Ancestry explains the blunted ventilatory response to sustained hypoxia and lower exercise ventilation of Quechua altitude natives

Abstract

-Andean highaltitude (HA) natives have a low (blunted) hypoxic ventilatory response (HVR), lower effective alveolar ventilation, and lower ventilation (VE) at rest and during exercise compared with acclimatized newcomers to HA. Despite blunted chemosensitivity and hypoventilation, Andeans maintain comparable arterial O 2 saturation (SaO 2 ). This study was designed to evaluate the influence of ancestry on these trait differences. At sea level, we measured the HVR in both acute (HVR-A) and sustained (HVR-S) hypoxia in a sample of 32 male Peruvians of mainly Quechua and Spanish origins who were born and raised at sea level. We also measured resting and exercise VE after 10 -12 h of exposure to altitude at 4,338 m. Native American ancestry proportion (NAAP) was assessed for each individual using a panel of 80 ancestry-informative molecular markers (AIMs). NAAP was inversely related to HVR-S after 10 min of isocapnic hypoxia (r ϭ Ϫ0.36, P ϭ 0.04) but was not associated with HVR-A. In addition, NAAP was inversely related to exercise VE (r ϭ Ϫ0.50, P ϭ 0.005) and ventilatory equivalent (VE/V O2, r ϭ Ϫ0.51, P ϭ 0.004) measured at 4,338 m. Thus Quechua ancestry may partly explain the wellknown blunted HVR (10,35,36,57,62) at least to sustained hypoxia, and the relative exercise hypoventilation at altitude of Andeans compared with European controls. Lower HVR-S and exercise VE could reflect improved gas exchange and/or attenuated chemoreflex sensitivity with increasing NAAP. On the basis of these ancestry associations and on the fact that developmental effects were completely controlled by study design, we suggest both a genetic basis and an evolutionary origin for these traits in Quechua. genetic markers; admixture; arterial saturation; Andes THE HYPOXIC VENTILATORY RESPONSE (HVR) is the increase in ventilation (VE) that occurs when arterial blood oxygen partial pressure PO 2 decreases (60). Typically, on acute exposure to hypoxia, VE increases to a peak in the first few minutes and thereafter declines somewhat to a level higher than control depending on the level of hypoxia (13,49). This attenuation of VE has been termed the hypoxic ventilatory decline (HVD), and it is usually assessed by protocols that give a sustained hypoxic exposure greater than ϳ10 min. The sustained vs. acute response has not been systematically evaluated in Andean highland natives, but groups from this region appear to have a lower or "blunted" acute HVR and a lower effective alveolar ventilation compared with high altitude (HA)-acclimatized control groups from the lowlands (10,35,36,43,57,61,62). Andeans also have lower VE during exercise at HA compared with acclimatized lowland controls (7,32,55,66). These traits may be unique to Andeans, as many studies show normal HVR and higher VE in natives of the Himalayan plateau (2,21,25,29,75). However, little is known about the underlying genetic and/or environmental basis for ventilatory trait differences between populations. One possibility is that there are genes at which allele frequencies differ ...

Serum testosterone levels and excessive erythrocytosis during the process of adaptation to high altitudes

“…32 Moreover, no studies have been conducted in humans during the daytime to show an association between ventilation and testosterone levels at HA. The classic ventilatory blunting of healthy high-altitude natives 24 does not necessarily result in lower SpO 2 . Therefore, it can be argued that high-altitude natives do not ventilate more because it is not necessary, possibly because of improved gas exchange (e.g., pulmonary diffusion).…”

“…24 One of the causes of hypoventilation at HA seems to be sleep apnoea. 25 At HA, normal people often develop periodic breathing during sleep and recurring periods of hyperpnoea and apnoea.…”

Human high-altitude adaptation: forward genetics meets the HIF pathway

“…Andeans exhibit no increase in resting ventilation levels over low-altitude values at rest or during exercise (Chiodi 1957;Brutsaert et al 2000) and a blunted HVR (Chiodi 1957;Beall et al 1997a) that is commonly lower than sea-level values. Pointing to a genetic basis for this trait, the Andean HVR has been associated with Quechua ancestry (Brutsaert et al 2005), thus suggesting an evolutionary origin. Tibetans maintain equal or higher resting ventilation compared with other acclimatized Asian and European populations measured at the same altitude Ge et al 1994;Beall et al 1997a;Moore et al 2001b), and, notably, their resting ventilation is 1.5 times higher than that observed among the Andean Aymara (Beall et al 1997a).…”

Phenotypic plasticity and genetic adaptation to high-altitude hypoxia in vertebrates

“…For example, the enhanced ventilatory response to acute hypoxia in the high-altitude bar-headed goose (Anser indicus) is partly due to an insensitivity to hypocapnia (Fig.2) (Scott and Milsom, 2007;Scott and Milsom, 2009), whereas responses of high-altitude humans generally involve changes in O 2 sensitivity (Brutsaert, 2007). Other highland species or populations exhibit a blunted ventilatory response to acute hypoxia (Blake and Banchero, 1985;Brutsaert et al, 2005), which would be maladaptive at high altitudes without compensatory changes at other steps in the O 2 transport pathway that maintain peripheral O 2 supply. As might also be the case for hypoxic desensitization, this blunted response might help maintain blood CO 2 /pH homeostasis or it might reduce the costs of breathing Powell, 2007).…”