UC San Diego

Human ascent to high altitude (> 3500m) involves changes in ventilatory activity to compensate for decreased O2 availability (hypoxia). High-altitude communities of the Andean Altiplano in South America and the Qinghai-Tibetan Plateau in Asia have differing physiological responses to hypoxia; many Andeans have a lower hypoxic ventilatory response (HVR) compared to Tibetans. This reduced sensitivity to hypoxia may have clinical implications, as more Andeans are diagnosed with chronic mountain sickness (syndrome of low oxygen saturation and high hemoglobin concentration) than Tibetans. In mice, the gene encoding the α1 catalytic subunit of the AMP-activated protein kinase (PRKAA1) is involved in ventilatory control. A genomic region containing PRKAA1 has been reported as a site of natural selection in Andeans and is associated with increased uterine artery (UA) diameter and birth weight in newborns. However, the role of PRKAA1 in ventilation in humans living at high-altitude has not been explored. Here, in a cohort of Andean highlanders, a composite of multiple signals (CMS) test of selection in combination with variant annotation identified a putatively causal promoter variant rs10035235(C>T). Genotype-phenotype association tests found the T allele to be associated with an increased HVR in males. The functional effects of rs10035235(T) on gene expression and transcription factor-DNA binding were assessed via luciferase and EMSA supershift assays, respectively. rs10035235(T) was found to increase expression and have less binding to HOXC9 when compared to rs10035235(C). These findings show the role of genetic variation in ventilatory responses to hypoxia.