This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Understanding mechanisms and the genetic control of ventilation behavior and ventilatory response to hypoxia is crucial to ascent to altitude. Abundant evidence indicates that nitric oxide (NO) is relevant to underlying mechanisms and modulations many common disorders where hypoxemia and/or sleep disordered breathing may occur and produce illness. Our goal is to create a map linking genes that associate with traits of ventilatory behavior (respiratory frequency, tidal volume, and response to hypoxia and sleep). We have observed phenotype variations; we also find variability in ventilation, oxygenation, and exhaled NO in high altitude populations. Hence, we propose to test the hypothesis that associations will exist between the variations in NOS genes and the response to hypoxia in humans. In humans exhaled NO production offers a non-invasive method for assessment of NO production and function. We have reported substantial variation in exhaled NO levels at sea level and especially in high altitude native populations where chronic hypoxia acts as a force for natural selection on minute ventilation, hypoxic ventilatory response (HVR), and hematocrit). Tibetans at 4200m have an average roughly 50% higher exhaled NO than Andean highlanders at 3900m and both have higher exhaled NO than sea-level natives at sea level. The range of variation in exhaled NO among the highlanders is wider than and includes the sea level range.
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