Adaptive PRKAA1 variant in Andeans is associated with improved ventilation and sleep phenotypes

Lawrence E.S.; Gu W.; Kong M.C.; Fassardi S.; Anza-Ramirez C.; Moya E.A.; Heinrich E.C.; Yu J.J.; Orr J.E.; Cao S.Y.; Sanchez-Azofra A.; Cole A.M.; Hall J.E.; Lin A.; DeYoung P.N.; Vizcardo-Galindo G.; Macarlupu J.-L.; Figueroa-Mujíca R.; Bermudez D.; Corante N.; Cavalleri G.L.; Gaio E.; Evans A.M.; Powell F.L.; Malhotra A.; Salem R.M.; Villafuerte F.C.; Simonson T.S. · iScience (2025) · DOI: 10.1016/j.isci.2025.112911

Resumen

Highland groups have adapted to the extreme selective pressures of hypoxia at high altitude via alterations in the oxygen-transport cascade. PRKAA1, which encodes the catalytic subunit of the AMP-activated protein kinase (AMPK), is a notable target of natural selection in Andeans and has been associated with protective fetal phenotypes in this population. AMPK is a universal cellular energy sensor involved in a multitude of physiological processes, including ventilation and the hypoxic ventilatory response (HVR) in animal models. We localized a signal of positive selection and identified a regulatory promoter variant (rs10035235, C>T) of adaptive significance that is associated with ventilatory and sleep phenotypes in male Andean highlanders as well as sleep phenotypes in publicly available lowland cohorts. This work identifies a functional, adaptive, and likely pleiotropic regulatory variant in PRKAA1 in Andeans that may accentuate hypoxia-induced ventilation and provide protection from sleep-disordered breathing in both high- and lowland populations.

Instituciones: Universidad Peruana Cayetano Heredia