With improvements in transportation and picturesque images continuously being shared upon social media, more and more individuals are looking to hit higher levels of altitude.
From Mount Kilimanjaro in Tanzania to Mount Everest in Asia, millions of people flock to mountains annually to reach the summit points and get that all important photographic proof. Prior to these extended climbs, people undergo strict regimens with endurance training and leg strengthening to prepare them for the climb ahead.
Despite dedicated practice, many individuals fail to make it to the top and have to retreat to lower ground. Yet others, who are far less experienced can carry on climbing! Is this because they were more prepared? Or is it something inherent that is impacting them?
In this blog, we take a sneak ‘peak’ into the genetics of altitude sickness and explore the value that genetic testing could provide in predicting susceptible individuals.
At the top of the mountain, it’s peak
More than 30 million people in the US annually visit high altitudes and are at risk of developing altitude sickness. The earliest description of altitude sickness is attributed to a Chinese text from around 30 BCE, which referred to “Big Headache Mountains”. In simplistic terms, altitude sickness is the harmful effect of high altitude. It is caused by rapid exposure to low amounts of oxygen at high elevation.
The most common form of altitude sickness is acute mountain sickness (AMS), which usually begins within a few hours of ascent. AMS occurs in about 20% of people after rapidly climbing to 2,500 metres (8,000ft) and 40% of people going to 3,000 metres (10,000 ft). At higher altitudes, humans can get either high-altitude pulmonary oedema (HAPE) or high-altitude cerebral oedema (HACE). Both of these conditions are life-threatening and can lead to coma or death. The incidence of HACE has been reported to be 0.1% to 2% at elevation in excess of 3,000 m (12,000 ft). In comparison, at 4,500 metres the incidence of HAPE is 0.6% to 6%, and at 5,500 metres the incidence is 2% to 15%.
People have different susceptibilities to altitude sickness. It is also associated with a range of different symptoms. Symptoms typically include:
- Primary symptoms: Headaches are the primary symptom used to diagnose altitude sickness. Other symptoms include nausea, vomiting, fatigue or weakness, dizziness or light-headedness, swelling of hands, feet and face, nose bleeding and shortness of breath.
- Severe symptoms: Pulmonary oedema (fluid in the lungs) e.g., dry cough, shortness of breath even when resting and fever, and cerebral oedema (swelling of the brain) e.g., headache that does not respond to analgesics, unsteady gait, gradual loss of consciousness, increased nausea and vomiting and retinal haemorrhage. Descent to lower latitudes can help alleviate and save those affected by HAPE and HACE.
A mountain of evidence
Attitude sickness affects 25% to 85% of people travelling to high altitudes. The incidence rate depends on various factors, including gender, age, physical health, prior exposure, rate of ascent and genetic predisposition.
Proceed at your own risk
While AMS and HACE affect men and women equally, men have been found to be five times more likely to develop HAPE. Additionally, previous studies have suggested that age is a predisposing factor for AMS, yet so far these findings have been inconsistent. For example, one study at Colorado ski resorts showed that younger individuals had a higher risk of AMS than older individuals. Yet, this study was uncontrolled, and the results were likely affected by a greater exercise intensity in the younger age group. In addition, a meta-analysis from 2018, suggested that there is no association between age and the risk of AMS.
Our exercise capability diminishes with increased altitude. This is because of a decline in our ventilatory response due to decreased oxygen levels present at high altitudes. Although those who are in good physical health can adapt better to these changes during rapid ascent, data actually suggests that their risk of AMS is similar to individuals in poorer physical health. Nonetheless, those with pre-existing conditions should be cautious when considering ascents to high altitudes. For example, those with heart failure are not advised to spend time in such conditions. The advice for patients with lung disease varies depending on the underlying disease, its severity, and the anticipated altitude.
Moreover, individuals ascending from sea-level are at a higher risk for AMS than those living at higher elevation. For example, in the study at the Colorado ski resorts, the risk of developing AMS was 27% for residents arriving from sea-level compared to 8.4% for those residing above 1,000 metres. Another risk factor of AMS is sleeping altitude. The prevalence of AMS in a study ranged from 9% at 2,850 metres to 53% at 4,559 metres among mountaineers staying at huts in the Swiss Alps.
The leading cause of altitude sickness is ascending to extreme heights too rapidly. When ascending to very high altitudes, a difference of a few days in acclimatisation can have a significant impact on the prevalence of AMS and the severity of symptoms.
Naturally, a prior history of AMS is also an important predictor for developing AMS on subsequent climbs. Conversely, a history of recent or extreme altitude exposure is associated with a lower risk of AMS.
The genetics behind it
An area of particular interest that has been the subject of several research studies, is the role that our genetics play in our susceptibility to altitude sickness.
Since the early 1990s, anthropologists and physiologists have sought to determine whether there has been genetic adaptation to high latitudes. Some populations have lived and worked at high altitudes for thousands of years. Some of the best-known populations are the Sherpas and Tibetans in the Himalaya, and the Quecha and Ayamara in the Andes. Living permanently at such altitudes puts these populations at risk for chronic mountain sickness (CMS). However, the high-altitude populations have done so for millennia without any apparent complications. This form of adaptation is now considered an example of natural selection in action.
For example, there are two pieces of information that support the existence of Andean genetic adaptation to high altitude.
The first piece of evidence is provided by studies that have demonstrated that native highland populations exhibit unique oxygen transport traits compared with acclimatised newcomers.
The second piece of evidence comes from genomic studies that have shown signals of recent positive selection within specific gene regions. Nonetheless, few investigations have been able to show how these genes regions affect specific physiological characteristics.
The HIF pathway
Some of the key genes that have been explored have been within the hypoxia-inducible factor (HIF) pathway (Figure 1). HIF is a heterodimer protein composed of an oxygen-sensitive alpha subunit and a constitutively expressed beta subunit. Under normoxic conditions, HIF-alpha is hydroxylated by oxygen-dependent prolyl hydroxylases (PHDs). After this, HIF-alpha is ubiquitinated by the von Hippel-Lindau tumour suppressor protein (pVHL) and degraded by proteasomes. PHD requires oxygen as a co-substrate. Therefore, under hypoxic conditions, its activity decreases. This allows HIF-alpha to dimerise with HIF-beta and translocate to the nucleus. In the nucleus, the HIF complex binds to hypoxia response elements in gene promoters to regulate the expression of genes that coordinate increased oxygen supply to hypoxic tissue. While HIF is certainly central for governing transcriptional responses to hypoxia, existing SNP data indicates that the HIF-pathway has not been disproportionately acted upon by natural selection.
The fastest evolution seen in humans
Tibetan adaptation to high altitude is the fastest process of phenotypically observable evolution in humans. It is estimated to have occurred a few thousand years ago when the Tibetans split up from the mainland Chinese population.
A study in 2010, using genome sequences from 50 Tibetan and 40 Han Chinese individuals, identified a strong signal in the EPAS1 gene (encodes HIF-2alpha). A single SNP showed a 78% frequency difference between Tibetan and mainland Chinese samples, demonstrating the fastest genetic change observed in any human gene to date. Tibetans with two mutated alleles were found to have significantly lower haemoglobin concentrations and could still do well at high altitudes. High haemoglobin concentrations are a cardinal feature of CMS.
A different route
The patterns of genetic adaptations among the Andeans are largely distinct from those of the Tibetans. Both populations show evidence of positive natural selection in different genes/gene regions. So far, only one gene has been found as being acted upon by natural selection in both Andeans and Tibetans – EGLN1, which encodes PHD2. Several other genes showing evidence of natural selection have been identified among Andeans, including some involved in vasoregulation (PRKAA1, NOS2), vascular growth (VEGFB, ELTD1), cerebral blood flow (CBS) and oxidative defence (FAM213A). One whole-genome sequencing study also identified three gene regions – BRINP3, NOS2 and TBX5 – that have been associated with cardiovascular function. In addition, among the Quechua people, researchers have identified a significant variation in NOS3 (the gene encoding endothelial nitric oxide synthase, eNOS), which is associated with higher levels of nitric oxide in high altitude.
The role of ACE
Another genetic factor that has been suggested to contribute to high-altitude performance is a polymorphism within the angiotensin-converting enzyme (ACE) gene. ACE is a central component of the renin–angiotensin system (RAS), which controls blood pressure. Polymorphisms within this gene result in a greater ability to adapt to high altitude and has also been found to be more prevalent in elite mountaineers and endurance athletes than in the general population. Interestingly, there has been some recent evidence to suggest that higher elevation can attenuate SARS-CoV-2 infection and death rates. Some data has reported decreased ACE2 expression in hypoxic environments. However, this data is currently conflicting, making it critical to further understand the impact of high altitude on ACE2 expression as a mechanism of SARS-CoV-2 infection.
An omics approach
Aside from genetic susceptibility, researchers are also exploring the physiological effects high-altitude hypoxia and acclimatisation has on the body. An ongoing multifaceted research program – AltitudeOmics – aims to describe a phenotype for successful acclimatisation and assess its retention, and use these findings to conduct mechanistic studies of the human transcriptome, epigenome, metabolome and proteome. Specifically, the team are investigating how healthy people respond to high altitude rather than mountaineers. For example, one study from the program combined targeted metabolomic and proteomic profiling of skeletal muscle with mitochondrial respirometry and systemic metabolic assessments of healthy volunteers at their resident altitude near sea level as well at 16 days following high-altitude hypoxia acclimatisation. The results showed that an integration of aerobic and anaerobic metabolism is required for muscle hypoxia adaptation.
Learning the slopes
The most effective and reliable treatment, which is the only option in many cases, is to descend. In fact, attempts to stabilise the patient at altitude can be dangerous. Nonetheless, there are some treatments that can be used:
- Oxygen: Oxygen can be used for mild to moderate AMS below 3,700 metres (12,000 ft).
- Gamow bag: In more serious cases, a portable plastic hyperbaric chamber inflated with a foot pump can be used to reduce the effective altitude. This is used more to evacuate severe AMS patients than to treat them at altitude.
- Painkillers: Non-steroidal anti-inflammatory drugs (NSAIDs), such as ibuprofen, and paracetamol (acetaminophen) can be used to help alleviate symptoms like headache and nausea.
- Acetazolamide: This drug can help quicken altitude acclimatisation. The drug, however, is not a cure-all; some subjects taking this drug can still develop AMS.
- Steroids: Steroids, particularly dexamethasone, can be used to treat symptoms of pulmonary or cerebral oedema.
- Hydration: Increased water intake can also help in acclimatisation to replace the fluids lost through heavier breathing. However, over-hydration can cause dangerous hyponatremia.
- Pre-acclimatisation: Spending time at altitude prior to undertaking a higher ascent can reduce the likelihood of developing AMS.
The CDC has advised that dexamethasone be reserved for treatment of severe AMS and HACE during descent and noted that nifedipine (calcium channel blocker) may prevent HAPE. There is also some interest in phosphodiesterase inhibitors, such as sildenafil, that have been shown to prevent HAPE in susceptible individuals and may also be effective in patient management. However, this research has been limited by the possibility that these drugs may worsen headaches.
A military mission
While not everyone wakes up one morning and decides to ascend to high altitudes, there are particular areas where identifying susceptibility may be useful. For example, many soldiers in the military are subjected to high altitudes where even breathing can be a struggle. Troops not only have to function in these conditions, but they may also have to fight at altitudes that only serious mountaineers have reached. In fact, during the 1962 Sino-Indian War, more Indian soldiers died from altitude sickness than from enemy fire, as rapid deployment did not allow for sufficient acclimatisation.
In these circumstances, it would be beneficial to develop a genetic test that could help predict which soldiers will fall ill when flown to high altitudes. This would hopefully prevent anyone from falling seriously ill and would reduce the amount of money spent on treatments. Some effective drugs can also have unwanted side effects, such as blurred vision and excess blood acidity.
In pursuit of a genetic test
The pursuit for a genetic test for altitude sickness began over a decade ago in Robert Roach’s lab at the University of Colorado.
In 2010, 28 people in Roach’s lab ascended to an altitude of 4,875 metres – but there was a twist – the team did not actually leave the ground. Roach placed the volunteers in a hypobaric chamber and gradually removed the air to mimic high altitude. He recruited a mixture of susceptible individuals and those who had never experienced problems with high altitude before.
As expected, he found that about half of the volunteers felt sick in the chamber. From here, Roach took and analysed blood samples from the volunteers, and searched for genetic differences between the individuals. The algorithm he developed identified six genes that were expressed at unusually high or low levels in people who felt sick, some of these genes were linked to oxygen transport.
Roach found that analysing the expression levels of those six genes alone was enough to distinguish between the people who became ill from those who did not with about 95% accuracy. The following year, Roach collaborated with Benjamin Levine of the University of Texas Southwestern Medical Center to try his genetic test on a large group of volunteers. Around 140 fit men and women were taken ~4,000 metres above sea level. The results from this analysis showcased that the RNA-based gene signature was equally effective in predicting AMS susceptibility and resistance.
Since then, the researchers have added additional datasets into the overall analysis, including data from the AltitudeOmics project, to assess the effectiveness. The development of such a genetic test would not only help treat altitude sickness but could help military leaders strategise.
Ain’t no mountain high enough
Excluding Antarctica, only 2.5% of the world’s land mass lies above 3,000 metres. Despite this, these heights still attract millions of visitors every year. With the growth of ecotourism and global travel, the number of people of all ages who want to climb to these very high and even extreme altitudes is likely to grow. While most people prepare themselves for the physical aspects of hiking, many high-altitude travellers will be poorly prepared for their trip and naive about the associated risks.
Further investigation into the genetic aetiology of AMS will be important to increase our understanding of the underlying mechanisms of the condition. In turn, this will enhance our capacity for prediction, prevention and/or treatment.
Identifying at-risk individuals through screening of genetic markers could also help individuals take extra precautions or prophylactic medication before travelling. Integrating this information with environmental factors will also contribute to healthy and enjoyable travel within the world’s highlands. It may also give some of us an excuse to quit when we get tired after 5 minutes of climbing!
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- Jabr F. Mountain Maladies: Genetic Screening Susses Out Susceptibility to Altitude Sickness. Scientific American. 2012.