Genetic Risk Factors of Chronic Mountain Sickness

Abstract

Chronic mountain sickness (CMS) is a pathological condition resulting from the loss of adaptation to high altitude. The syndrome is characterized by an excessive number of red blood cells (Excessive Erythropoiesis) associated with a high concentration of hemoglobin, hypoxemia and sometimes pulmonary hypertension. In the Peruvian Andes, the estimated prevalence of this condition is higher than 10% in the adult population living above 2500 m. The pathophysiology is not yet clearly established. Alteration of the control of ventilation, especially during sleep could induce a severe hypoxemia that would trigger excessive secretion of erythropoietin (EPO), leading to increased red cell production. We collected clinical and physiological data and blood samples in a cohort of 143 CMS patients and 101 control subjects living at high altitude in Cerro de Pasco (4300m). Leukocytes DNA was extracted by salting out procedure, DNA was quantified and qualified with NanoDrop™ 2000. We performed a genome wide association study using an Illumina HumanOmni5 array (4,301,332 SNPs). CMS was associated with low arterial O2 saturation and high body mass index. We evidenced several genes that could be related to a susceptibility to develop CMS or pulmonary hypertension (ATM, NPAT, PPARGC1A, ATP9A, WWOX). These pathways revealed as submitted to recent positive selection. Moreover, the admixture level of European low lander ancestry in the genome of this population seemed to influence the occurrence of CMS and the polymorphism of selected genes. A replication study is planned to confirm our preliminary results.