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Molecular Biology Reports

, Volume 39, Issue 4, pp 4697–4708 | Cite as

Mitochondrial genetic background plays a role in increasing risk to asthma

  • Emily Zifa
  • Zoe Daniil
  • Eleutheria Skoumi
  • Maria Stavrou
  • Kostantinos Papadimitriou
  • Marini Terzenidou
  • Konstantinos Kostikas
  • Vasileios Bagiatis
  • Konstantinos I. Gourgoulianis
  • Zissis Mamuris
Article

Abstract

A number of studies suggest that mitochondrial dysfunction plays a role in the pathogenesis of asthma. To shed light for the first time on the role of the mitochondrial genome in the etiology of asthma we analyzed the mitochondrial tRNA genes and part of their flanking regions in patients with asthma compared with a set of healthy controls. We found a total of 10 mutations in 56 out of 76 asthmatic patients. Four of these mutations were not found in the control group, five were observed at a significantly lower frequency in controls, but none of the combinations of mutations detected in asthma patients was observed in the controls. Furthermore, we observed that 27.6% of the asthma patients (vs. 4% of the controls) belonged to the haplogroup U (Fisher test P = 0.00) and a positive significant correlation was found between the occurrence of the haplogroup U and the severity of the disease (Fisher test P = 0.02). Whereas further studies in larger cohorts are needed to confirm these observations we suggest that the mitochondrial genetic background plays a key role in asthma development.

Keywords

Mitochondrial RNA Mutations Asthma Haplogroup U 

Notes

Acknowledgments

This work was financed by the Postgraduate Courses “Biotechnology-quality Assessment in Nutrition and the Environment” and “Applications of Molecular Biology-Genetics. Diagnostic Biomarkers” of the Department of Biochemistry and Biotechnology, University of Thessaly, Greece.

References

  1. 1.
    Global initiative for asthma. Global Strategy for Asthma Management and Prevention (2009 update) www.ginasthma.com/
  2. 2.
    Borish L, Culp JA (2008) Asthma: a syndrome composed of heterogeneous diseases. Ann Allergy Asthma Immunol 101:1–8PubMedCrossRefGoogle Scholar
  3. 3.
    Holgate ST (1999) Genetic and environmental interaction in allergy and asthma. J Allergy Clin Immunol 104:1139–1146PubMedCrossRefGoogle Scholar
  4. 4.
    Burke W, Fesinmeyer M, Reed K, Hampson L, Carlsten C (2003) Family history as a predictor of asthma risk. Am J Prev Med 24:160–169PubMedCrossRefGoogle Scholar
  5. 5.
    von Mutius E (2009) Gene-environment interactions in asthma. J Allergy Clin Immunol 123:3–11CrossRefGoogle Scholar
  6. 6.
    Holloway JW, Beghe B, Holgate ST (1999) The genetic basis of atopic asthma. Clin Exp Allergy 29:1023–1032PubMedCrossRefGoogle Scholar
  7. 7.
    Vercelli D (2008) Discovering susceptibility genes for asthma and allergy. Nat Rev Immunol 8:169–182PubMedCrossRefGoogle Scholar
  8. 8.
    Postma DS, Koppelman GH (2009) Genetics of asthma: where are we and where do we go? Proc Am Thorac Soc 6:283–287PubMedCrossRefGoogle Scholar
  9. 9.
    Cox L (2008) Allergen immunotherapy and asthma: efficacy, safety, and other considerations. Allergy Asthma Proc 29:580–589PubMedCrossRefGoogle Scholar
  10. 10.
    Henricks PA, Nijkamp FP (2001) Reactive oxygen species as mediators in asthma. Pulm Pharmacol Ther 14:409–420PubMedCrossRefGoogle Scholar
  11. 11.
    Hansen JM, Zhang H, Jones DP (2006) Mitochondrial thioredoxin-2 has a key role in determining tumor necrosis factor-alpha-induced reactive oxygen species generation, NF-kappaB activation, and apoptosis. Toxicol Sci 91:643–650PubMedCrossRefGoogle Scholar
  12. 12.
    Marí M, Morales A, Colell A, García-Ruiz C, Fernández-Checa JC (2009) Mitochondrial glutathione, a key survival antioxidant. Antioxid Redox Signal 11:2685–2700PubMedCrossRefGoogle Scholar
  13. 13.
    Kuwano K (2007) Epithelial cell apoptosis and lung remodeling. Cell Mol Immunol 4:419–429PubMedGoogle Scholar
  14. 14.
    Lee YA, Shin MH (2009) Mitochondrial respiration is required for activation of ERK1/2 and caspase-3 in human eosinophils stimulated with hydrogen peroxide. J Investig Allergol Clin Immunol 19:188–194PubMedGoogle Scholar
  15. 15.
    Konrádová V, Copová C, Suková B, Houstĕk J (1985) Ultrastructure of the bronchial epithelium in three children with asthma. Pediatr Pulmonol 1:182–187PubMedCrossRefGoogle Scholar
  16. 16.
    Hayashi T, Ishii A, Nakai S, Hasegawa K (2004) Ultrastructure of goblet-cell metaplasia from Clara cell in the allergic asthmatic airway inflammation in a mouse model of asthma in vivo. Virchows Arch 444:66–73PubMedCrossRefGoogle Scholar
  17. 17.
    Mabalirajan U, Dinda AK, Kumar S, Roshan R, Gupta P, Sharma SK, Ghosh B (2008) Mitochondrial structural changes and dysfunction are associated with experimental allergic asthma. J Immunol 181:3540–3548PubMedGoogle Scholar
  18. 18.
    Mabalirajan U, Dinda AK, Sharma SK, Ghosh B (2009) Esculetin restores mitochondrial dysfunction and reduces allergic asthma features in experimental murine model. J Immunol 183:2059–2067PubMedCrossRefGoogle Scholar
  19. 19.
    Robertson JD, Orrenius S (2000) Molecular mechanisms of apoptosis induced by cytotoxic chemicals. Crit Rev Toxicol 30:609–627PubMedCrossRefGoogle Scholar
  20. 20.
    Nel AE, Diaz-Sanchez D, Li N (2001) The role of particulate pollutants in pulmonary inflammation and asthma: evidence for the involvement of organic chemicals and oxidative stress. Curr Opin Pulm Med 7:20–26PubMedCrossRefGoogle Scholar
  21. 21.
    Li N, Sioutas C, Cho A, Schmitz D, Misra C, Sempf J, Wang M, Oberley T, Froines J, Nel A (2003) Ultrafine particulate pollutants induce oxidative stress and mitochondrial damage. Environ Health Perspect 111:455–460PubMedCrossRefGoogle Scholar
  22. 22.
    Aguilera-Aguirre L, Bacsi A, Saavedra-Molina A, Kurosky A, Sur S, Boldogh I (2009) Mitochondrial dysfunction increases allergic airway inflammation. J Immunol 183:5379–5387PubMedCrossRefGoogle Scholar
  23. 23.
    Fahn HJ, Wang LS, Kao SH, Chang SC, Huang MH, Wei YH (1998) Smoking-associated mitochondrial DNA mutations and lipid peroxidation in human lung tissues. Am J Respir Cell Mol Biol 19:901–909PubMedGoogle Scholar
  24. 24.
    Fukuda T, Mochida S, Fukushima Y, Makino S (1995) Detection of allergen-induced genes in peripheral blood mononuclear cells of patients with allergic asthma using subtractive hybridization. J Allergy Clin Immunol 96:1076–1082PubMedCrossRefGoogle Scholar
  25. 25.
    Polonikov AV, Ivanov VP, Solodilova MA, Kozhukhov MA, Panfilov VI, Bulgakova IV (2009) Polymorphism -930A > G of the cytochrome b gene is a novel genetic marker of predisposition to bronchial asthma. Ter Arkh 81:31–35PubMedGoogle Scholar
  26. 26.
    Jones M, Mitchell P, Wang JJ, Sue C (2004) MELAS A3243G mitochondrial DNA mutation and age related maculopathy. Am J Ophthalmol 138:1051–1053PubMedCrossRefGoogle Scholar
  27. 27.
    Shanske AL, Shanske S, Silvestri G, Tanji K, Wertheim D, Lipper S (1993) MELAS point mutation with unusual clinical presentation. Neuromuscul Disord 3:191–193PubMedCrossRefGoogle Scholar
  28. 28.
    Schmuczerova J, Brdicka R, Dostal M, Sram RJ, Topinka J (2009) Genetic variability of HVRII mtDNA in cord blood and respiratory morbidity in children. Mutat Res 666:1–7PubMedCrossRefGoogle Scholar
  29. 29.
    Rabe KF, Hurd S, Anzueto A, Barnes PJ, Buist SA, Calverley P, Fukuchi Y, Jenkins C, Rodriguez-Roisin R, van Weel C, Zielinski J (2007) Global strategy for the diagnosis, management, and prevention of chronic obstructive pulmonary disease: GOLD executive summary. Am J Respir Crit Care Med 176:532–555PubMedCrossRefGoogle Scholar
  30. 30.
    Wenzel SE, Fahy JV, Irvin CG, Peters SP, Spector S, Szefler SJ (2000) Proceedings of the ATS Workshop on Refractory Asthma: current understanding, recommendations and unanswered questions. Am J Respir Crit Care Med 162:2341–2351Google Scholar
  31. 31.
    Lewin HA, Stewart-Haynes JA (1992) A simple method for DNA extraction from leukocytes for use in PCR. Biotechniques 13:522–524PubMedGoogle Scholar
  32. 32.
    Orita M, Iwahana H, Kanazawa H, Hayashi K, Sekiya T (1989) Detection of polymorphisms of human DNA by gel electrophoresis as single-strand conformation polymorphisms. Proc Natl Acad Sci (USA) 86:2766–2770CrossRefGoogle Scholar
  33. 33.
    Andrews RM, Kubacha I, Chinnery PF, Lightowlers RN, Turnbull DM, Howell N (1999) Reanalysis and revision of the Cambridge reference sequence for human mitochondrial DNA. Nat Genet 23:147PubMedCrossRefGoogle Scholar
  34. 34.
    Raby BA, Klanderman B, Murphy A, Mazza S, Camargo CA Jr, Silverman EK, Weiss ST (2007) A common mitochondrial haplogroup is associated with elevated total serum IgE levels. J Allergy Clin Immunol 120:351–358PubMedCrossRefGoogle Scholar
  35. 35.
    Barrett EG (2008) Maternal influence in the transmission of asthma susceptibility. Pulm Pharmacol Ther 21:474–484PubMedCrossRefGoogle Scholar
  36. 36.
    Lim RH, Kobzik L (2009) Maternal transmission of asthma risk. Am J Reprod Immunol 61:1–10PubMedCrossRefGoogle Scholar
  37. 37.
    van den Ouweland JM, Bruining GJ, Lindhout D, Wit JM, Veldhuyzen BF, Maassen JA (1992) Mutations in mitochondrial tRNA genes: non-linkage with syndromes of Wolfram and chronic progressive external ophthalmoplegia. Nucleic Acids Res 20:679–682PubMedCrossRefGoogle Scholar
  38. 38.
    Pulkes T, Sweeney MG, Hanna MG (2000) Increased risk of stroke in patients with the A12308G polymorphism in mitochondria. Lancet 356:2068–2069PubMedCrossRefGoogle Scholar
  39. 39.
    Crimi M, Del Bo R, Galbiati S, Sciacco M, Bordoni A, Bresolin N, Comi GP (2003) Mitochondrial A12308G polymorphism affects clinical features in patients with single mtDNA macrodeletion. Eur J Hum Genet 11:896–898PubMedCrossRefGoogle Scholar
  40. 40.
    Grasso M, Diegoli M, Brega A, Campana C, Tavazzi L, Arbustini E (2001) The mitochondrial DNA mutation T12297C affects a highly conserved nucleotide of tRNA(Leu(CUN)) and is associated with dilated cardiomyopathy. Eur J Hum Genet 9:311–315PubMedCrossRefGoogle Scholar
  41. 41.
    Herrnstadt C, Howell N (2004) An evolutionary perspective on pathogenic mtDNA mutations: haplogroup associations of clinical disorders. Mitochondrion 4:791–798PubMedCrossRefGoogle Scholar
  42. 42.
    Castro MG, Huerta C, Reguero JR, Soto MI, Doménech E, Alvarez V, Gómez-Zaera M, Nunes V, González P, Corao A, Coto E (2006) Mitochondrial DNA haplogroups in Spanish patients with hypertrophic cardiomyopathy. Int J Cardiol 112:202–206PubMedCrossRefGoogle Scholar
  43. 43.
    Mancuso M, Calsolaro V, Orsucci D, Siciliano G, Murri L (2009) Is there a primary role of the mitochondrial genome in Alzheimer’s disease? J Bioenerg Biomembr 41:411–416PubMedCrossRefGoogle Scholar
  44. 44.
    Fesahat F, Houshmand M, Panahi MS, Gharagozli K, Mirzajani F (2007) Do haplogroups H and U act to increase the penetrance of Alzheimer’s disease? Cell Mol Neurobiol 27:329–334PubMedCrossRefGoogle Scholar
  45. 45.
    Ghabaee M, Omranisikaroudi M, Amrisaroukolaei S, Meysamie A, Sahraian MA, Bayati A, Sanati MH, Houshman M, Sadeghian H, Vajihazaman K (2009) Mitochondrial mutation in Iranian patients with multiple sclerosis, correlation between haplogroups H, A and clinical manifestations. Cell Mol Neurobiol 29:341–346PubMedCrossRefGoogle Scholar
  46. 46.
    Crispim D, Canani LH, Gross JL, Tschiedel B, Souto KE, Roisenberg I (2006) The European-specific mitochondrial cluster J/T could confer an increased risk of insulin-resistance and type 2 diabetes: an analysis of the m.4216T > C and m.4917A > G variants. Ann Hum Genet 70:488–495PubMedCrossRefGoogle Scholar
  47. 47.
    Ji Y, Zhang AM, Jia X, Zhang YP, Xiao X, Li S, Guo X, Bandelt HJ, Zhang Q, Yao YG (2008) Mitochondrial DNA haplogroups M7b1’2 and M8a affect clinical expression of leber hereditary optic neuropathy in Chinese families with the m.11778G > A mutation. Am J Hum Genet 83:760–768PubMedCrossRefGoogle Scholar
  48. 48.
    Wolf C, Gramer E, Müller-Myhsok B, Pasutto F, Wissinger B, Weisschuh N (2010) Mitochondrial haplogroup U is associated with a reduced risk to develop exfoliation glaucoma in the German population. BMC Genet 28:11–18Google Scholar
  49. 49.
    Majamaa K, Finnilä S, Turkka J, Hassinen IE (1998) Mitochondrial DNA haplogroup U as a risk factor for occipital stroke in migraine. Lancet 352:455–456PubMedCrossRefGoogle Scholar
  50. 50.
    van der Walt JM, Dementieva YA, Martin ER, Scott WK, Nicodemus KK, Kroner CC, Welsh-Bohmer KA, Saunders AM, Roses AD, Small GW, Schmechel DE, Murali Doraiswamy P, Gilbert JR, Haines JL, Vance JM, Pericak-Vance MA (2004) Analysis of European mitochondrial haplogroups with Alzheimer disease risk. Neurosci Lett 365:28–32PubMedCrossRefGoogle Scholar
  51. 51.
    Bai RK, Leal SM, Covarrubias D, Liu A, Wong LJ (2007) Mitochondrial genetic background modifies breast cancer risk. Cancer Res 67:4687–4694PubMedCrossRefGoogle Scholar
  52. 52.
    Czarnecka AM, Krawczyk T, Zdrozny M, Lubiński J, Arnold RS, Kukwa W, Scińska A, Golik P, Bartnik E, Petros JA (2010) Mitochondrial NADH-dehydrogenase subunit 3 (ND3) polymorphism (A10398G) and sporadic breast cancer in Poland. Breast Cancer Res Treat 121:511–518PubMedCrossRefGoogle Scholar
  53. 53.
    Mayr-Wohlfart U, Paulus C, Henneberg A, Rödel G (1996) Mitochondrial DNA mutations in multiple sclerosis patients with severe optic involvement. Acta Neurol Scand 94:167–171PubMedCrossRefGoogle Scholar
  54. 54.
    Mayr-Wohlfart U, Rödel G, Henneberg A (1997) Mitochondrial tRNA(Gln) and tRNA(Thr) gene variants in Parkinson’s disease. Eur J Med Res 2:111–113PubMedGoogle Scholar
  55. 55.
    Grasbon-Frodl EM, Kösel S, Sprinzl M, von Eitzen U, Mehraein P, Graeber MB (1999) Two novel point mutations of mitochondrial tRNA genes in histologically confirmed Parkinson disease. Neurogenetics 2:121–127PubMedCrossRefGoogle Scholar
  56. 56.
    Seyedhassani SM, Houshmand M, Kalantar SM, Aflatoonian A, Modabber G, Hadipour F, Fallahzadeh M (2010) The point mutations of mitochondrial tRNAthreonine and proline in idiopathic repeated pregnancy loss. Iranian J Reprod Med 8:45–50Google Scholar
  57. 57.
    Jaksch M, Kleinle S, Scharfe C, Klopstock T, Pongratz D, Müller-Höcker J, Gerbitz KD, Liechti-Gallati S, Lochmuller H, Horvath R (2001) Frequency of mitochondrial transfer RNA mutations and deletions in 225 patients presenting with respiratory chain deficiencies. J Med Genet 38:665–673PubMedCrossRefGoogle Scholar
  58. 58.
    Khusnutdinova E, Gilyazova I, Ruiz-Pesini E, Derbeneva O, Khusainova R, Khidiyatova I, Magzhanov R, Wallace DC (2008) A mitochondrial etiology of neurodegenerative diseases: evidence from Parkinson’s disease. Ann N Y Acad Sci 1147:1–20PubMedCrossRefGoogle Scholar
  59. 59.
    Carter RW (2007) Mitochondrial diversity within modern human populations. Nucleic Acids Res 35:3039–3045PubMedCrossRefGoogle Scholar
  60. 60.
    Klemm T, Neumann S, Trülzsch B, Pistrosch F, Hanefeld M, Paschke R (2001) Search for mitochondrial DNA mutation at position 3243 in German patients with a positive family history of maternal diabetes mellitus. Exp Clin Endocrinol Diabetes 109:283–287PubMedCrossRefGoogle Scholar
  61. 61.
    Shen Z, Zheng J, Chen B, Peng G, Zhang T, Gong S, Zhu Y, Zhang C, Li R, Yang L, Zhou J, Cai T, Jin L, Lu J, Guan MX (2011) Frequency and spectrum of mitochondrial 12S rRNA variants in 440 Han Chinese hearing impaired pediatric subjects from two otology clinics. J Transl Med 9:4–15Google Scholar
  62. 62.
    Wei Q, Lu Y, Zhang Y, Chen Z, Xing G, Cao X (2009) Mutation analysis of mitochondrial 12S rRNA gene G709A in a maternally inherited pedigree with non-syndromic deafness. Zhonghua Yi Xue Yi Chuan Xue Za Zhi 26:610–614PubMedGoogle Scholar
  63. 63.
    Mkaouar-Rebai E, Tlili A, Masmoudi S, Louhichi N, Charfeddine I, Ben Amor M, Lahmar I, Driss N, Drira M, Ayadi H, Fakhfakh F (2006) Mutational analysis of the mitochondrial 12S rRNA and tRNASer(UCN) genes in Tunisian patients with nonsyndromic hearing loss. Biochem Biophys Res Commun 340:1251–1258PubMedCrossRefGoogle Scholar
  64. 64.
    Mkaouar-Rebai E, Tlili A, Masmoudi S, Charfeddine I, Fakhfakh F (2008) New polymorphic mtDNA restriction site in the 12S rRNA gene detected in Tunisian patients with non-syndromic hearing loss. Biochem Biophys Res Commun 369:849–852PubMedCrossRefGoogle Scholar
  65. 65.
    Rydzanicz M, Wróbel RM, Cywińska K, Froehlich D, Gawecki W, Szyfter W, Szyfter K (2009) Screening of the general Polish population for deafness-associated mutations in mitochondrial 12S rRNA and tRNA Ser(UCN) genes. Genet Test Mol Biomarkers 13:167–172PubMedCrossRefGoogle Scholar
  66. 66.
    Bykhovskayaa Y, Mengeshaa E, Fischel-Ghodsian N (2009) Phenotypic expression of maternally inherited deafness is affected by RNA modification and cytoplasmic ribosomal proteins. Mol Gen Met 97:297–304CrossRefGoogle Scholar
  67. 67.
    Pello R, Martín MA, Carelli V, Nijtmans LG, Achilli A, Pala M, Torroni A, Gómez-Durán A, Ruiz-Pesini E, Martinuzzi A, Smeitink JA, Arenas J, Ugalde C (2008) Mitochondrial DNA background modulates the assembly kinetics of OXPHOS complexes in a cellular model of mitochondrial disease. Hum Mol Genet 17:4001–4011PubMedCrossRefGoogle Scholar
  68. 68.
    Lynch M (1996) Mutation accumulation in transfer RNAs: molecular evidence for Muller’s ratchet in mitochondrial genomes. Mol Biol Evol 13:209–220PubMedGoogle Scholar
  69. 69.
    Zifa E, Giannouli S, Theotokis P, Stamatis C, Mamuris Z, Stathopoulos C (2007) Mitochondrial tRNA mutations. Clinical and functional Perturbations. RNA Biol 4:38–66PubMedCrossRefGoogle Scholar
  70. 70.
    Ruiz-Pesini E, Wallace DC (2006) Evidence for adaptive selection acting on the tRNA and rRNA genes of human mitochondrial DNA. Hum Mutat 27:1072–1081PubMedCrossRefGoogle Scholar
  71. 71.
    Sarzi E, Brown MD, Lebon S, Chretien D, Munnich A, Rotig A, Procaccio V (2007) A novel recurrent mitochondrial DNA mutation in ND3 gene is associated with isolated complex I deficiency causing Leigh syndrome and dystonia. Am J Med Genet 143:33–41PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media B.V. 2011

Authors and Affiliations

  • Emily Zifa
    • 1
  • Zoe Daniil
    • 2
  • Eleutheria Skoumi
    • 1
  • Maria Stavrou
    • 1
  • Kostantinos Papadimitriou
    • 1
  • Marini Terzenidou
    • 1
  • Konstantinos Kostikas
    • 2
  • Vasileios Bagiatis
    • 1
  • Konstantinos I. Gourgoulianis
    • 2
  • Zissis Mamuris
    • 1
  1. 1.Laboratory of Genetics, Comparative and Evolutionary Biology, Department of Biochemistry and BiotechnologyUniversity of ThessalyLarissaGreece
  2. 2.Respiratory Medicine DepartmentUniversity of Thessaly School of Medicine, University Hospital of LarissaLarissaGreece

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