High-altitude Native Populations Research Articles

Emerging Evidence for Association of Transsulfuration Pathway with Hypoxia Responses

When people ascend to a high altitude (HA), the body’s oxygen (O2) sensing mechanisms can sense perturbation in partial pressure and trigger adaptive responses. Rapid ascending to HA without ample time for acclimatization culminates in high-altitude illnesses, which can derail the body functioning of lowlanders moving to HA. High-altitude native populations have undergone positive natural selection to efficiently overcome the challenges of chronic hypobaric hypoxia (HH) and thus offer a unique model to understand physiological and genetic adaptations at high altitudes. In addition, evolutionary shreds of evidence propose that sulfur belonging to the same periodic table family can mimic oxygen to bypass its metabolic oxygen demand and modulate energy production.Intriguingly, our group has identified a strong association between diminished hydrogen sulfide (H2S)levels and HH-induced pathological responses. We have recently presented experimental evidence of cysteine deficit, which functionally regulates both lowered levels of endogenous H2S and HH-induced neuropathological responses. In this review, we sought to understand the role of H2S and the transsulfuration pathway at HA.

Angiotensin-Converting Enzyme (ACE) gene polymorphism and arterial blood pressure among the Tawang Monpa of Eastern Himalayan Mountains: Is there a signature of natural selection?

The present paper aims to characterize the Angiotensin-converting enzyme (ACE) genotype, with particular emphasis on its association with arterial oxygen saturation, arterial blood pressure, hemoglobin [Hb] concentration, and ventilatory measures among the Tawang Monpa, a high-altitude native population of the Eastern Himalaya, India. A cross-sectional sample of 168Monpa participants from Tawang town, Arunachal Pradesh, India, was selected who live at an altitude of ∼3,200 meters (m) above sea level. For each participant, height, weight, and skinfold thickness were measured, based on which body mass index (BMI, kg/m2) and percentage of body fat (%BF) were calculated. Physiological measures, such as the transcutaneous arterial oxygen saturation (SaO2), hemoglobin [Hb] concentration, forced vital capacity (FVC), forced expiratory volume in 1-second (FEV1), and systemic arterial blood pressure were measured. First, the peripheral venous blood samples (four ml) were drawn, and then white blood cells were separated for the ACE genotyping of each participant. Unlike high-altitude natives from Peru and Ladakh, who exhibit high frequencies of II homozygotes, the Tawang Monpa shows a significantly high frequency of ID heterozygotes (p<0.0001). In addition, no significant association was identified between ACE gene polymorphism and arterial blood pressure, oxygen saturation at rest, vital capacity, or [Hb] concentration. The results suggest that the association of the ACE gene with resting SaO2 is inconsistent across native populations living under hypobaric hypoxia. Further, ACE I/D gene polymorphism may not be under natural selection in specific native populations, including Tawang Monpa, for their adaptation to high-altitude hypoxia.

The normal distribution of the hypoxic ventilatory response and methodological impacts: a meta-analysis and computational investigation.

The hypoxic ventilatory response (HVR) is the increase in breathing in response to reduced arterial oxygen pressure. Over several decades, studies have revealed substantial population-level differences in the magnitude of the HVR as well as significant inter-individual variation. In particular, low HVRs occur frequently in Andean high-altitude native populations. However, our group conducted hundreds of HVR measures over several years and commonly observed low responses in sea-level populations as well. As a result, we aimed to determine the normal HVR distribution, whether low responses were common, and to what extent variation in study protocols influence these findings. We conducted a comprehensive search of the literature and examined the distributions of HVR values across 78 studies that utilized step-down/steady-state or progressive hypoxia methods in untreated, healthy human subjects. Several studies included multiple datasets across different populations or experimental conditions. In the final analysis, 72 datasets reported mean HVR values and 60 datasets provided raw HVR datasets. Of the 60 datasets reporting raw HVR values, 35 (58.3%) were at least moderately positively skewed (skew > 0.5), and 21 (35%) were significantly positively skewed (skew > 1), indicating that lower HVR values are common. The skewness of HVR distributions does not appear to be an artifact of methodology or the unit with which the HVR is reported. Further analysis demonstrated that the use of step-down hypoxia versus progressive hypoxia methods did not have a significant impact on average HVR values, but that isocapnic protocols produced higher HVRs than poikilocapnic protocols. This work provides a reference for expected HVR values and illustrates substantial inter-individual variation in this key reflex. Finally, the prevalence of low HVRs in the general population provides insight into our understanding of blunted HVRs in high-altitude adapted groups. KEY POINTS: The hypoxic ventilatory response (HVR) plays a crucial role in determining an individual's predisposition to hypoxia-related pathologies. There is notable variability in HVR sensitivity across individuals as well as significant population-level differences. We report that the normal distribution of the HVR is positively skewed, with a significant prevalence of low HVR values amongst the general healthy population. We also find no significant impact of the experimental protocol used to induce hypoxia, although HVR is greater with isocapnic versus poikilocapnic methods. These results provide insight into the normal distribution of the HVR, which could be useful in clinical decisions of diseases related to hypoxaemia. Additionally, the low HVR values found within the general population provide insight into the genetic adaptations found in populations residing in high altitudes.

Prevalence of Hypertension in a Tribal Land Locked Population at High Altitude.

Introduction. Extensive pubmed search reveals paucity of data on prevalence of hypertension in tribal population at high altitude. The data is all the more scarce from our part of India. Studies among tribal populations at high altitudes provide an interesting epidemiological window to study human evolution and adaptation to hypobaric hypoxia. Material and Methods. 401 participants above the age of 20 years were evaluated for blood pressure using a stratified simple random technique among villages located at high altitude. Results. Out of a total of 401 individuals studied 43 (males: 35; females: 8) were identified as hypertensive yielding a crude prevalence of 10.7%. The prevalence was higher in males (35/270; 12.9%) as compared to females (8/131; 6%). Prevalence was the highest in the age group of 30–39 among males (16/35; 45.7%) while it was the highest in the age group of 40–49 among females (7/8; 87%). Conclusions. Prevalence of 10.5% is noteworthy when interpreted in light of prevalence of hypertension in general population especially if hypobaric hypoxia is considered to have a protective effect on blood pressure in high altitude native populations.

Genetic factors associated with exercise performance in atmospheric hypoxia.

Background and Objective‘Natural selection’ has been shown to have enriched the genomes of high-altitude native populations with genetic variants of advantage in this hostile hypoxic environment. In lowlanders who ascend to altitude, genetic factors may also contribute to the substantial interindividual variation in exercise performance noted at altitude. We performed a systematic literature review to identify genetic variants of possible influence on human hypoxic exercise performance, commenting on the strength of any identified associations.Criteria for considering studies for this reviewAll studies of the association of genetic factors with human hypoxic exercise performance, whether at sea level using ‘nitrogen dilution of oxygen’ (normobaric hypoxia), or at altitude or in low-pressure chambers (field or chamber hypobaric hypoxia, respectively) were sought for review.Search strategy for identification of studiesTwo electronic databases were searched (Ovid MEDLINE, Embase) up to 31 January 2014. We also searched the reference lists of relevant articles for eligible studies. All studies published in English were included, as were studies in any language for which the abstract was available in English.Data collection and analysisStudies were selected and data extracted independently by two reviewers. Differences regarding study inclusion were resolved through discussion. The quality of each study was assessed using a scoring system based on published guidelines for conducting and reporting genetic association studies.ResultsA total of 11 studies met all inclusion criteria and were included in the review. Subject numbers ranged from 20 to 1,931 and consisted of healthy individuals in all cases. The maximum altitude of exposure ranged from 2,690 to 8,848 m. The exercise performance phenotypes assessed were mountaineering performance (n = 5), running performance (n = 2), and maximum oxygen consumption ( dot{V} O2max) (n = 4). In total, 13 genetic polymorphisms were studied, four of which were associated with hypoxic exercise performance. The adenosine monophosphate deaminase (AMPD1) C34T (rs17602729), beta2-adrenergic receptor (ADRB2) Gly16Arg single nucleotide polymorphism (SNP) (rs1042713), and androgen receptor CAG repeat polymorphisms were associated with altitude performance in one study, and the angiotensin I-converting enzyme (ACE) insertion/deletion (I/D) (rs4646994) polymorphism was associated with performance in three studies. The median score achieved in the study quality analysis was 6 out of 10 for case–control studies, 8 out of 10 for cohort studies with a discrete outcome, 6 out of 9 for cohort studies with a continuous outcome, and 4.5 out of 8 for genetic admixture studies.ConclusionThe small number of articles identified in the current review and the limited number of polymorphisms studied in total highlights that the influence of genetic factors on exercise performance in hypoxia has not been studied in depth, which precludes firm conclusions being drawn. Support for the association between the ACE-I allele and improved high-altitude performance was the strongest, with three studies identifying a relationship. Analysis of study quality highlights the need for future studies in this field to improve the conduct and reporting of genetic association studies.Electronic supplementary materialThe online version of this article (doi:10.1007/s40279-015-0309-8) contains supplementary material, which is available to authorized users.

Genetic Variations in Renin-Angiotensin-Aldosterone System (RAAS) Genes Could Contribute to High Altitude Pulmonary Edema: Review

Background: At High Altitude (HA) (elevation >2500m), inevitable hypobaric hypoxia leads to development of symptoms associated with low oxygen pressure in many non acclimatized sojourners which includes severe forms of altitude mountain sickness (AMS) such as high altitude pulmonary edema (HAPE) and high altitude cerebral edema (HACE). These syndromes are reportedly less common in high altitude native population than in lowlanders which can be attributed to genetic adaptations that have taken place over generations. Methods: Numerous genetic studies have been associated with hypoxic adaptation and susceptibility to high altitude conditions. An increased pulmonary arterial pressure (PAP) and fluid loss has been observed in all forms of AMS with varied intensity. Since renin-angiotensin-aldosterone system (RAAS) has a critical function of maintaining homeostasis in closed circulatory system, the polymorphisms occurring in the genes of RAAS pathway could likely be contributing towards acclimatization/mal-adaptation to high altitude maladies. In view of above, this review has been compiled to associate the genetic variations in RAAS with adaptation/acclimatization to high altitude conditions. Results: Studies conducted so far relate allele frequencies of polymorphic loci in genes encoding components of RAAS pathway such as angiotensinogen (AGT), angiotensin converting enzyme (ACE), angiotensin receptors (AT1) and aldosterone synthase (CYP11B2) and associate them with hypertension, regulation of blood pressure and maintenance of osmotic balance in the body. Conclusions: In this review, various studies have been put together comprehensively indicating the involvement of genetic variants of RAAS genes in resistance or sensitivity of an individual towards development of HAPE.

A Variant of the Endothelial Nitric Oxide Synthase Gene (NOS3) Associated with AMS Susceptibility Is Less Common in the Quechua, a High Altitude Native Population

Endothelial nitric oxide synthase (eNOS) is a vascular enzyme that produces nitric oxide, a transient signaling molecule that by vasodilatation regulates blood flow and pressure. Nitric oxide is believed to play roles in both short-term acclimatization and long-term evolutionary adaptation to environmental hypoxia. Several laboratories, including ours, have shown that variants in NOS3 (the gene encoding eNOS) are overrepresented in individuals with altitude-related illnesses such as high altitude pulmonary edema (HAPE) and acute mountain sickness (AMS), suggesting that NOS3 genotypes contribute to altitude tolerance. To further test our hypothesis that the G allele at the G894T polymorphism in NOS3 (dbSNP number: rs1799983; protein polymorphism Glu298Asp) is beneficial in hypoxic environments, we compared frequencies of this allele in an altitude-adapted Amerindian population, Quechua of the Andean altiplano, with those in a lowland Amerindian population, Maya of the Yucatan Peninsula. While common in both populations, the G allele was significantly more frequent in the highlanders. Taken together, our data suggest that this variant in NOS3, which has been previously associated with higher levels of nitric oxide, contributes to both acclimatization and adaptation to altitude.

Evolutionary adaptation to high altitude: a view from in utero.

A primary focus within biological anthropology has been to elucidate the processes of evolutionary adaptation. Frisancho helped to move anthropology towards more mechanistic explanations of human adaptation by drawing attention to the importance of the functional relevance of human variation. Using the natural laboratory of high altitude, he and others asked whether the unique physiology of indigenous high-altitude residents was the result of acclimatization, developmental plasticity, and/or genetic adaptation in response to the high-altitude environment. We approach the question of human adaptation to high altitude from a somewhat unique vantage point; namely, by examining physiological characteristics-pregnancy and pregnancy outcome-which are closely associated with reproductive fitness. Here we review the potent example of high-altitude native population's resistance to hypoxia-associated reductions in birth weight, which is often associated with higher infant morbidity and mortality at high altitude. With the exception of two recent publications, these comparative birth weight studies have utilized surnames, self-identification, and/or linguistic characteristics to assess ancestry, and none have linked 'advantageous' phenotypes to specific genetic variations. Recent advancements in genetic and statistical tools have enabled us to assess individual ancestry with higher resolution, identify the genetic basis of complex phenotypes and to infer the effect of natural selection on specific gene regions. Using these technologies our studies are now directed to determine the genetic variations that underlie the mechanisms by which high-altitude ancestry protects fetal growth and, in turn, to further our understanding of evolutionary processes involved in human adaptation to high altitude.

Lessons in hypoxic adaptation from high-altitude populations

An increase in hemoglobin level is seen in virtually all lowlanders who move to or train at altitude; however, studies of high-altitude native populations illustrate that this response is not necessary for successful long-term residence. Indigenous populations living at the same altitude have differences not only in hemoglobin level but also in other traits like oxygen saturation. Support for a genetic causation for differences in features of oxygen transport, namely hemoglobin levels and oxygen saturation, is derived from kindred studies among the highlander populations. Indeed, evidence from Tibet suggests that inferred genes for high oxygen saturation are associated with higher offspring survival. It may be that signaling molecules like nitric oxide and transcription factors such as hypoxia-inducible factor could act as an upstream regulator for highlander traits. However, the preponderance of data suggests that it is unlikely that one process or even a common set of processes is responsible for successful biologic adaptation shown in all three resident high-altitude populations. Future studies will require the ability to identify combinations of genetic variants with outcomes including expression levels, appropriate phenotypes, and functional responses.

Birth weight among Tibetans at different altitudes in India: Are Tibetans better protected from IUGR?

We report the variation in birth weight among the Tibetans at different altitudes in India to test the hypothesis of greater protection from intrauterine growth retardation (IUGR) among Tibetan compared with other high-altitude native populations. We found that the birth weight of Tibetans at Leh (3521 m, high altitude) is quite similar to what has been reported previously for Tibetans at similar altitudes and is significantly higher than the low-altitude native populations living at similar altitudes. Tibetan birth weights are greater than those of other ethnic groups, both at high and low altitudes. Compared with Tibetans at high altitude (Leh, India; 3521 m), Tibetans at low altitudes (Bylakuppe, India; 800 m and Chandragiri, India; 970 m) have heavier birth weights. This finding is similar to what has been observed previously for other high-altitude native populations. Greater protection from IUGR is not observed for Tibetans compared with other high-altitude native populations as was reported previously. Genetic potential for birth weight is seemingly manifested only at low altitude.

Genetic variation in hypoxia-inducible factor 1α and its possible association with high altitude adaptation in Sherpas

Hypoxic stress at high altitude requires adaptations in several physiological functions to ensure the optimal oxygenation of all cells. Several lines of evidence suggested that high-altitude native populations such as Sherpas have been genetically adapted to their stressful environment. We investigated the genetic variation in the hypoxia-inducible factor (HIF)-1α gene in Sherpas as compared with Japanese, native lowlanders, and found a novel dinucleotide repeat polymorphism in intron 13 of the HIF-1α gene. GT15 allele was more frequent in Japanese than in Sherpas with statistical significance, while GT14 allele was significantly more frequent in Sherpas as compared with Japanese. A possible genetic variation in the HIF-1α gene might function in adaptation to living at high altitude. Because the activity of HIF-1 is regulated by multiple steps including the transcriptional level, the effect of the polymorphism in intron 13 on the cellular hypoxic responses remains to be elucidated.

Beta2-adrenergic receptor allele frequencies in the Quechua, a high altitude native population.

The beta2-adrenergic receptor is involved in the control of numerous physiological processes and, as the primary catecholamine receptor in the lungs, is of particular importance in the regulation of pulmonary function. There are several polymorphic loci in the beta2-adrenergic receptor gene that have alleles that alter receptor function, including two (A/G46, G/C79) that increase agonist sensitivity. As such a phenotype may increase vaso and bronchial dilation, thereby facilitating air and blood flow through the lungs, we hypothesized that selection may have favoured these alleles in high altitude populations as part of an adaptive strategy to deal with the hypoxic conditions characteristic of such environments. We tested this hypothesis by determining the allele frequencies for these two polymorphisms, as well one additional missense mutation (C/T491) and two silent mutations (G/A252 and C/A523) in 63 Quechua speaking natives from communities located between 3200 and 4200 m on the Peruvian altiplano. These frequencies were compared with those of two lowland populations, one native American (Na-Dene from the west coast of Canada) and one Caucasian of Western European descent. The Quechua manifest many of the pulmonary characteristics of high altitude populations and differences in allele frequencies between the Quechua and lowlanders could be indicative of a selective advantage conferred by certain genotypes in high altitude environments. Allele frequencies varied between populations at some loci and patterns of linkage disequilibrium differed between the old-world and new-world samples; however, as these populations are not closely related, significant variation would be expected due to stochastic effects alone. Neither of the alleles associated with increased receptor sensitivity (A46, G79) was significantly over-represented in the Quechua compared with either lowland group. The Quechua were monomorphic for the C allele at base 79. This variant has been associated with body mass index; however no clearly defined metabolic phenotype has been established. In addition, we sequenced the coding region of the gene in three unrelated Quechua to determine if there were any other polymorphisms common in this population. None were detected.

Genetic polymorphisms in the Renin-Angiotensin system in high-altitude and low-altitude Native American populations.

Cardiovascular disease (CVD) is reportedly less common in high-altitude native populations than in lowlanders. To some extent, this is due to cultural and demographic factors; however, increased cardiovascular efficiency contributing to hypoxia adaptation may also be involved. Numerous genetic variants have been associated with cardiovascular health. If the decreased incidence of CVD in modern high-altitude populations reflects selective pressures having favoured the transmission of these alleles in their antecedents, it would be expected that these alleles would be more common in highlanders than in lowlanders. We tested this hypothesis by determining the allele frequencies of five polymorphic loci in genes encoding components of the renin-angiotensin system (RAS) that have alleles associated with hypertension and cardiovascular disease in a high-altitude native Andean population, Quechua from the Peruvian altiplano, and in a lowland Amerindian population, Maya from the Yucatan peninsula. The polymorphisms examined were 1) the insertion/deletion polymorphism in intron 16 of the angiotensin converting enzyme (ACE) gene; 2) the A/G2350 transition (ACE-8) in intron 17 of the ACE gene; 3) the A/C1166 transversion in the 3' untranslated region of the angiotensin II receptor (type 1) gene (AGTR1); 4) the G/AI9-83 transition in intron 8 of the renin gene (REN); and 5) the T/C704 (Met235Thr) transition mutation in angiotensinogen (AGT). There was no evidence for an over-representation of the RAS alleles associated with cardiovascular fitness in the high-altitude Amerindian population when compared to the lowland Amerindian population.

The evidence for hereditary factors contributing to high altitude adaptation in Andean natives: a review.

Humans have occupied the high plateaus and mountain valleys of the Andes and the Himalayas for thousands of years. Although sea level natives can, and often do, travel in these rarefied reaches, there is little doubt that natives born and raised in the "thin" air are better equipped to deal with the reduced availability of oxygen at altitude. What fraction of the hypoxia defense response of high altitude native populations is due to developmental adaptations acquired during growth and what fraction is due to a genetic component reflecting the effects of selective transmission of beneficial genetic variants through hundreds of generations of antecedents is as yet unresolved. This paper summarizes some of the studies that have been undertaken to address this issue in Andean indigenous populations, primarily with respect to those adaptations thought to be involved in the uptake, distribution and utilization of oxygen in children and adults. Specifically, it focuses on changes in chest morphology, pulmonary function, metabolism and hematology. Space constraints preclude extending this review to the large body of literature concerning prenatal and maternal adaptations although this critical stage in development has likely been subject to significant selective pressures. It is apparent that both nature and nurture influence the acquisition of a high altitude phenotype in humans and while there is some evidence for genetic adaptation in Andean highlanders, it is evident that these characteristics are expressed in concert with substantial environment-dependent developmental adjustments.

Ventilation and hypoxic ventilatory response of Tibetan and Aymara high altitude natives.

Newcomers acclimatizing to high altitude and adult male Tibetan high altitude natives have increased ventilation relative to sea level natives at sea level. However, Andean and Rocky Mountain high altitude natives have an intermediate level of ventilation lower than that of newcomers and Tibetan high altitude natives although generally higher than that of sea level natives at sea level. Because the reason for the relative hypoventilation of some high altitude native populations was unknown, a study was designed to describe ventilation from adolescence through old age in samples of Tibetan and Andean high altitude natives and to estimate the relative genetic and environmental influences. This paper compares resting ventilation and hypoxic ventilatory response (HVR) of 320 Tibetans 9-82 years of age and 542 Bolivian Aymara 13-94 years of age, native residents at 3,800-4,065 m. Tibetan resting ventilation was roughly 1.5 times higher and Tibetan HVR was roughly double that of Aymara. Greater duration of hypoxia (older age) was not an important source of variation in resting ventilation or HVR in either sample. That is, contrary to previous studies, neither sample acquired hypoventilation in the age ranges under study. Within populations, greater severity of hypoxia (lower percent of oxygen saturation of arterial hemoglobin) was associated with slightly higher resting ventilation among Tibetans and lower resting ventilation and HVR among Aymara women, although the associations accounted for just 2-7% of the variation. Between populations, the Tibetan sample was more hypoxic and had higher resting ventilation and HVR. Other systematic environmental contrasts did not appear to elevate Tibetan or depress Aymara ventilation. There was more intrapopulation genetic variation in these traits in the Tibetan than the Aymara sample. Thirty-five percent of the Tibetan, but none of the Aymara, resting ventilation variance was due to genetic differences among individuals. Thirty-one percent of the Tibetan HVR, but just 21% of the Aymara, HVR variance was due to genetic differences among individuals. Thus there is greater potential for evolutionary change in these traits in the Tibetans. Presently, there are two different ventilation phenotypes among high altitude natives as compared with sea level populations at sea level: lifelong sustained high resting ventilation and a moderate HVR among Tibetans in contrast with a slightly elevated resting ventilation and a low HVR among Aymara.

Major gene for percent of oxygen saturation of arterial hemoglobin in Tibetan highlanders

This report employs a statistical genetic approach to analyze quantitative oxygen transport variables in a high-altitude (4,850-5,450 m) native Tibetan population and demonstrates the presence of a major gene influencing % O2 saturation of arterial hemoglobin. This result suggests the hypothesis that individuals with the dominant allele for higher % O2 saturation have a selective advantage at high altitude. Studies of the biologically distinctive Himalayan and Andean populations have greatly influenced thinking about ongoing human evolution and adaptation; this is the first statistical evidence for a major gene enhancing oxygen transport in a high-altitude native population.

Developmental responses to high altitude hypoxia.

AbstractFrom a review of published literature on developmental responses to high altitude, three major conclusions are derived. First, the small birth weight of high altitude native populations are adaptive responses to reduce the oxygen requirements, while the relative increase in the placental weight is a compromise mechanism to increase the volume and surface area for a better oxygenation. Second, the small stature of the high altitude native is due to slow prenatal and postnatal growth. Third, the enlarged chest size, increased lung volumes and predominance of the right ventricle of the heart are due to accelerated development during childhood and adolescence. However, there is not adequate information to determine whether or not the developmental responses of the high altitude native are population‐specific, based on a genetic structure different from that of sea level populations. Hence, the need for further study of developmental factors is emphasized.