regression. RESULTS: The prevalence of DM (fasting DM)/IHG (fasting IHG) was 8.9% (6.5%)/25.1% (12.7%), respectively, in all participants. This prevalence was higher in urban dwellers (9.5% (7.1%)/28.5% (11.7%)) and in farmers (8.5% (6.1%)/28.5% (18.3%)) compared with nomads (8.2% (5.7%)/15.7% (9.7%)) (p=0.0140/0.0001). Dwelling at high altitude was significantly associated with fasting IHG+fasting DM/fasting DM (ORs for >4500 and 3500-4499 m were 3.59/4.36 and 2.07/1.76 vs <3500 m, respectively). After adjusting for lifestyle change, hypoxaemia and polycythaemia were closely associated with glucose intolerance. CONCLUSIONS: Socioeconomic factors, hypoxaemia and the effects of altitudes >3500 m play a major role in the high prevalence of glucose intolerance in highlanders. Tibetan highlanders may be vulnerable to glucose intolerance, with polycythaemia as a sign of poor hypoxic adaptation, accelerated by lifestyle change and ageing.

Prevalence of hypertension at high altitude: cross-sectional survey in Ladakh, Northern India 2007-2011.

OBJECTIVE: Prevalence of hypertension was examined in a widely dispersed (45 110 km(2)) representative group of Ladakhi in Northern India. The influence of hypoxic environment of wide-ranged altitude (2600-4900 m) and lifestyle change on hypertension was studied. METHODS: 2800 participants (age 20-94 years) were enrolled. Systolic blood pressure ≥140 mm Hg and/or diastolic blood pressure of ≥90 mm Hg and/or taking current anti-hypertensive medicine was defined as hypertension. Height and weight for body mass index and SpO2 were examined. The rural population comprised six subdivisions with a distinct altitude, dietary and occupational pattern. Participants in the urban area of Leh consist of two groups, that is, migrants settled in Leh from the Changthang nomadic area, and dwellers born in Leh. The prevalence of hypertension in the two groups was compared with that in the farmers and nomads in rural areas. The effects of ageing, hypoxia, dwelling at high altitude, obesity, modernised occupation, dwelling in an urban area, and rural-to-urban migration to hypertension were analysed by multiple logistic regression. RESULTS: The prevalence of hypertension was 37.0% in all participants and highest in migrants settled in Leh (48.3%), followed by dwellers born in Leh town (41.1%) compared with those in rural areas (33.5). The prevalence of hypertension in nomads (all: 27.7%, Tibetan/Ladakhi: 19.7/31.9%)) living at higher altitude (4000-4900 m) was relatively low. The associated factors with hypertension were ageing, overweight, dwelling at higher altitude, engagement in modernised sedentary occupations, dwelling in urban areas, and rural-to-urban migration. The effects of lifestyle change and dwelling at high altitude were independently associated with hypertension by multivariate analysis adjusted with confounding factors. CONCLUSIONS: Socioeconomic and cultural factors play a big role with the effect of high altitude itself on high prevalence of hypertension in highlanders in Ladakh.

Lungs at high-altitude: genomic insights into hypoxic responses.

Hypobaric hypoxia at high altitude (HA) results in reduced blood arterial oxygen saturation, perfusion of organs with hypoxemic blood, and direct hypoxia of lung tissues. The pulmonary complications in the cells of the pulmonary arterioles due to hypobaric hypoxia are the basis of the pathophysiological mechanisms of high-altitude pulmonary edema (HAPE). Some populations that have dwelled at HA for thousands of years have evolutionarily adapted to this environmental stress; unadapted populations may react with excessive physiological responses that impair health. Individual variations in response to hypoxia and the mechanisms of HA adaptation provide insight into physiological responses. Adaptive and maladaptive responses include alterations in pathways such as oxygen sensing, hypoxia signaling, K(+)- and Ca(2+)-gated channels, redox balance, and the renin-angiotensin-aldosterone system. Physiological imbalances are linked with genetic susceptibilities, and nonhomeostatic responses in gene regulation that occur by small RNAs, histone modification, and DNA methylation predispose susceptible humans to these HA illnesses. Elucidation of the interaction of these factors will lead to a more comprehensive understanding of HA adaptations and maladaptations and will lead to new therapeutics for HA disorders related to hypoxic lungs.

Domain specific changes in cognition at high altitude and its correlation with hyperhomocysteinemia.

Though acute exposure to hypobaric hypoxia is reported to impair cognitive performance, the effects of prolonged exposure on different cognitive domains have been less studied. The present study aimed at investigating the time dependent changes in cognitive performance on prolonged stay at high altitude and its correlation with electroencephalogram (EEG) and plasma homocysteine. The study was conducted on 761 male volunteers of 25-35 years age who had never been to high altitude and baseline data pertaining to domain specific cognitive performance, EEG and homocysteine was acquired at altitude ≤240 m mean sea level (MSL). The volunteers were inducted to an altitude of 4200-4600 m MSL and longitudinal follow-ups were conducted at durations of 03, 12 and 18 months. Neuropsychological assessment was performed for mild cognitive impairment (MCI), attention, information processing rate, visuo-spatial cognition and executive functioning. Total homocysteine (tHcy), vitamin B12 and folic acid were estimated. Mini Mental State Examination (MMSE) showed temporal increase in the percentage prevalence of MCI from 8.17% on 03 months of stay at high altitude to 18.54% on 18 months of stay. Impairment in visuo-spatial executive, attention, delayed recall and procedural memory related cognitive domains were detected following prolonged stay in high altitude. Increase in alpha wave amplitude in the T3, T4 and C3 regions was observed during the follow-ups which was inversely correlated (r = -0.68) to MMSE scores. The tHcy increased proportionately with duration of stay at high altitude and was correlated with MCI. No change in vitamin B12 and folic acid was observed. Our findings suggest that cognitive impairment is progressively associated with duration of stay at high altitude and is correlated with elevated tHcy in the plasma. Moreover, progressive MCI at high altitude occurs despite acclimatization and is independent of vitamin B12 and folic acid.

Disaster-related psychiatric disorders among survivors of flooding in Ladakh, India.

BACKGROUND: Heavy rainfall in northern India in August 2010 caused flash floods, seriously damaging homes and infrastructure. There have been no major disasters in the history of Ladakh, and no surveys on post-disaster psychiatric disorders have been conducted in this area. AIMS AND METHODS: To examine the impact of this disaster in Ladakh one month post-disaster, we visited Choglamsar, located near the town of Leh, where the flood had the most severe impact. In total, 318 survivors (mean age: 58.6 years; female-male ratio: 59.7%; Tibetan refugees: 86.2%) participated in the survey. We used the two-item Patient Health Questionnaire (PHQ-2) along with questions covering background characteristics and disaster exposure. A psychiatrist interviewed the survivors with a single or double positive score in the PHQ-2 or with post-traumatic stress disorder (PTSD) symptoms. RESULTS AND CONCLUSION: There were only two PTSD cases and five of major depressive disorders. PTSD and depression were less common in the Tibetan cultural areas than in other areas. The social background and temperamental characteristics of the Tibetan culture may play a suppressive role in psychiatric disorders.

Polymorphisms of renin--angiotensin system genes as a risk factor for high-altitude pulmonary oedema.

The genes of the renin--angiotensin system (RAS) play an important role in the regulation of pulmonary vascular tone. Although studies on individual genes polymorphisms have reported association with high-altitude pulmonary oedema (HAPE), studies on multiple genes or epistasis are lacking. We therefore investigated the association of the RAS polymorphisms with HAPE. In a case-control design, we screened 163 HAPE-resistant/controls (HAPE-r) and 160 HAPEpatients (HAPE-p) of Indian origin for eight polymorphisms of four RAS genes, ACE, AGT, AGTR1 and AGTR2. Significant difference in genotype and allele frequencies of the ACE I/D and AGT M235T polymorphisms was observed between HAPE-p and HAPE-r (p < 0.05). In three-locus haplotype analysis of AGT the haplotype GTM was significantly higher in HAPE-p (29%) and haplotype GTT in HAPE-r (27%) after Bonferroni correction (p < 0.006). The differences were insignificant for polymorphisms from AGTR1 and AGTR2. The MDR (multifactor dimensional reduction) approach for gene--gene interaction depicted individual polymorphism M235T as the best disease predicting model (cross validation consistency, CVC = 10/10). We found a significant association of D allele of ACE and M allele of AGT with HAPE. The findings are supported at the haplotypic level as well as through nested genetic interaction between the RAS gene polymorphisms using the MDR approach.

Population based study to assess prevalence and risk factors of gastroesophageal reflux disease in a high altitude area.

AIM: We did a population-based cross-sectional study to investigate the prevalence and risk factors of gastroesophageal reflux disease (GERD) in a high altitude area. METHODS: An observational study using a validated questionnaire consisting of demographic, lifestyle and dietary characteristics was administered in an interview based format by two clinicians on a sample of adult population residing in urban area and rural high altitude areas of Ladakh. Presence of GERD was defined as a score of ≥4 using a previously validated symptom score based on the severity and frequency of heartburn and regurgitation. Other factors studied were body mass index (BMI), oxygen saturation levels by pulse oximetry and serum lipid profile. A multivariate analysis was done to find out risk factors for symptomatic GERD. RESULTS: Of the 905 subjects analyzed, there were 399 (44.1%) men; 469 (51.8%) were from rural background and 722 (79.8%) lived in areas 3,000 m above sea level. Symptomatic GERD was present in 169 (18.7%) subjects. Regurgitation occurred once a week in 34.8% and heartburn occurred in 42.9% of subjects. Sixteen (9.5%) had moderate-severe disease activity while 153 (90.5%) had mild disease. Three hundred and eighty-eight (42.7%) and 315 (34.8%) subjects had symptom of heartburn and regurgitation (at least once a week), respectively. On multivariate analysis, risk factors for GERD were age ≤50 years (OR: 1.508, 95% CI: 1.028-2.213), sedentary lifestyle (OR: 2.78, 95% CI: 1.016-7.638), lower intake of salt tea (OR: 1.663, 95% CI: 1.014-2.726); whereas the protective factors were no intake of meat (OR: 0.841, 95% CI: 0.715-0.990), intake of fresh fruits ≥1/week (OR: 0.631, 95% CI: 0.409-0.973), and serum LDL ≤150 mg/dL (OR: 0.435, 95% CI: 0.218-0.868). CONCLUSION: This population-based study in a high altitude area in India suggests a high prevalence (18.7%) of GERD. A younger age group, sedentary lifestyle, serum LDL >150 mg/dL, high consumption of meat, low consumption of salted tea and low consumption of fresh fruits were significant risk factors for development of GERD.

Probable role of beta2-adrenergic receptor gene haplotype in high-altitude pulmonary oedema.

BACKGROUND AND OBJECTIVE: The role of beta2-adrenergic receptor (ADRB2) in pulmonary oxygenation has been ascertained during altitude acclimatization, physical performance and lung fluid clearance, but little is known about its association with high-altitude pulmonary oedema (HAPE), a non-cardiogenic pulmonary oedema. METHODS: In a case-control study, 110 unrelated HAPE patients (HAPE-p) and 143 unrelated HAPE-resistant (HAPE-r) controls matched on age and ethnicity were used to examine the association between eight single nucleotide polymorphisms (SNP) and disease. The eight SNP including three tag-SNP were genotyped from promoter and exonic regions of ADRB2. Robust methods for predicting geneotype-phenotype interactions, for example, multidimensional reduction (MDR) and moving-window haplotype analysis were applied. RESULTS: The haplotypes from 46A/G and 79C/G SNP of ADRB2 were associated with HAPE. The MDR model depicting disease association through genotype-genotype and genotype-phenotype interaction included SNP 46A/G, 79C/G and 523C/A. Its haplotype 46G_79C_523C was significantly overrepresented in HAPE-r (P = 0.0001; chi(2) = 14.95; OR = 4.52; 95% CI: 1.98-10.3). The global haplotype test showed significant association with HAPE (LRchi(2) = 86.69, P < 0.0001). A moving-window analysis revealed that haplotype -367C/T_46A/G_79C/G differed significantly between HAPE-p and HAPE-r (LRchi(2) = 22.5, P = 0.002). The MDR model depicted SNP 46A/G, 79C/G and 523C/A as the best combination predicting disease. conclusions: The haplotypes of ADRB2 consisting of the SNP, 46A/G and 79C/G, have a greater power for predicting HAPE.

Adaptation and mal-adaptation to ambient hypoxia; Andean, Ethiopian and Himalayan patterns.

The study of the biology of evolution has been confined to laboratories and model organisms. However, controlled laboratory conditions are unlikely to model variations in environments that influence selection in wild populations. Thus, the study of "fitness" for survival and the genetics that influence this are best carried out in the field and in matching environments. Therefore, we studied highland populations in their native environments, to learn how they cope with ambient hypoxia. The Andeans, African highlanders and Himalayans have adapted differently to their hostile environment. Chronic mountain sickness (CMS), a loss of adaptation to altitude, is common in the Andes, occasionally found in the Himalayas; and absent from the East African altitude plateau. We compared molecular signatures (distinct patterns of gene expression) of hypoxia-related genes, in white blood cells (WBC) from Andeans with (n = 10), without CMS (n = 10) and sea-level controls from Lima (n = 20) with those obtained from CMS (n = 8) and controls (n = 5) Ladakhi subjects from the Tibetan altitude plateau. We further analyzed the expression of a subset of these genes in Ethiopian highlanders (n = 8). In all subjects, we performed the studies at their native altitude and after they were rendered normoxic. We identified a gene that predicted CMS in Andeans and Himalayans (PDP2). After achieving normoxia, WBC gene expression still distinguished Andean and Himalayan CMS subjects. Remarkably, analysis of the small subset of genes (n = 8) studied in all 3 highland populations showed normoxia induced gene expression changes in Andeans, but not in Ethiopians nor Himalayan controls. This is consistent with physiologic studies in which Ethiopians and Himalayans show a lack of responsiveness to hypoxia of the cerebral circulation and of the hypoxic ventilatory drive, and with the absence of CMS on the East African altitude plateau.

Heterozygotes of NOS3 polymorphisms contribute to reduced nitrogen oxides in high-altitude pulmonary edema.

STUDY OBJECTIVES: High-altitude pulmonary edema (HAPE), which develops on exertion under hypoxic conditions, aggravates due to endothelial dysfunction. Repeat events of the disorder suggests of genetic susceptibility. Endothelial nitric oxide synthase gene (NOS3), a regulator of vasodilation, has emerged as a strong candidate marker. In the present study, we investigated G894T, 27-base-pair 4b/4a (variable number of tandem repeat), -922A/G, and -786T/C polymorphisms of NOS3, individually or in combination, for an association with HAPE. DESIGN: A cross-sectional case control study. SETTINGS: Blood samples of HAPE-resistant lowlanders (HAPE-r) were obtained at sea level, and blood samples of patients with HAPE (HAPE-p) were obtained at Sonam Norboo Memorial Hospital, Leh, at 3,500 m. PARTICIPANTS: The study groups consisted of 60 HAPE-r inducted two to three times to altitudes > 3,600 m; and 72 HAPE-p, who had HAPE on their first visit to high altitude. RESULTS: Nitrogen oxides (NOx) at 77.9 +/- 28.6 micromol/L were significantly elevated in HAPE-r as compared to 42.39 +/- 12.93 micromol/L in HAPE-p (p < 0.0001). Genotype distribution of G894T and 4b/4a polymorphisms was significantly different in the two groups (p = 0.001 and 0.009, respectively). Haplotype analysis revealed -922A/G and -786T/C polymorphisms in complete linkage disequilibrium. The wild-type haplotypes G-b (G894T, 4b/4a), G-A (G894T, -922A/G), and G-b-A (G894T, 4b/4a, -922A/G) were significantly overrepresented in HAPE-r (p < 0.0001, p = 0.03, and p = 0.02, respectively). The heterozygote genotype combination GTba as compared to wild-type combination GGbb was significantly higher in HAPE-p (chi2 = 18.62, p = 0.00009; odds ratio, 7.20; 95% confidence interval, 2.82 to 18.38). The combination of four heterozygotes GTbaAGTC was overrepresented in HAPE-p (p = 0.04), whereas the wild-type genotype combination GGbbAATT was overrepresented in HAPE-r (p = 0.002). Furthermore, the GGbb combination correlated with significantly elevated NOx as compared to remaining combinations as a whole in both HAPE-r and HAPE-p (p = 0.01 and 0.004, respectively). CONCLUSIONS: Reduced NOx and combination of heterozygotes associate with the susceptibility to HAPE. The study impels another step toward application of NOx as a diagnostic marker for HAPE. The NOS3 GTba and GTbaAGTC genotype combinations may find application as genetic markers for predicting the risk for HAPE.

Predominance of interaction among wild-type alleles of CYP11B2 in Himalayan natives associates with high-altitude adaptation.

Sojourners visiting high-altitude (HA) (>2500 m) are susceptible to HA disorders; on the contrary, HA natives are well adapted to the extreme hypoxic environment. High aldosterone levels are believed to be involved in HA disorders, we, therefore, envisaged role of CYP11B2 gene variants in HA adaptation and therefore investigated the -344T/C, intron-2 conversion (Iw/Ic), K173R, and A5160C polymorphisms. In addition, polymorphisms in AGT, AT1R, ATP1A1, ADRB2, and GSTP1 genes were also investigated. The study comprised of 662 subjects, comprising of 426 Himalayan highlanders (HLs) and 236 lowlanders (LLs). The -344T/C and K173R polymorphisms were found to be in complete linkage disequilibrium. The wild-type allele -344T and combination of wild-type homozygous genotypes between -344T/C, Iw/Ic, and A5160C polymorphisms, containing all the six wild-type alleles were over-represented in the HLs (p < 0.0001, and p = 0.008, respectively). The wild-type haplotypes -344T-Iw, -344T-5160A, and -344T-Iw-5160A also showed over-representation in the HLs (p < 0.0001). Furthermore, greater the number of wild-type alleles, lower was the ARR (p < 0.05). The genotype distribution in remaining genes did not differ. To conclude, the over-representation of wild-type -344T allele, genotype combinations and haplotypes of CYP11B2, and their correlation with lower aldosterone levels associate with HA adaptation in the HLs. Such an allelic presentation in sojourners may help them cope with adverse HA environment.

Endothelin-1 gene variants and levels associate with adaptation to hypobaric hypoxia in high-altitude natives.

High-altitude natives are adapted to hypobaric hypoxia, suggestive of genetic basis of adaptation. Since endothelin-1 (ET-1) is of prime importance in high-altitude disorders in sojourners, we envisaged the role of allelic variants of ET-1 in high-altitude adaptation. Four ET-1 polymorphisms, viz., (CT)(n)-(CA)(n) repeat, -3A/-4A, G2288T, and Lys198Asn, were investigated in 426 highlanders (HLs) and 236 lowlanders (LLs). The plasma ET-1 levels, SBP and BMI were significantly lower in the HLs than those in LLs (p<0.0001). The Longer-repeats (31-45), G allele, Longer-repeats/GG, and Longer-repeats/Lys198Lys combinations were overrepresented in the HLs (p<0.0001, p=0.03, p<0.0001, and p<0.0001, respectively). The Longer-repeats, -3A/-3A, GG and Lys198Lys genotypes associated with significantly lower ET-1 levels in the HLs (p<0.0001, p=0.001, p<0.0001, and p<0.0001, respectively). Combinations of Longer-repeats with -3A/-3A, GG, and Lys198Lys genotypes, and -3A/-3A/Lys198Lys combination revealed association with lower ET-1 levels in the HLs (p<0.001). The study reports over-representation of Longer-repeats, G allele, and wild-type genotype combinations in high-altitude natives. Interaction between these alleles and association with lower ET-1 levels strengthen their association with high-altitude adaptation. Presence of such alleles in sojourners may help in acclimatization.