Evidence for a genetic basis for altitude-related illness

Altitude-related illnesses are a family of interrelated pulmonary, cerebral, hematological, and cardiovascular medical conditions associated with the diminished oxygen availability at moderate to high altitudes. The acute forms of these debilitating and potentially fatal conditions, which include acute mountain sickness (AMS), high altitude pulmonary edema (HAPE), and high altitude cerebral edema (HACE), often develop in incompletely acclimatized lowlanders shortly after ascent, whereas, the chronic conditions, such as chronic mountain sickness (CMS) and high altitude pulmonary hypertension (HAPH), usually afflict native or long-term highlanders and may reflect a loss of adaptation. Anecdotal reports of particularly susceptible people or families are frequently cited as evidence that certain individuals have an innate susceptibility (or resistance) to developing these conditions and, in recent decades, there have been a number of studies designed to characterize the physiology of individuals predisposed to these conditions, as well as to identify the specific genetic variants that contribute to this predisposition. This paper reviews the epidemiological evidence for a genetic component to the various forms of altitude-related illness, such as innate susceptibility, familial clustering, and patterns of population susceptibility, as well as the molecular evidence for specific genetic risk factors. While the evidence supports some role for genetic background in the etiology of altitude-related illness, limitations in individual studies and a general lack of corroborating research limit the conclusions that can be drawn about the extent of this contribution and the specific genes or pathways involved. The paper closes with suggestions for future work that could support and expand on previous studies, as well as provide new insights.