EPAS1 and EGLN1 associations with high altitude sickness in Han and Tibetan Chinese at the Qinghai–Tibetan Plateau Norman E. Buroker a, ⁎, Xue-Han Ning a, b , Zhao-Nian Zhou c , Kui Li d , Wei-Jun Cen d , Xiu-Feng Wu c , Wei-Zhong Zhu c , C. Ronald Scott a , Shi-Han Chen a a Department of Pediatrics, University of Washington, Seattle, WA 98195, USA b Divisions of Cardiology, Seattle Children's Hospital, Institute, Foundation, Seattle, WA 98105, USA c Laboratory of Hypoxia Physiology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, China d Lhasa People Hospital, Lhasa, Tibet, China abstract article info Article history: Submitted 22 August 2011 Available online xxxx (Communicated by Y.W. Kan, M.D., FRS, 13 April 2012) Keywords: Acute mountain sickness Chronic mountain sickness EPAS1 EGLN1 High altitude sickness (HAS) occurs among humans visiting or inhabiting high altitude environments. Genet- ic differences in the EPAS1 and EGLN1 genes have been found between lowland (Han) and highland (Tibetan) Chinese. Three SNPs within EPAS1 and EGLN1 were evaluated in Han and Tibetan patients with acute moun- tain sickness (AMS) and chronic mountain sickness (CMS). We compared 85 patients with AMS to 79 Han unaffected with mountain sickness (MS) as well as 45 CMS patients to 34 unaffected Tibetan subjects. The three SNPs studied were EPAS1 [ch2: 46441523 (hg18], EGLN1 (rs480902) and (rs516651). Direct sequencing was used to identify individual genotypes for the three SNPs. Age was found to be significantly associated with the EPAS1 SNP in the CMS patients while heart rate (HR) and oxygen saturation level of hemoglobin (SaO 2 ) were found to be significantly associated with the EGLN1 (rs480902) SNP in the Han patients with AMS. The individuals with CMS were found to diverge significantly for the EPAS1 SNP compared to their Ti- betan control group as measured by genetic distance (0.123) indicating positive selection of the EPAS-G allele with age and illness. The EGLN1 (rs480902) SNP had a significant correlation with hematocrit (HCT), HR and SaO 2 in AMS patients. AMS and CMS were found to be significantly associated with the EPAS1 and EGLN1 SNPs compared to their Han and Tibetan control groups, respectively, indicating these nucleotide alterations have a physiological effect for the development of high altitude sickness. © 2012 Elsevier Inc. All rights reserved. Introduction High altitude illness arises from two different diseases: acute and chronic mountain sickness. Acute mountain sickness (AMS) is very common in lowlanders who ascend from sea level to altitudes greater than 2600 meters and is characterized by headache, lightheadedness, breathlessness, fatigue, insomnia, anorexia, and nausea [1,2]. Symp- toms begin two to three hours after ascent. The condition is generally self limiting; most symptoms disappear after 2 to 3 days, although in- somnia may persist [3]. AMS must be treated as an emergency; the ill- ness will resolve if no further altitude is gained; however in some cases descent to a lower altitude may be necessary in order to reverse the condition. Chronic mountain sickness (CMS) is characterized by polycythemia and severe hypoxemia, which is reversible upon de- scent from high altitudes [4,5]. Hematologic, neurologic, cardiac and respiratory symptoms are manifestations of the disease. The most common symptoms are bone and muscle pain, headaches, dizziness, dyspnea, insomnia, tinnitus, mental fatigue, and a loss of appetite. The severity of the condition increases with advancing age [6]. CMS is a syndrome resulting from the loss of human adaptation to high al- titude and can occur in permanent residents residing in this environ- ment [7,8]. The precise pathogenesis of AMS and CMS is not well understood, but hypoxia is likely to be a major factor [9–13]. This raises the question of why some individuals are susceptible to AMS and CMS while others are not, under the same hypoxic conditions. Ti- betans may be one of the oldest high-altitude adapted ethnic groups in the world with origins from the Neolithic period based on current genetic data [14–17]. Although AMS and CMS are different diseases and are treated differently, they both arise in humans at high altitudes. Recently genetic evidence has been accumulating that differenti- ates between human populations which have adapted to low versus high altitude environments over thousands of years [18–24]. The ge- netic perspectives of high altitude adaptation in humans were reviewed a few years ago [25], and since then human genome se- quencing has provided many new genetic loci associated with high altitude adaptation [24,26]. Over the years a body of evidence for Blood Cells, Molecules, and Diseases xxx (2012) xxx–xxx ⁎ Corresponding author at: Department of Pediatrics, University of Washington, RR335 HSB, Box 356320, 1959 NE Pacific St., Seattle, WA 98195, USA. Fax: +1 206 616 0471. E-mail address: nburoker@u.washington.edu (N.E. Buroker). YBCMD-01623; No. of pages: 7; 4C: 3 1079-9796/$ – see front matter © 2012 Elsevier Inc. All rights reserved. doi:10.1016/j.bcmd.2012.04.004 Contents lists available at SciVerse ScienceDirect Blood Cells, Molecules, and Diseases journal homepage: www.elsevier.com/locate/ybcmd Please cite this article as: N.E. Buroker, et al., Blood Cells Mol. Diseases (2012), doi:10.1016/j.bcmd.2012.04.004