Most humans living at altitudes above 4000m develop polycythemia, classically thought of as an adaptation to enhance O2 transport and hence muscular performance. It is thus surprising to find that many healthy Tibetan high altitude natives are not polycythemic. Our recent work has shown that loss of polycythemia is associated with positive selection resulting from adaption in several genes, especially those related to hypoxia. Our preliminary physiological studies have shown that enhanced exercise capacity is associated with increased cardiac output and diffusive transport of oxygen in muscle, although the precise genetic underpinnings and the order of selective events are unknown. We hypothesize that polycythemia is a misguided response to altitude and that native Tibetan highlanders have evolutionary changes related to cardiac and muscle structure/function, in addition to potential alterations in ventilatory responses that have enabled their successful existence despite physiological challenges of high-altitude hypoxia. We will test these hypotheses in both a physiological and genomics context by determining: 1) if our previous associations between exercise capacity and O2 transport pathway conductances are associated with [Hb] in Tibetan females and Han Chinese of both sexes and whether adaptive haplotypes are correlated with these physiological data;2) whether structural/functional alterations in heart and muscle are related to our physiological findings in Aim 1 and whether resting hypoxic and hypercapnic ventilatory responses are associated with [Hb] in Tibetan men and women;and 3) if precise genetic variants relate to the above physiological measurements and/or [Hb] and decipher the order of selective events that have occurred over evolutionary time.

Public Health Relevance

In our previous genetic studies, we showed that Tibetans have genetic adaptations to high- altitude associated with loss of polycythemia, and our preliminary physiological studies show that this loss is accompanied by enhanced exercise capacity through increased cardiac output and diffusive transport of O2 in muscle, yet the functional basis of these findings, and especially their temporal evolutionary sequence, is unknown. The goal of this proposal is to determine the physiological and genetic factors responsible for Tibetan adaptations by assessing exercise capacity, each step of the oxygen transport cascade (primarily focused on cardiac and muscle structure/function), precise genetic targets that afford evolutionary advantages, and the relationships among these factors and relatively lower hemoglobin levels in adapted Tibetans. Considering decreased oxygen availability may be a cause or effect of various diseases (e.g., potentially fatal altitude illness, heart and lung disease, stroke, hypertension, and cancer), our results will have broad implications for disease treatment and prevention.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Career Transition Award (K99)
Project #
1K99HL118215-01A1
Application #
8635881
Study Section
Special Emphasis Panel (ZHL1-CSR-P (O1))
Program Officer
Carlson, Drew E
Project Start
2014-01-17
Project End
2015-01-18
Budget Start
2014-01-17
Budget End
2015-01-18
Support Year
1
Fiscal Year
2014
Total Cost
$84,817
Indirect Cost
$6,283
Name
University of California San Diego
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
804355790
City
La Jolla
State
CA
Country
United States
Zip Code
92093
Simonson, T S; Wei, G; Wagner, H E et al. (2014) Increased blood-oxygen binding affinity in Tibetan and Han Chinese residents at 4200 m. Exp Physiol 99:1624-35