[156], [157], [158], [159], [160] and [161] Some of these mutations (P317R, H374R) likely affect iron-chelation at the catalytic center, which is critical for PHD enzymatic activity. Furthermore, H374R was associated with paraganglioma development, indicating that PHD2 may function as a tumor suppressor. [157] and [160] Chronic mountain sickness (CMS), also known as Monge’s disease, affects long-term high-altitude (> 2500 m) residents or natives, and is associated with excessive erythrocytosis (females, Hgb ≥ 19 g/dL; males, Hgb ≥ 21 g/dL), hypoxemia, pulmonary hypertension, right-sided heart failure and neurologic

symptoms, such as headache, fatigue, tinnitus, insomnia, EPZ015666 in vitro paresthesia and loss of memory.[162], [163] and [164] The disease was fist described in high altitude dwellers on the South American Altiplano, where it affects ~ 5–15% of the population.[162] and [164] CMS is usually alleviated by descent to low altitude or by phlebotomy.[162] and [163] While the disease is prevalent in the Andean population, it is less common in native Tibetans, who live at comparable altitude. In contrast, Tibetan residents of Han Chinese descent are much

more frequently affected by CMS, which represents a major public INK 128 nmr health burden.[164], [165], [166] and [167] Prevalence of CMS is higher in men than in women, increases with altitude and age, and is more likely to develop in the presence of lung diseases, smoking and environmental pollution.164 The pathogenesis of CMS is thought to result, at least partly, from an abnormal, i.e. blunted, ventilatory response.164 Aside from differences in susceptibility to CMS, native Tibetans and Andeans differ in their baseline physiologic responses to high altitude. Native Tibetans have higher resting ventilation and hypoxic ventilatory response

at comparable altitudes, lower oxygen saturation of arterial Methane monooxygenase hemoglobin and lower hemoglobin concentrations (15.6 g/dL versus 19.2 g/dL in males)[168] and [169] There is also less intrauterine growth retardation and better neonatal oxygenation among native Tibetans compared to native Andeans or Han Chinese.[166] and [170] Furthermore, differences in energy metabolism have been described, which need further characterization.171 These differences in physiologic phenotypes reflect divergence in genetic adaptation and selection, which result from differences in length of high-altitude habitation (~ between 25,000 and 50,000 years for native residents on the Tibetan plateau, compared to ~ 10,000 years for the Andean Altiplano and ~ 60 years for Tibetan residents of Han Chinese descent), the degree of geographical isolation (Tibetan plateau > South American Altiplano) and gene pool stability.