# Respiratory and genomic contributions to adaptive/maladaptive hypoxia responses

> **NIH NIH R01** · UNIVERSITY OF CALIFORNIA, SAN DIEGO · 2021 · $476,300

## Abstract

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.

## Key facts

- **NIH application ID:** 10159952
- **Project number:** 5R01HL145470-03
- **Recipient organization:** UNIVERSITY OF CALIFORNIA, SAN DIEGO
- **Principal Investigator:** Tatum S Simonson
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $476,300
- **Award type:** 5
- **Project period:** 2019-05-10 → 2024-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10159952

## Citation

> US National Institutes of Health, RePORTER application 10159952, Respiratory and genomic contributions to adaptive/maladaptive hypoxia responses (5R01HL145470-03). Retrieved via AI Analytics 2026-06-11 from https://api.ai-analytics.org/grant/nih/10159952. Licensed CC0.

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