iScience (Aug 2025)
Adaptive PRKAA1 variant in Andeans is associated with improved ventilation and sleep phenotypes
- Elijah S. Lawrence,
- Wanjun Gu,
- Mitchell C. Kong,
- Santiago Fassardi,
- Cecilia Anza-Ramirez,
- Esteban A. Moya,
- Erica C. Heinrich,
- James J. Yu,
- Jeremy E. Orr,
- Steven Y. Cao,
- Ana Sanchez-Azofra,
- Amy M. Cole,
- James E. Hall,
- Andrew Lin,
- Pamala N. DeYoung,
- Gustavo Vizcardo-Galindo,
- Jose-Luis Macarlupu,
- Rómulo Figueroa-Mujíca,
- Daniela Bermudez,
- Noemi Corante,
- Gianpiero L. Cavalleri,
- Eduardo Gaio,
- A. Mark Evans,
- Frank L. Powell,
- Atul Malhotra,
- Rany M. Salem,
- Francisco C. Villafuerte,
- Tatum S. Simonson
Affiliations
- Elijah S. Lawrence
- Department of Medicine, Division of Pulmonary, Critical Care, Sleep Medicine, and Physiology University of California, San Diego, La Jolla, CA, USA
- Wanjun Gu
- Department of Medicine, Division of Pulmonary, Critical Care, Sleep Medicine, and Physiology University of California, San Diego, La Jolla, CA, USA; Herbert Wertheim School of Public Health and Longevity Sciences, University of California, San Diego, La Jolla, CA, USA
- Mitchell C. Kong
- Department of Medicine, Division of Pulmonary, Critical Care, Sleep Medicine, and Physiology University of California, San Diego, La Jolla, CA, USA; Department of Bioengineering, University of California, San Diego, La Jolla, CA, USA
- Santiago Fassardi
- Department of Medicine, Division of Pulmonary, Critical Care, Sleep Medicine, and Physiology University of California, San Diego, La Jolla, CA, USA
- Cecilia Anza-Ramirez
- Fisiología del Transporte de Oxígeno y Adaptación a la Altura-LID, Departamento de Ciencias Biológicas y Fisiológicas, Facultad de Ciencias e Ingeniería, Universidad Perúana Cayetano Heredia, Lima, Peru
- Esteban A. Moya
- Department of Medicine, Division of Pulmonary, Critical Care, Sleep Medicine, and Physiology University of California, San Diego, La Jolla, CA, USA
- Erica C. Heinrich
- Department of Medicine, Division of Pulmonary, Critical Care, Sleep Medicine, and Physiology University of California, San Diego, La Jolla, CA, USA; Division of Biomedical Sciences, School of Medicine, University of California, Riverside, Riverside, CA, USA
- James J. Yu
- Department of Medicine, Division of Pulmonary, Critical Care, Sleep Medicine, and Physiology University of California, San Diego, La Jolla, CA, USA
- Jeremy E. Orr
- Department of Medicine, Division of Pulmonary, Critical Care, Sleep Medicine, and Physiology University of California, San Diego, La Jolla, CA, USA
- Steven Y. Cao
- Herbert Wertheim School of Public Health and Longevity Sciences, University of California, San Diego, La Jolla, CA, USA
- Ana Sanchez-Azofra
- Department of Medicine, Division of Pulmonary, Critical Care, Sleep Medicine, and Physiology University of California, San Diego, La Jolla, CA, USA
- Amy M. Cole
- School of Pharmacy and Biomolecular Sciences, Royal College of Surgeons in Ireland, Dublin, Ireland
- James E. Hall
- Department of Medicine, Division of Pulmonary, Critical Care, Sleep Medicine, and Physiology University of California, San Diego, La Jolla, CA, USA
- Andrew Lin
- Department of Medicine, Division of Pulmonary, Critical Care, Sleep Medicine, and Physiology University of California, San Diego, La Jolla, CA, USA
- Pamala N. DeYoung
- Department of Medicine, Division of Pulmonary, Critical Care, Sleep Medicine, and Physiology University of California, San Diego, La Jolla, CA, USA
- Gustavo Vizcardo-Galindo
- Fisiología del Transporte de Oxígeno y Adaptación a la Altura-LID, Departamento de Ciencias Biológicas y Fisiológicas, Facultad de Ciencias e Ingeniería, Universidad Perúana Cayetano Heredia, Lima, Peru
- Jose-Luis Macarlupu
- Fisiología del Transporte de Oxígeno y Adaptación a la Altura-LID, Departamento de Ciencias Biológicas y Fisiológicas, Facultad de Ciencias e Ingeniería, Universidad Perúana Cayetano Heredia, Lima, Peru
- Rómulo Figueroa-Mujíca
- Fisiología del Transporte de Oxígeno y Adaptación a la Altura-LID, Departamento de Ciencias Biológicas y Fisiológicas, Facultad de Ciencias e Ingeniería, Universidad Perúana Cayetano Heredia, Lima, Peru
- Daniela Bermudez
- Fisiología del Transporte de Oxígeno y Adaptación a la Altura-LID, Departamento de Ciencias Biológicas y Fisiológicas, Facultad de Ciencias e Ingeniería, Universidad Perúana Cayetano Heredia, Lima, Peru
- Noemi Corante
- Fisiología del Transporte de Oxígeno y Adaptación a la Altura-LID, Departamento de Ciencias Biológicas y Fisiológicas, Facultad de Ciencias e Ingeniería, Universidad Perúana Cayetano Heredia, Lima, Peru
- Gianpiero L. Cavalleri
- School of Pharmacy and Biomolecular Sciences, Royal College of Surgeons in Ireland, Dublin, Ireland
- Eduardo Gaio
- Laboratório de Fisiologia Respiratória, Faculdade de Medicina, Universidade de Brasília, Brasilia, Brazil
- A. Mark Evans
- Centre for Discovery Brain Sciences, Hugh Robson Building, Edinburgh Medical School, University of Edinburgh, Edinburgh, UK
- Frank L. Powell
- Department of Medicine, Division of Pulmonary, Critical Care, Sleep Medicine, and Physiology University of California, San Diego, La Jolla, CA, USA
- Atul Malhotra
- Department of Medicine, Division of Pulmonary, Critical Care, Sleep Medicine, and Physiology University of California, San Diego, La Jolla, CA, USA
- Rany M. Salem
- Herbert Wertheim School of Public Health and Longevity Sciences, University of California, San Diego, La Jolla, CA, USA
- Francisco C. Villafuerte
- Fisiología del Transporte de Oxígeno y Adaptación a la Altura-LID, Departamento de Ciencias Biológicas y Fisiológicas, Facultad de Ciencias e Ingeniería, Universidad Perúana Cayetano Heredia, Lima, Peru
- Tatum S. Simonson
- Department of Medicine, Division of Pulmonary, Critical Care, Sleep Medicine, and Physiology University of California, San Diego, La Jolla, CA, USA; Corresponding author
- Journal volume & issue
-
Vol. 28,
no. 8
p. 112911
Abstract
Summary: 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.
