Bolivian Aymara Natives with Chronic Mountain Sickness Have Autonomous BFU-E Growth

Abstract

BackgroundErythrocytosis / polycythemia is divided into primary and secondary. Primary polycythemia can be either acquired; i.e. polycythemia vera (PV) due to somatic JAK2 mutation, or congenital due to germ-line DNA changes (erythropoietin (EPO) receptor and VHL mutations in Chuvash polycythemia). These mutations are expressed within erythroid progenitors, drive increased erythropoiesis and are detected by hypersensitive or autonomous EPO BFU-E responses. In contrast, secondary erythrocytosis (SE), such as seen with cardiopulmonary pathologies, is driven by the circulating EPO.Chronic mountain sickness (CMS) is characterized by high altitude pathological erythrocytosis and by cognitive and neurological impairments. CMS is found in subjects living in high altitude (2500 meters and higher). In La Paz, Bolivia, (3600m) there is 7% incidence of CMS erythrocytosis.Some human populations (Tibetans, Andean Quechuas and Aymaras, and Ethiopians) are adapted to very high altitudes and their adapted phenotypes and, in some instances, evolutionarily selected haplotypes, have been reported. Whole genome was evaluated in Andeans and two genes, SENP1 and ANP32D were found to be evolutionarily selected and correlated with presence or absence of erythrocytosis. The genes down-regulation in hypoxia had survival benefit in Drosophila ortholog (1).SENP1 desumoylate GATA-1 and other regulatory proteins and is critical for definitive erythropoiesis (2,3).Here we evaluated native Aymara La Paz dwellers with three types of polycythemia: CMS, SE secondary to cardiopulmonary disease, and PV, by clinical studies and by in vitro evaluation of erythroid progenitors, and compared them to non-polycythemic subjects.Patients and MethodsComplete blood count was performed by automatic hematologic counter (Micro 60, USA). Serum EPO was measured by Elisa (R&D System, USA) and JAK2V617F mutation analysis by PCR assay. Erythroid progenitors were isolated by density gradient centrifugation and cultured in methylcellulose medium with and without EPO (Stem Cell technologies, Canada) at 370 C and 5 % CO2. BFU-E colonies reading was carried out according to standardized criteria at 7 and 14 days.ResultsTableNormal Control(n=10)CMS (n=15)Secondary Erythrocytosis(n=10)PolycythemiaVera (n=5)1.Gender M/F10/015/010/03/2Age (range)42 (40-47)48 (29-58)53 (34-72)67 (42-74)Hb g/dl (SD)16.2 (+ 0.9)20.3 (+ 0.9)22.8 (+ 1.4)20.0 (+ 2.5)Ret % (SD)1.3 (+ 0.1)2.9 (+ 1.3)3.6 (+ 1.2)2.1 (+ 0.3)WBC /ul (SD)6300 (+ 1600)7200 (+ 1900)6600 (+ 1700)16600 (+ 4800)PLT 103 ul (SD)273 (+ 80)229 (+ 58)193 (+ 54)604 (+ 177)sEPO mUI/ml (SD)10.0 (+ 3.9)10.5 (+ 2.2)82.9 (+ 30.4)3.0 (+ 1.2)JAK2V617F, No. (%)0 (0)0 (0)0 (0)100ApoptosisNormalDelayedNormalDelayedBFU-E: EEC0 (0-0)10 (2-25)0 (0-0)45 (25-70)