Clinical Autonomic Research

, 19:335

A role for succinate dehydrogenase genes in low chemoresponsiveness to hypoxia?

  • Jean-Paul Richalet
  • Anne-Paule Gimenez-Roqueplo
  • Séverine Peyrard
  • Annabelle Vénisse
  • Laure Marelle
  • Nelly Burnichon
  • Anissa Bouzamondo
  • Xavier Jeunemaitre
  • Michel Azizi
  • Jean-Luc Elghozi
Research Article

Abstract

The detection of hypoxia by the carotid bodies elicits a ventilatory response of utmost importance for tolerance to high altitude. Germline mutations in three genes encoding subunit B, C and D of succinate dehydrogenase (SDHB, SDHC and SDHD) have been associated with paragangliomas of the carotid body. We hypothesized that SDH dysfunction within the carotid body could result in low chemoresponsiveness and intolerance to high altitude. The frequency of polymorphisms of SDHs, hypoxia-inducible factor type 1 (HIF1α) and angiotensin converting enzyme (ACE) genes was compared between 40 subjects with intolerance to high altitude and a low hypoxic ventilatory response at exercise (HVRe ≤ 0.5 ml min−1 kg−1; HVR− group) and 41 subjects without intolerance to high altitude and a high HVRe (≥0.80 ml min−1 kg−1; HVR+). We found no significant association between low or high HVRe and (1) the allele frequencies for nine single nucleotide polymorphisms (SNPs) in the SDHD and SDHB genes, (2) the ACE insertion/deletion polymorphism and (3) four SNPs in the HIF1α gene. However, a marginal significant association was found between the synonymous polymorphism c.18A>C of the SDHB gene and chemoresponsiveness: 8/40 (20%) in the HVR− group and 3/41 (7%) in the HVR+ group (p = 0.12). A principal component analysis showed that no subject carrying the 18C allele had both high ventilatory and cardiac response to hypoxia. In conclusion, no clear association was found between gene variants involved in oxygen sensing and chemoresponsiveness, although some mutations in the SDHB and SDHD genes deserve further investigations in a larger population.

Keywords

Altitude tolerance Hypoxia Carotid bodies Ventilation 

References

  1. 1.
    Aldashev AA, Sarybaev AS, Sydykov AS, Kalmyrzaev BB, Kim EV, Mamanova LB, Maripov R, Kojonazarov BK, Mirrakhimov MM, Wilkins MR, Morrell NW (2002) Characterization of high-altitude pulmonary hypertension in the Kyrgyz: association with angiotensin-converting enzyme genotype. Am J Respir Crit Care Med 166:1396–1402CrossRefPubMedGoogle Scholar
  2. 2.
    Amar L, Bertherat J, Baudin E, Ajzenberg C, Bressac-de Paillerets B, Chabre O, Chamontin B, Delemer B, Giraud S, Murat A, Niccoli-Sire P, Richard S, Rohmer V, Sadoul JL, Strompf L, Schlumberger M, Bertagna X, Plouin PF, Jeunemaitre X, Gimenez-Roqueplo AP (2005) Genetic testing in pheochromocytoma or functional paraganglioma. J Clin Oncol 23:8812–8818CrossRefPubMedGoogle Scholar
  3. 3.
    Appenzeller O, Minko T, Qualls C, Pozharov V, Gamboa J, Gamboa A, Wang Y (2006) Gene expression, autonomic function and chronic hypoxia:lessons from the Andes. Clin Auton Res 16:217–222CrossRefPubMedGoogle Scholar
  4. 4.
    Astrom K, Cohen JE, Willett-Brozick JE, Aston CE, Baysal BE (2003) Altitude is a phenotypic modifier in hereditary paraganglioma type 1: evidence for an oxygen-sensing defect. Hum Genet 113:228–237CrossRefPubMedGoogle Scholar
  5. 5.
    Basnyat B, Murdoch DR (2003) High-altitude illness. Lancet 361:1967–1974CrossRefPubMedGoogle Scholar
  6. 6.
    Baysal B (2006) A phenotypic perspective on mammalian oxygen sensor candidates. Ann N Y Acad Sci 1073:221–233CrossRefPubMedGoogle Scholar
  7. 7.
    Bigham AW, Kiyamu M, León-Velarde F, Parra EJ, Rivera-Ch M, Shriver MD, Brutsaert TD (2008) Angiotensin-converting enzyme genotype and arterial oxygen saturation at high altitude in Peruvian Quechua. High Alt Med Biol 9:167–178CrossRefPubMedGoogle Scholar
  8. 8.
    Brugniaux JV, Schmitt L, Robach P, Jeanvoine H, Zimmermann H, Nicolet G, Duvallet A, Fouillot J-P, Richalet J-P (2006) Living high-training low: tolerance and acclimatization in elite endurance athletes. Eur J Appl Physiol 96:66–77CrossRefPubMedGoogle Scholar
  9. 9.
    Burtscher M, Flatz M, Faulhaber M (2004) Prediction of susceptibility to acute mountain sickness by SaO2 values during short-term exposure to hypoxia. High Alt Med Biol 5:335–340PubMedGoogle Scholar
  10. 10.
    Dehnert C, Weymann J, Montgomery HE, Woods D, Maggiorini M, Scherrer U, Gibbs JS, Bärtsch P (2002) No association between high-altitude tolerance and the ACE I/D gene polymorphism. Med Sci Sports Exerc 34:1928–1933CrossRefPubMedGoogle Scholar
  11. 11.
    Droma Y, Hanaoka M, Ota M, Katsuyama Y, Koizumi T, Fujimoto K, Kobayashi T, Kubo K (2002) Positive association of the endothelial nitric oxide synthase gene polymorphisms with high-altitude pulmonary edema. Circulation 106:826–830CrossRefPubMedGoogle Scholar
  12. 12.
    Gao W, Gao Y, Zhang G, Song L, Sun B, Shi J (2005) Hypoxia-induced expression of HIF-1alpha and its target genes in umbilical venous endothelial cells of Tibetans and immigrant Han. Comp Biochem Physiol C Toxicol Pharmaco 141:93–100CrossRefGoogle Scholar
  13. 13.
    Gimenez-Roqueplo AP, Burnichon N, Amar L, Favier J, Jeunemaitre X, Plouin PF (2008) Recent advances in the genetics of phaeochromocytoma and functional paraganglioma. Clin Exp Pharmacol Physiol 35:376–379CrossRefPubMedGoogle Scholar
  14. 14.
    Hackett PH, Roach RC (2004) High altitude cerebral edema. High Alt Med Biol 5:136–146CrossRefPubMedGoogle Scholar
  15. 15.
    Hanaoka M, Droma Y, Hotta J, Matsuzawa Y, Kobayashi T, Kubo K, Ota M (2003) Polymorphisms of the tyrosine hydroxylase gene in subjects susceptible to high-altitude pulmonary edema. Chest 123:54–58CrossRefPubMedGoogle Scholar
  16. 16.
    Hohenhaus E, Paul A, McCullough RE, Kucherer H, Bartsch P (1995) Ventilatory and pulmonary vascular response to hypoxia and susceptibility to high altitude pulmonary oedema. Eur Respir J 8:1825–1833CrossRefPubMedGoogle Scholar
  17. 17.
    Hotta J, Hanaoka M, Droma Y, Katsuyama Y, Ota M, Kobayashi T (2004) Polymorphisms of renin-angiotensin system genes with high-altitude pulmonary edema in Japanese subjects. Chest 126:825–830CrossRefPubMedGoogle Scholar
  18. 18.
    Huang J, Lemire BD (2009) Mutations in the C. elegans succinate dehydrogenase iron–sulfur subunit promote superoxide generation and premature aging. J Mol Biol 3:559–569CrossRefGoogle Scholar
  19. 19.
    Jedlickova K, Stockton DW, Chen H, Stray-Gundersen J, Witkowski S, Ri-Li G, Jelinek J, Levine BD, Prchal JT (2003) Search for genetic determinants of individual variability of the erythropoietin response to high altitude. Blood Cells Mol Dis 31:175–182CrossRefPubMedGoogle Scholar
  20. 20.
    Koehle MS, Wang P, Guenette JA, Rupert JL (2006) No association between variants in the ACE and angiotensin II receptor 1 genes and acute mountain sickness in Nepalese pilgrims to the Janai Purnima Festival at 4380 m. High Alt Med Biol 7:281–289CrossRefPubMedGoogle Scholar
  21. 21.
    León-Velarde F, Mejía O (2008) Gene expression in chronic high altitude diseases. High Alt Med Biol 9:130–139CrossRefPubMedGoogle Scholar
  22. 22.
    Mejía OM, Prchal J, León-Velarde F, Hurtado A, Stockton DW (2005) Genetic association analysis of chronic mountain sickness in an Andean high-altitude population. Heamatologica 90:13–19Google Scholar
  23. 23.
    Mortimer H, Patel S, Peacock AJ (2004) The genetic basis of high-altitude pulmonary oedema. Pharmacol Ther 101:183–192CrossRefPubMedGoogle Scholar
  24. 24.
    Richalet JP, Kéromès A, Dersch B, Corizzi F, Mehdioui H, Pophillat B, Chardonnet H, Tassery F, Herry JP, Rathat C, Chaduteau C, Darnaud B (1988) Caractéristiques physiologiques des alpinistes de haute altitude. Sci Sport 3:89–108CrossRefGoogle Scholar
  25. 25.
    Richalet JP (1995) High-altitude pulmonary oedema. Still a place for controversy? Thorax 50:923–929CrossRefPubMedGoogle Scholar
  26. 26.
    Richalet JP, Herry JP (2006) Médecine de l’alpinisme et des sports de montagne, 4th edn. Masson, ParisGoogle Scholar
  27. 27.
    Rivera-Ch M, Huicho L, Bouchet P, Richalet JP, León-Velarde F (2008) Effect of acetazolamide on ventilatory response in subjects with chronic mountain sickness. Respir Physiol Neurobiol 162:184–189CrossRefPubMedGoogle Scholar
  28. 28.
    Rodríguez-Cuevas S, López-Garza J, Labastida-Almendaro S (1998) Carotid body tumors in inhabitants of altitudes higher than 2000 meters above sea level. Head Neck 20:374–378CrossRefPubMedGoogle Scholar
  29. 29.
    Rupert JL, Koehle MS (2006) Evidence for a genetic basis for altitude-related illness. High Alt Med Biol 7:150–167CrossRefPubMedGoogle Scholar
  30. 30.
    Saxena S, Kumar R, Madan T, Gupta V, Muralidhar K, Sarma PU (2005) Association of polymorphisms in pulmonary surfactant protein A1 and A2 genes with high-altitude pulmonary edema. Chest 128:1611–1619CrossRefPubMedGoogle Scholar
  31. 31.
    Suzuki K, Kizaki T, Hitomi Y, Nukita M, Kimoto K, Miyazawa N, Kobayashi K, Ohnuki Y, Ohno H (2003) Genetic variation in hypoxia-inducible factor 1alpha and its possible association with high altitude adaptation in Sherpas. Med Hypotheses 61:385–389CrossRefPubMedGoogle Scholar
  32. 32.
    The Lake Louise Consensus on The Definition and Quantification of Altitude Illness (1992) In: Sutton JR, Coates G, Houston CS (eds) Hypoxia and mountain medicine. Queen City Printers Inc., Burlington, pp 327–330Google Scholar
  33. 33.
    Thompson J, Raitt J, Hutchings L, Drenos F, Bjargo E, Loset A, Grocott M, Montgomery H, Caudwell Xtreme Everest Research Group (2007) Angiotensin-converting enzyme genotype and successful ascent to extreme high altitude. High Alt Med Biol 8:278–285CrossRefPubMedGoogle Scholar
  34. 34.
    Williams AG, Rayson MP, Jubb M, World M, Woods DR, Hayward M, Martin J, Humphries SE, Montgomery HE (2000) The ACE gene and muscle performance. Nature 403:614CrossRefPubMedGoogle Scholar
  35. 35.
    Zhou F, Wang F, Li F, Yuan J, Zeng H, Wei Q, Tanguay RM, Wu T (2005) Association of hsp70-2 and hsp-hom gene polymorphisms with risk of acute high-altitude illness in a Chinese population. Cell Stress Chaperones 10:349–356CrossRefPubMedGoogle Scholar

Copyright information

© Springer-Verlag 2009

Authors and Affiliations

  • Jean-Paul Richalet
    • 1
    • 2
  • Anne-Paule Gimenez-Roqueplo
    • 4
    • 5
    • 6
    • 9
  • Séverine Peyrard
    • 7
    • 8
    • 9
  • Annabelle Vénisse
    • 4
    • 5
    • 6
    • 9
  • Laure Marelle
    • 7
  • Nelly Burnichon
    • 4
    • 5
    • 6
    • 7
  • Anissa Bouzamondo
    • 10
  • Xavier Jeunemaitre
    • 4
    • 5
    • 6
    • 9
  • Michel Azizi
    • 7
    • 8
    • 9
  • Jean-Luc Elghozi
    • 3
    • 9
  1. 1.Université Paris 13, UFR SMBH EA2363Bobigny CedexFrance
  2. 2.AP-HP, Hôpital Avicenne, Service de Physiologie, Explorations Fonctionnelles et Médecine du SportBobignyFrance
  3. 3.AP-HP, Hôpital Necker, UF de Pharmacologie CliniqueParisFrance
  4. 4.AP-HP, Hôpital Européen Georges Pompidou, Département de GénétiqueParisFrance
  5. 5.INSERMParisFrance
  6. 6.Collège de FranceParisFrance
  7. 7.AP-HP, Hôpital Européen Georges Pompidou, Centre d’Investigations Cliniques 9201ParisFrance
  8. 8.INSERM, Centre d’Investigations Cliniques 9201ParisFrance
  9. 9.Université Paris DescartesParisFrance
  10. 10.Société Française de CardiologieParisFrance

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