Project Summary/Abstract The ability to use oxygen effectively is essential for survival. Many significant human diseases, including cardiopulmonary disease, hypertension, sleep apnea, and cancer involve a disruption in oxygen homeostasis. Human populations at high altitude have been challenged by hypoxia for hundreds of generations and show both unique physiological responses to this environmental stress and extremely strong natural selection for genes involved in oxygen transport, which can be demonstrated in relatively small studies. For example, we were the first to demonstrate a relationship between genes in the hypoxia inducible factor (HIF) pathway under natural selection and relatively lower hemoglobin concentration, which is further associated with exercise capacity, in Tibetans. Here we propose a similar integrative and targeted approach to identify the genetic determinants of both adaptive and maladaptive cardiopulmonary responses to hypoxia in Andean natives, who show a wide range of cardiorespiratory phenotypes, including chronic mountain sickness (CMS) rare among Tibetans. CMS is characterized by excessive erythrocytosis, arterial hypoxemia, carbon dioxide retention, and blunted ventilatory chemoreflexes, which are also traits associated with poor outcomes in patients with chronic heart and lung disease. We propose to test the overarching hypothesis that individual differences in cardiopulmonary phenotypes (hemoglobin concentration, arterial oxygen saturation, hypoxic/hypercapnic ventilatory and cardiovascular responses) are predicted by (1) a lack of adaptive variants and/or (2) altered epigenetic regulation at loci identified with powerful state-of-the-art genomic analyses of Andean men and women with and without CMS. We will also test the hypothesis that the severity of sleep apnea underlies epigenetic changes that further modify cardiopulmonary responses as previously demonstrated in animal studies of intermittent hypoxia. Finally, we will determine if genetic and epigenetic variants result in gain- or loss-of-function to pursue therapeutic options for mitigating maladaptive responses to hypoxia in patients at sea level with chronic heart and lung disease.