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

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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.

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Acknowledgments

We thank Dr. Rhona Jack, Department of Laboratory Medicine, Seattle Children’s Hospital, Institute, Foundation for her constructive criticism in reviewing this manuscript. This study was supported in part by the grants from Children’s Hospital and Regional Medical Center (HR5836), National Natural Science Foundation (No. 38970307 and No.30393130) and National Basic Research Program of China “973” (No. 2006CB504100).

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Authors and Affiliations

  1. Department of Pediatrics, University of Washington, Seattle, WA, 98195, USA

    Norman E. Buroker, C. Ronald Scott & Shi-Han Chen

  2. Division of Cardiology, Seattle Children’s Hospital, Institute, Foundation, Seattle, WA, 98105, USA

    Xue-Han Ning

  3. Laboratory of Hypoxia Physiology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai, China

    Zhao-Nian Zhou, Xiu-Feng Wu & Wei-Zhong Zhu

  4. Lhasa People Hospital, Lhasa, Tibet, China

    Kui Li & Wei-Jun Cen

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  1. Norman E. Buroker
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Correspondence to Norman E. Buroker.

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Buroker, N.E., Ning, XH., Zhou, ZN. et al. AKT3, ANGPTL4, eNOS3, and VEGFA associations with high altitude sickness in Han and Tibetan Chinese at the Qinghai-Tibetan Plateau. Int J Hematol 96, 200–213 (2012). https://doi.org/10.1007/s12185-012-1117-7

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