AKT3, ANGPTL4, eNOS3, and VEGFA associations with high altitude sickness in Han and Tibetan Chinese at the Qinghai-Tibetan Plateau

Abstract

Mountain sickness (MS) occurs among humans visiting or inhabiting high altitude environments. We conducted genetic analyses of the AKT3, ANGPTL4, eNOS3 and VEGFA genes in lowland (Han) and highland (Tibetan) Chinese. Ten single nucleotide polymorphisms (SNPs) were evaluated in Han and Tibetan patients with acute (A) and chronic (C) MS. We compared 74 patients with AMS to 79 Han unaffected with MS, as well as 48 CMS patients to 31 unaffected Tibetans. The ten SNPs studied are AKT3 (rs4590656, rs2291409), ANGPTL4 (rs1044250), eNOS3 (rs1007311, rs1799983) and VEGFA (rs79469752, rs13207351, rs28357093, rs1570360, rs3025039). Direct sequencing was used to identify individual genotypes for these SNPs. Hemoglobin (Hb), hematocrit (Hct), and red blood cell count (RBC) were found to be significantly associated with the AKT3 SNP (rs4590656), Hb was found to be associated with the eNOS3 SNP (rs1007311), and RBC was found to be significantly associated with the VEGFA SNP (rs1570360) in Tibetan patients with CMS. CMS patients were found to diverge significantly for both eNOS3 SNPs as measured by genetic distance (0.042, 0.047) and for the VEGFA SNP (rs28357093) with a genetic distance of 0.078 compared to their Tibetan control group. Heart rate (HR) was found to be significantly associated with the eNOS3 SNP (rs1799983) and arterial oxygen saturation of hemoglobin (SaO2) was found to be significantly associated with the VEGFA SNPs (rs13207351, rs1570360) in Han patients with AMS. The Han and Tibetan control groups were found to diverge significantly for the ANGPTL4 SNP and VEGFA SNP (rs28357093), as measured by genetic distances of 0.049 and 0.073, respectively. Seven of the SNPs from non-coding regions are found in the transcriptional factor response elements and their possible role in gene regulation was evaluated with regard to MS. AMS and CMS were found to be significantly associated with the four genes compared to their Han and Tibetan control groups, respectively, indicating that these nucleotide alterations have a physiological effect for the development of high altitude sickness.

SNPs, Linkage Disequilibrium and Transcriptional Factor Binding Sites Associated with Acute Mountain Sickness among Han Chinese at the Qinghai-Tibetan Plateau

“…The people from the control group had lived at the 3600 M altitude for at least six months prior to being sampled. These sampling procedures have been previously described [8][9][10]31].…”

“…The Vector NTI Advance 11 computer program from Invitrogen, Carlsbad, CA, was used to develop the primers for genotyping each SNP. The genotyping methods and genotyping for each SNP have been previously outlined and reported [8][9][10]31]. The SNPs and genes used in the present study are found in (Table 1).…”

“…The illness will resolve itself if no additional altitude is attempted; however, in some cases the descent to a lower altitude is necessary in order to reverse the condition. The precise pathogenesis of AMS is not well understood, but hypoxia is considered to be the major factor [4][5][6][7], which raises the question of why some individuals are susceptible to the sickness while others are not, under the same high altitude environment.In an effort to provide in cite into this question, we have previously published on known genetic associations of simple nucleotide polymorphisms (SNPs) with high altitude sickness [8][9][10][11]. In the present study, we examine the interaction of seventeen SNPs in nine genes [8][9][10][11] with regard to AMS and the effect these SNPs have on potential changes in transcriptional factor binding sites (TFBS).…”

“…We also included SNPs from three genes in the vascular endothelial growth factor (VEGF) signaling pathway [9] where the VEGFA protein is a growth factor activator for angiogenesis, vasculogenesis and endothelial cell growth. Four VEGFA SNPs (rs79469752, rs13207351, rs28357093 and rs1570360) are found in the promoter region while a fifth VEGFA SNP (rs3025039) is located in the 3'UTR region.…”

“…LD between SNPs in the regulatory region of a gene can be used as a method of identifying associations of certain haplotypes that lead to sickness or disease in a population [9,11].This can be achieved when levels of LD between SNPs within haplotypes are seen to change substantially in a disease or sickness group when compared to the normal baseline population. In such cases, the relationship between LD, SNPs and TFBS can be used to identify potential binding changes for TFs responsible for gene regulation.…”