OJBD  Vol.3 No.3 , September 2013
SNPs and TFBS Associated with High Altitude Sickness*
The rSNPs for the genes AKT3 (rs4590656), EGLN1 (rs480902), eNOS3 (rs1007311), and VEGFA (rs699947, rs13207311, rs1570360, rs2010963) have been significantly associated with the physiological parameters in high altitude sickness Han or Tibetan Chinese patients at the Qinghai-Tibetan plateau. The alleles of each rSNP have been found to create unique transcriptional factor binding sites for transcription factors that affect the process of hypoxia gene expression in this high altitude hypoxia environment.

Cite this paper
N. Buroker, X. Ning, Z. Zhou, K. Li, W. Cen, X. Wu, W. Zhu, C. Ronald Scott and S. Chen, "SNPs and TFBS Associated with High Altitude Sickness*," Open Journal of Blood Diseases, Vol. 3 No. 3, 2013, pp. 85-93. doi: 10.4236/ojbd.2013.33018.
[1]   E. Pennisi, “The Biology of Genomes, Disease Risk Links to Gene Regulation,” Science, Vol. 332, No. 6033, 2011, p. 1031. doi:10.1126/science.332.6033.1031

[2]   V. Kumar, C. Wijmenga and S. Withoff, “From Genome-Wide Association Studies to Disease Mechanisms: Celiac Disease as a Model for Autoimmune Diseases,” Seminars in Immunopathology, Vol. 34, No. 4, 2012, pp. 567-580. doi:10.1007/s00281-012-0312-1

[3]   L. A. Hindorff, P. Sethupathy, H. A. Junkins, E. M. Ramos, J. P. Mehta, F. S. Collins and T. A. Manolio, “Potential Etiologic and Functional Implications of Genome-Wide Association Loci for Human Diseases and Traits,” Proceedings of the National Academy of Sciences, Vol. 106, No. 23, 2009, pp. 9362-9367. doi:10.1073/pnas.0903103106

[4]   V. Kumar, H. J. Westra, J. Karjalainen, D. V. Zhernakova, T. Esko, B. Hrdlickova, R. Almeida, A. Zhernakova, E. Reinmaa, U. Vosa, M. H. Hofker, R. S. Fehrmann, J. Fu, S. Withoff, A. Metspalu, L. Franke and C. Wijmenga, “Human Disease-Associated Genetic Variation Impacts Large Intergenic Non-Coding RNA Expression,” PLoS Genetics, Vol. 9, No. 1, 2013, Article ID: e1003201. doi:10.1371/journal.pgen.1003201

[5]   W. Cookson, L. Liang, G. Abecasis, M. Moffatt and M. Lathrop, “Mapping Complex Disease Traits with Global gene expression,” Nature Reviews Genetics, Vol. 10, No. 3, 2009, pp. 184-194. doi:10.1038/nrg2537

[6]   T. Pastinen, “Genome-Wide Allele-Specific Analysis: Insights into Regulatory Variation,” Nature Reviews Genetics, Vol. 11, No. 8, 2010, pp. 533-538. doi:10.1038/nrg2815

[7]   F. C. Sille, R. Thomas, M. T. Smith, L. Conde and C. F. Skibola, “Post-GWAS Functional Characterization of Susceptibility Variants for Chronic Lymphocytic Leukemia,” PLoS One, Vol. 7, No. 1, 2012, Article ID: e29632. doi:10.1371/journal.pone.0029632

[8]   J. Bratosiewicz-Wasik, J. Smolen-Dzirba, C. Watala, A. J. Rozemuller, C. Jansen, W. Spliet, G. H. Jansen, T. J. Wasik and P. P. Liberski, “Association of the PRNP Regulatory Region Polymorphisms with the Occurrence of Sporadic Creutzfeldt-Jakob Disease,” Folia Neuropathologica, Vol. 50, No. 1, 2012, pp. 68-73.

[9]   J. C. Knight, “Functional Implications of Genetic Variation in Non-Coding DNA for Disease Susceptibility and Gene Regulation,” Clinical Science, Vol. 104, No. 5, 2003, pp. 493-501. doi:10.1042/CS20020304

[10]   X. Wang, D. J. Tomso, X. Liu and D. A. Bell, “Single Nucleotide Polymorphism in Transcriptional Regulatory Regions and Expression of Environmentally Responsive Genes,” Toxicology and Applied Pharmacology, Vol. 207, No. 2, 2005, pp. 84-90. doi:10.1016/j.taap.2004.09.024

[11]   B. N. Chorley, X. Wang, M. R. Campbell, G. S. Pittman, M. A. Noureddine and D. A. Bell, “Discovery and Verification of Functional Single Nucleotide Polymorphisms in Regulatory Genomic Regions: Current and Developing Technologies,” Mutation Research/Reviews in Mutation Research, Vol. 659, No. 1-2, 2008, pp. 147-157. doi:10.1016/j.mrrev.2008.05.001

[12]   N. E. Buroker, X. H. Ning, Z. N. Zhou, K. Li, W. J. Cen, X. F. Wu, W. Z. Zhu, C. R. Scott and S. H. Chen, “EPAS1 and EGLN1 Associations with High Altitude Sickness in Han and Tibetan Chinese at the Qinghai-Tibetan Plateau, Blood Cells,” Molecules & Diseases, Vol. 49, No. 2, 2012, pp. 67-73.

[13]   N. E. Buroker, X. H. Ning, Z. N. Zhou, K. Li, W. J. Cen, X. F. Wu, W. Z. Zhu, C. R. Scott and S. H. Chen, “AKT3, ANGPTL4, eNOS3, and VEGFA Associations with High Altitude Sickness in Han and Tibetan Chinese at the Qinghai-Tibetan Plateau,” International Journal of Hematology, Vol. 96, No. 2, 2012, pp. 200-213.

[14]   N. E. Buroker, X. H. Ning, Z. N. Zhou, K. Li, W. J. Cen, X. F. Wu, W. Z. Zhu, C. R. Scott and S. H. Chen, “VEGFA SNPs and Transcriptional Factor Binding Sites Associated with High Altitude Sickness in Han and Tibetan Chinese at the Qinghai-Tibetan Plateau,” The Journal of Physiological Sciences, Vol. 63, No. 3, 2013, pp. 183-193. doi:10.1007/s12576-013-0257-8

[15]   P. H. Hackett and R. C. Roach, “High-Altitude Illness,” The New England Journal of Medicine, Vol. 345, No. 2, 2001, pp. 107-114. doi:10.1056/NEJM200107123450206

[16]   P. Bartsch, D. M. Bailey, M. M. Berger, M. Knauth and R. W. Baumgartner, “Acute Mountain Sickness: Controversies and Advances,” High Altitude Medicine & Biology, Vol. 5, No. 2, 2004, pp. 110-124. doi:10.1089/1527029041352108

[17]   X. H. Ning and S. P. Li, “Health Care at High Altitude—Self-Care Universal Health Book,” Shanghai Science and Technology Publishing House, Shanghai, 2006, pp. 66-68.

[18]   C. Monge, “Chronic Mountain Sickness,” Physiological Reviews, Vol. 23, No. 1, 1943, pp. 166-184.

[19]   R. M. Winslow and C. C. E. Monge, “Hypoxia, Polycythemia, and Chronic Mountain Sickness,” Johns Hopkins University Press, 1987.

[20]   T. Y. Wu, W. S. Li, L. Y. Wei, et al., “A Preliminary Studies on the Diagonosis of Chronic Mountain Sickness in Tibetan Populations,” Press Commmittee of the 3rd World congress on Mountain Medicine and High Altitude Physiology, Matsumoto, 1998.

[21]   F. Leon-Velarde, R. G. McCullough, R. E. McCullough and J. T. Reeves, “Proposal for Scoring Severity in Chronic Mountain Sickness (CMS). Background and Conclusions of the CMS Working Group,” Advances in Experimental Medicine and Biology, Vol. 543, 2003, pp. 339-354. doi:10.1007/978-1-4419-8997-0_24

[22]   J. B. West, “The Physiologic Basis of High-Altitude Diseases,” Annals of Internal Medicine, Vol. 141, No. 10, 2004, pp. 789-800. doi:10.7326/0003-4819-141-10-200411160-00010

[23]   R. B. Schoene, “Illnesses at High Altitude,” Chest, Vol. 134, No. 2, 2008, pp. 402-416. doi:10.1378/chest.07-0561

[24]   K. P. Strohl, “Lessons in Hypoxic Adaptation from High-Altitude Populations,” Sleep and Breathing, Vol. 12, No. 2, 2008, pp. 115-121. doi:10.1007/s11325-007-0135-9

[25]   M. H. Wilson, S. Newman and C. H. Imray, “The Cerebral Effects of Ascent to High Altitudes,” The Lancet Neurology, Vol. 8, No. 2, 2009, pp. 175-191. doi:10.1016/S1474-4422(09)70014-6

[26]   D. Martin and J. Windsor, “From Mountain to Bedside: Understanding the Clinical Relevance of Human Acclimatisation to High-Altitude Hypoxia,” Postgraduate Medical Journal, Vol. 84, No. 998, 2008, pp. 622-627. doi:10.1136/pgmj.2008.068296

[27]   B. Su, J. Xiao, P. Underhill, R. Deka, W. Zhang, J. Akey, W. Huang, D. Shen, D. Lu, J. Luo, J. Chu, J. Tan, P. Shen, R. Davis, L. Cavalli-Sforza, R. Chakraborty, M. Xiong, R. Du, P. Oefner, Z. Chen and L. Jin, “Y-Chromosome Evidence for a Northward Migration of Modern Humans into Eastern Asia during the Last Ice Age,” The American Journal of Human Genetics, Vol. 65, No. 6, 1999, pp. 1718-1724. doi:10.1086/302680

[28]   B. Su, C. Xiao, R. Deka, M. T. Seielstad, D. Kangwan-pong, J. Xiao, D. Lu, P. Underhill, L. Cavalli-Sforza, R. Chakraborty and L. Jin, “Y Chromosome Haplotypes Reveal Prehistorical Migrations to the Himalayas,” Human Genetics, Vol. 107, No. , 2000, pp. 582-590. doi:10.1007/s004390000406

[29]   A. Torroni, J. A. Miller, L. G. Moore, S. Zamudio, J. Zhuang, T. Droma and D. C. Wallace, “Mitochondrial DNA Analysis in Tibet: Implications for the Origin of the Tibetan Population and Its Adaptation to High Altitude,” American Journal of Physical Anthropology, Vol. 93, No. 2, 1994, pp. 189-199. doi:10.1002/ajpa.1330930204

[30]   R. Du, C. Xiao and L. L. Cavalli-Sforza, “Genetic Distances between Chinese Populations Calculated on Gene Frequencies of 38 Loci,” Science in China Series C: Life Sciences, Vol. 40, No. 6, 1997, pp. 613-621. doi:10.1007/BF02882691

[31]   J. C. Knight, “Regulatory Polymorphisms Underlying Complex Disease Traits,” Journal of Molecular Medicine, Vol. 83, No. 2, 2005, pp. 97-109. doi:10.1007/s00109-004-0603-7

[32]   X. Wang, D. J. Tomso, B. N. Chorley, H. Y. Cho, V. G. Cheung, S. R. Kleeberger and D. A. Bell, “Identification of Polymorphic Antioxidant Response Elements in the Human Genome,” Human Molecular Genetics, Vol. 16, No. 10, 2007, pp. 1188-1200. doi:10.1093/hmg/ddm066

[33]   L. Prokunina and M. E. Alarcon-Riquelme, “Regulatory SNPs in Complex Diseases: Their Identification and Functional Validation,” Expert Reviews in Molecular Medicine, Vol. 6, No. 10, 2004, pp. 1-15. doi:10.1017/S1462399404007690

[34]   P. R. Buckland, “The Importance and Identification of Regulatory Polymorphisms and Their Mechanisms of Action,” Biochimica et Biophysica Acta (BBA)—Molecular Basis of Disease, Vol. 1762, No. 1, 2006, pp. 17-28. doi:10.1016/j.bbadis.2005.10.004

[35]   W. Sadee, D. Wang, A. C. Papp, J. K. Pinsonneault, R. M. Smith, R. A. Moyer and A. D. Johnson, “Pharmacogenomics of the RNA World: Structural RNA Polymorphisms in Drug Therapy,” Clinical Pharmacology & Therapeutics, Vol. 89, No. 3, 2011, pp. 355-365.

[36]   O. H. Hackett and O. Oelz, “The Diagnoses Accord with the Lake Louise Scoring System,” In: G. C. J. R. Sutton and C. S. Houston, Eds., Hypoxia and Mountainsickness, Pergamon Press, New York, 1992, pp. 327-330.

[37]   J. C. Bryne, E. Valen, M. H. Tang, T. Marstrand, O. Winther, I. da Piedade, A. Krogh, B. Lenhard and A. Sandelin, “JASPAR, the Open Access Database of Transcription Factor-Binding Profiles: New Content and Tools in the 2008 Update,” Nucleic Acids Research, Vol. 36, Suppl. 1, 2008, pp. D102-D106. doi:10.1093/nar/gkm955

[38]   A. Sandelin, W. Alkema, P. Engstrom, W. W. Wasserman and B. Lenhard, “JASPAR: An Open-Access Database for Eukaryotic Transcription Factor Binding Profiles,” Nucleic Acids Research, Vol. 32, Suppl. 1, 2004, pp. D91-D94. doi:10.1093/nar/gkh012

[39]   A. Sandelin, W. W. Wasserman and B. Lenhard, “Con-Site: Web-Based Prediction of Regulatory Elements Using Cross-Species Comparison,” Nucleic Acids Research, Vol. 32, Suppl. 2, 2004, pp. W249-W252. doi:10.1093/nar/gkh372

[40]   S. Aggarwal, S. Negi, P. Jha, P. K. Singh, T. Stobdan, M. A. Pasha, S. Ghosh, A. Agrawal, B. Prasher and M. Mukerji, “EGLN1 Involvement in High-Altitude Adaptation Revealed through Genetic Analysis of Extreme Constitution Types Defined in Ayurveda,” Proceedings of the National Academy of Sciences of the United States of America, Vol. 107, No. 44, 2010, pp. 18961-18966. doi:10.1073/pnas.1006108107

[41]   S. A. Gallagher and P. H. Hackett, “High-Altitude Illness,” Emergency Medicine Clinics of North America, Vol. 22, No. 2, 2004, pp. 329-355. doi:10.1016/j.emc.2004.02.001

[42]   B. Basnyat and D. R. Murdoch, “High-Altitude Illness,” The Lancet, Vol. 361, No. 9373, 2003, pp. 1967-1974. doi:10.1016/S0140-6736(03)13591-X

[43]   S. J. Jackson, J. Varley, C. Sellers, K. Josephs, L. Codrington, G. Duke, M. A. Njelekela, G. Drummond, A. I. Sutherland, A. A. Thompson and J. K. Baillie, “Incidence and Predictors of Acute Mountain Sickness among Trekkers on Mount Kilimanjaro,” High Altitude Medicine & Biology, Vol. 11, No. 3, 2010, pp. 217-222. doi:10.1089/ham.2010.1003

[44]   I. Singh, P. K. Khanna, M. C. Srivastava, M. Lal, S. B. Roy and C. S. Subramanyam, “Acute Mountain Sickness,” New England Journal of Medicine, Vol. 280, No. 4, 1969, pp. 175-184.

[45]   B. Basnyat, J. Lemaster and J. A. Litch, “Everest or Bust: A Cross Sectional, Epidemiological Study of Acute Mountainsickness at 4243 Meters in the Himalayas,” Aviation, Space, and Environmental Medicine, Vol. 70, No. 9. 1999, pp. 867-873.

[46]   M. Nemer and M. E. Horb, “The KLF Family of Transcriptional Regulators in Cardiomyocyte Proliferation and Differentiation,” Cell Cycle, Vol. 6, No. 2, 2007, pp. 117-121. doi:10.4161/cc.6.2.3718

[47]   Y. Liu, C. Zhang, J. Fan, L. Xiao, B. Yin, L. Zhou and S. Xia, “Comprehensive Analysis of Clinical Significance of Stem-Cell Related Factors in Renal Cell Cancer,” World Journal of Surgical Oncology, Vol. 9, 2011, p. 121. doi:10.1186/1477-7819-9-121

[48]   K. Takahashi, K. Tanabe, M. Ohnuki, M. Narita, T. Ichisaka, K. Tomoda and S. Yamanaka, “Induction of Pluripotent Stem Cells from Adult Human Fibroblasts by Defined Factors,” Cell, Vol. 131, No. 5, 2007, pp. 861-872. doi:10.1016/j.cell.2007.11.019

[49]   T. Suzuki, K. Aizawa, T. Matsumura and R. Nagai, “Vascular Implications of the Kruppel-Like Family of Transcription Factors,” Arteriosclerosis, Thrombosis, and Vascularbiology, Vol. 25, 2005, pp. 1135-1141. doi:10.1161/01.ATV.0000165656.65359.23

[50]   I. S. Kalra, M. M. Alam, P. K. Choudhary and B. S. Pace, “Kruppel-Like Factor 4 Activates HBG Gene Expression in Primary Erythroid Cells,” British Journal of Haematology, Vol. 154, No. 2, 2011, pp. 248-259. doi:10.1111/j.1365-2141.2011.08710.x

[51]   J. H. Shi, B. Zheng, S. Chen, G. Y. Ma and J. K. Wen, “Retinoic Acid Receptor Alpha Mediates All-trans-Retinoic Acid-Induced Klf4 Gene Expression by Regulating Klf4 Promoter Activity in Vascular Smooth Muscle Cells,” The Journal of Biological Chemistry, Vol. 287, 2012, pp. 10799-10811. doi:10.1074/jbc.M111.321836

[52]   P. M. Evans and C. Liu, “Roles of Krupel-Like Factor 4 in Normal Homeostasis, Cancer and Stem Cells,” Acta Biochimica et Biophysica Sinica, Vol. 40, No. 7, 2008, pp. 554-564.