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Synergistic effect of the genetic polymorphisms of the renin–angiotensin–aldosterone system on high-altitude pulmonary edema: a study from Qinghai-Tibet altitude

  • GENETIC EPIDEMIOLOGY
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Abstract

The pathogenesis of high-altitude pulmonary edema (HAPE) has been at least partially attributed to the local dysregulation of the renin–angiotensin–aldosterone system (RAAS) cascade. To address this issue, we conducted the largest nested case-control study to-date to explore the association between variations in RAAS genes and HAPE in Chinese population. We recruited 140 HAPE patients and 144 controls during the construction of Qinghai-Tibet railway and genotyped 10 gene polymorphisms evenly interspersed in 5 RAAS candidate genes. The data were analyzed by haplotype and multifactor dimensionality reduction (MDR). The single-locus analysis showed that CYP11B2 C-344T and K173R and ACE A-240T polymorphisms were significantly associated with HAPE after Bonferroni correction (P < 0.005). The linkage analysis constructed a linkage block including C-344T and K173R polymorphisms in complete linkage disequilibrium with each other, while occurred with significantly different frequencies between HAPE and control groups. The gene-gene interaction analysis found the overall best model including ACE A-240T and A2350G and CYP11B2 C-344T polymorphisms with strong synergistic effect. This model had a maximum testing accuracy of 68.61% and a maximum cross validation consistency of 9 out of 10 (P = 0.004). The homozygous genotype combination of −240AA, 2350GG and −344TT conferred high genetic susceptibility to HAPE, which was further strengthened by haplotype analysis. Our results add evidence for synergistic effect of RAAS gene polymorphisms on HAPE susceptibility. Moreover, we proposed a promising data-mining analytical approach (MDR) for detecting and characterizing gene-gene interactions.

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References

  1. Bartsch P, Mairbaurl H, Maggiorini M, Swenson ER. Physiological aspects of high-altitude pulmonary edema. J Appl Physiol 2005;98:1101–10.

    Article  PubMed  CAS  Google Scholar 

  2. Maggiorini M, Leon-Velarde F. High-altitude pulmonary hypertension: a pathophysiological entity to different diseases. Eur Respir J 2003;22:1019–25.

    PubMed  CAS  Google Scholar 

  3. Mortimer H, Patel S, Peacock AJ. The genetic basis of high-altitude pulmonary oedema. Pharmacol Ther 2004;101:183–92.

    Article  PubMed  CAS  Google Scholar 

  4. Moore JH. The ubiquitous nature of epistasis in determining susceptibility to common human diseases. Hum Hered 2003;56:73–82.

    Article  PubMed  Google Scholar 

  5. Moore JH, Williams SM. Traversing the conceptual divide between biological and statistical epistasis: systems biology and a more modern synthesis. Bioessays 2005;27:637–46.

    Article  PubMed  CAS  Google Scholar 

  6. Hultgren HN, Grover RF, Hartley LH. Abnormal circulatory responses to high altitude in subjects with a previous history of high-altitude pulmonary edema. Circulation 1971;44:759–70.

    PubMed  CAS  Google Scholar 

  7. Eldridge MW, Podolsky A, Richardson RS, Johnson DH, Knight DR, Johnson EC, Hopkins SR, Michimata H, Grassi B, Feiner J, Kurdak SS, Bickler PE, Wagner PD, Severinghaus JW. Pulmonary hemodynamic response to exercise in subjects with prior high-altitude pulmonary edema. J Appl Physiol 1996;81:911–21.

    PubMed  CAS  Google Scholar 

  8. Basnyat B, Murdoch DR. High-altitude illness. Lancet 2003;361:1967–74.

    Article  PubMed  Google Scholar 

  9. Hotta J, Hanaoka M, Droma Y, Droma Y, Katsuyama Y, Ota M, Kobayashi T. Polymorphisms of renin-angiotensin system genes with high-altitude pulmonary edema in Japanese subjects. Chest 2004;126:825–30.

    Article  PubMed  CAS  Google Scholar 

  10. Montgomery HE, Marshall R, Hemingway H, Myerson S, Clarkson P, Dollery C, Hayward M, Holliman DE, Jubb M, World M, Thomas EL, Brynes AE, Saeed N, Barnard M, Bell JD, Prasad K, Rayson M, Talmud PJ, Humphries SE. Human gene for physical performance. Nature 1998;393:221–2.

    Article  PubMed  CAS  Google Scholar 

  11. Woods DR, Montgomery HE. Angiotensin-converting enzyme and genetics at high altitude. High Alt Med Biol 2001;2:201–10.

    Article  PubMed  CAS  Google Scholar 

  12. Qadar Pasha MA, Khan AP, Kumar R, Grover SK, Ram RB, Norboo T, Srivastava KK, Selvamurthy W, Brahmachari SK. Angiotensin converting enzyme insertion allele in relation to high altitude adaptation. Ann Hum Genet 2001;65:531–6.

    Article  PubMed  CAS  Google Scholar 

  13. Woods DR, Pollard AJ, Collier DJ, Jamshidi Y, Vassiliou V, Hawe E, Humphries SE, Montgomery HE. Insertion/deletionpolymorphism of the angiotensin I-converting enzyme gene and artery oxygen saturation at high altitude. Am J Respir Crit Care Med 2002;166:362–6.

    Article  PubMed  Google Scholar 

  14. Keynes RJ, Smith GW, Slater JD, Brown MM, Brown SE, Payne NN, Jowett TP, Monge CC. Renin and aldosterone at high altitude in man. J Endocrinol 1982;92:131–40.

    PubMed  CAS  Google Scholar 

  15. Morrell NW, Morris KG, Stenmark KR. Role of angiotensin-converting enzyme and angiotensin II in development of hypoxia pulmonary hypertension. Am J Physiol 1995;269:H1186–94.

    PubMed  CAS  Google Scholar 

  16. Kumar R, Pasha Q, Khan AP, Gupta V. Renin angiotensin aldosterone system and ACE I/D gene polymorphism in high-altitude pulmonary edema. Aviat Space Environ Med 2004;75:981–3.

    PubMed  CAS  Google Scholar 

  17. Moore JH, Williams SM. New strategies for identifying gene-gene interactions in hypertension. Ann Med 2002;34:88–95.

    Article  PubMed  CAS  Google Scholar 

  18. Ritchie MD, Hahn LW, Roodi N, Bailey LR, Dupont WD, Parl FF, Moore JH. Multifactor-dimensionality reduction reveals high-order interactions among estrogen-metabolism genes in sporadic breast cancer. Am J Hum Genet 2001;69:138–47.

    Article  PubMed  CAS  Google Scholar 

  19. Ritchie MD, Hahn LW, Moore JH. Power of multifactor dimensionality reduction for detecting gene-gene interactions in the presence of genotyping error, missing data, phenocopy, and genetic heterogeneity. Genet Epidemiol 2003;24:150–7.

    Article  PubMed  Google Scholar 

  20. Hahn LW, Moore JH. Ideal discrimination of discrete clinical endpoints using multilocus genotypes. In Silico Biol 2004;4:183–94.

    PubMed  CAS  Google Scholar 

  21. Moore JH. Computational analysis of gene-gene interactions using multifactor dimensionality reduction. Expert Rev Mol Diagn 2004;4:795–803.

    Article  PubMed  CAS  Google Scholar 

  22. Moore JH, Gilbert JC, Tsai CT, Chiang FT, Holden T, Barney N, White BC. A flexible computational framework for detecting, characterizing, and interpreting statistical patterns of epistasis in genetic studies of human disease susceptibility. J Theor Biol 2006;241:252–61.

    Article  PubMed  Google Scholar 

  23. Martin ER, Ritchie MD, Hahn L, Kang S, Moore JH. A novel method to identify gene-gene effects in nuclear families: the MDR-PDT. Genet Epidemiol 2006;30:111–23.

    Article  PubMed  CAS  Google Scholar 

  24. Millstein J, Conti DV, Gilliland FD, Gauderman WJ. A testing framework for identifying susceptibility genes in the presence of epistasis. Am J Hum Genet 2006;78:15–27.

    Article  PubMed  CAS  Google Scholar 

  25. Andrew AS, Nelson HH, Kelsey KT, Moore JH, Meng AC, Casella DP, Tosteson TD, Schned AR, Karagas MR. Concordance of multiple analytical approaches demonstrates a complex relationship between DNA repair gene SNPs, smoking and bladder cancer susceptibility. Carcinogenesis 2006;27:1030–7.

    Article  PubMed  CAS  Google Scholar 

  26. Sanada H, Yatabe J, Midorikawa S, Hashimoto S, Watanabe T, Moore JH, Ritchie MD, Williams SM, Pezzullo JC, Sasaki M, Eisner GM, Jose PA, Felder RA. Single-nucleotide polymorphisms for diagnosis of salt-sensitive hypertension. Clin Chem 2006;52:352–60.

    Article  PubMed  CAS  Google Scholar 

  27. Brassat D, Motsinger AA, Caillier SJ, Erlich HA, Walker K, Steiner LL, Cree BA, Barcellos LF, Pericak-Vance MA, Schmidt S, Gregory S, Hauser SL, Haines JL, Oksenberg JR, Ritchie MD. Multifactor dimensionality reduction reveals gene-gene interactions associated with multiple sclerosis susceptibility in African Americans. Genes Immun 2006;7:310–5.

    Article  PubMed  CAS  Google Scholar 

  28. Cho YM, Ritchie MD, Moore JH, Park JY, Lee KU, Shin HD, Lee HK, Park KS. Multifactor-dimensionality reduction shows a two-locus interaction associated with Type 2 diabetes mellitus. Diabetologia 2004;47:549–54.

    Article  PubMed  CAS  Google Scholar 

  29. Zapata C, Carollo C, Rodriguez S. Sampling variance and distribution of the D’ measure of overall gametic disequilibrium between multiallelic loci. Ann Hum Genet 2001;65:395–406.

    Article  PubMed  CAS  Google Scholar 

  30. Moore JH, White BC. Tuning ReliefF for genome-wide genetic analysis. Lect Notes Comput Sci 2007;4447:166–75.

    Article  Google Scholar 

  31. Hahn LW, Ritchie MD, Moore JH. Multifactor dimensionality reduction software for detecting gene-gene and gene-environment interactions. Bioinformatics 2003;19:376–82.

    Article  PubMed  CAS  Google Scholar 

  32. The International HapMap Consortium. The International HapMap Project. Nature 2003;426:789–96.

    Article  CAS  Google Scholar 

  33. Moore JH, Ritchie MD. The challenges of whole-genome approaches to common diseases. JAMA 2004;291:1642–3.

    Article  PubMed  CAS  Google Scholar 

  34. Tsai CT, Lai LP, Lin JL, Chiang FT, Hwang JJ, Ritchie MD, Moore JH, Hsu KL, Tseng CD, Liau CS, Tseng YZ. Renin-angiotensin system gene polymorphisms and atrial fibrillation. Circulation 2004;109:1640–6.

    Article  PubMed  CAS  Google Scholar 

  35. Frankel WN, Schork NJ. Who’s afraid of epistasis? Nat Genet 1996;14:371–3.

    Article  PubMed  CAS  Google Scholar 

  36. Erdos EG. Conversion of angiotensin I to angiotensin II. Am J Med 1976;60:749–59.

    Article  PubMed  CAS  Google Scholar 

  37. Cargill RI, Lipworth BJ. Lisinopril attenuates acute hypoxic pulmonary vasoconstriction in humans. Chest 1996;109:424–9.

    Article  PubMed  CAS  Google Scholar 

  38. Clyne CD, Zhang Y, Slutsker L, Mathis JM, White PC, Rainey WE. Angiotensin II and potassium regulate human CYP11B2 transcription through common cis-elements. Mol Endocrinol 1997;11:638–49.

    Article  PubMed  CAS  Google Scholar 

  39. Hackett PH, Rennie D, Hofmeister SE, Grover RF, Grover EB, Reeves JT. Fluid retention and relative hypoventilation in acute mountain sickness. Respiration 1982;43:321–9.

    Article  PubMed  CAS  Google Scholar 

  40. Cox NJ, Bell GI. Disease associations. Chance, artifact, or susceptibility genes. Diabetes 1989;38:947–50.

    Article  PubMed  CAS  Google Scholar 

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Acknowledgements

We heartily thank the kind assistance and support of the faculty and doctors at battlefront. We also gratefully thank the dedicators for their enthusiastic participation. Our work is supported by three item National Science Foundation of China (Grant No. 30393130, 30470651 and 30271152) and National Basic Research Program (973 project) (2006 CB 504163).

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Authors and Affiliations

  1. National Laboratory of Medical Molecular Biology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences/Peking Union Medical College (CAMS/PUMC), No.5 Dong Dan San Tiao, Beijing, 100005, China

    Yue Qi, Wenquan Niu, Wenyu Zhou & Changchun Qiu

  2. Hospital of China Railway Construction Corporation, Geermu, Qing Hai Province, China

    Tongchun Zhu

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  1. Yue Qi
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  2. Wenquan Niu
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Correspondence to Changchun Qiu.

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Qi, Y., Niu, W., Zhu, T. et al. Synergistic effect of the genetic polymorphisms of the renin–angiotensin–aldosterone system on high-altitude pulmonary edema: a study from Qinghai-Tibet altitude. Eur J Epidemiol 23, 143–152 (2008). https://doi.org/10.1007/s10654-007-9208-0

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