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Genetics of ion homeostasis in Ménière’s Disease

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Aim of this work was to assess the role of polymorphisms belonging to genes involved in the regulation of ionic homeostasis in Caucasian patients with Ménière Disease (MD). We recruited 155 patients with definite Ménière Disease and 186 controls (Control Group 1) without a lifetime history of vertigo, overlapping with patients for age and rate of hypertension. We validated the positive results on 413 Caucasian subjects selected from a European general population (Control Group 2). The clinical history for migraine and hypertension was collected; genomic DNA was characterized for a panel of 33 SNPs encoding proteins involved in ionic transport. We found a higher rate of migraineurs in MD subjects compared to Group 1 (46.8 vs 15.5%, p = 0.00005). Four SNPs displayed differences in MD patients compared to Group 1 controls: rs3746951 and rs2838301 in SIK1 gene, rs434082 and rs487119 in SLC8A1; the p values of Chi-squared test for genotype frequencies are 0.009, 0.023, 0.009 and 0.048, respectively. SLC8A1 gene encodes for Na+-Ca++ exchanger, while SIK1 gene encodes for Salt Inducible Kinase 1, an enzyme associated with Na+-K+ ATPase function. The validation with Control Group 2 displayed that only rs3746951 and rs487119 are strongly associated to MD (p = 0.001 and p = 0.0004, respectively). These data support the hypothesis that a genetically induced dysfunction of ionic transport may act as a predisposing factors to develop MD.

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  1. 1.

    Sajjadi H, Paparella MM (2008) Ménière’s disease. Lancet 372:406–414. doi:10.1016/S0140-6736(08)61161-7

  2. 2.

    Merchant SN, Adams JC, Nadol JB Jr (2005) Pathophysiology of Ménière’s syndrome: are symptoms caused by endolymphatic hydrops? Otol Neurotol 26:74–81. doi:10.1097/00129492-200501000-00013

  3. 3.

    Vrabec JT (2010) Genetic investigations of Ménière’s disease. Otolaryngol Clin North Am 43:1121–1132. doi:10.1016/j.otc.2010.05.010

  4. 4.

    Morrison AW, Bailey ME, Morrison GA (2009) Familial Ménière’s disease: clinical and genetic aspects. J Laryngol Otol 123:29–37. doi:10.1017/S0022215108002788

  5. 5.

    Friedmann I, Fraser GR, Froggatt P (1966) Pathology of the ear in the cardioauditory syndrome of Jervell and Lange–Nielsen (recessive deafness with electrocardiographic abnormalities. J Laryngol Otol 80:451–470. doi:10.1017/s002221510006552x

  6. 6.

    Oh SK, Baek JI, Weigand KM et al (2015) A missense variant of the ATP1A2 gene is associated with a novel phenotype of progressive sensorineural hearing loss associated with migraine. Eur J Hum Genet 23:639–645. doi:10.1038/ejhg.2014.154

  7. 7.

    Beitz E, Kumagami H, Krippeit-Drews P, Ruppersberg JP, Schultz JE (1999) Expression pattern of aquaporin water channels in the inner ear of the rat. The molecular basis for a water regulation system in the endolymphatic sac. Hear Res 132:76–84. doi:10.1016/s0378-5955(99)00036-2

  8. 8.

    Knepper MA, Inoue T (1997) Regulation of aquaporin-2 water channel trafficking by vasopressin. Curr Opin Cell Biol 9:560–564. doi:10.1016/s0955-0674(97)80034-8

  9. 9.

    Takeda T, Takeda S, Kakigi A et al (2010) Hormonal aspects of Ménière’s disease on the basis of clinical and experimental studies. ORL J Otorhinolaryngol Relat Spec 71:1–19. doi:10.1159/000265113

  10. 10.

    Mallur PS, Weisstuch A, Pfister M et al (2010) Aquaporin-2 and -4: single nucleotide polymorphisms in Ménière’s disease patients. Audiol Med 8:18–23. doi:10.1159/000322346

  11. 11.

    Candreia C, Schmuziger N, Gürtler N (2010) Molecular analysis of aquaporin genes 1 to 4 in patients with Ménière’s Disease. Cell Physiol Biochem 26:787–792. doi:10.1159/000322346

  12. 12.

    Doi K, Sato T, Kuramasu T et al (2005) Ménière’s disease is associated with single nucleotide polymorphisms in the human potassium channel genes, KCNE1 and KCNE3. ORL J Otorhinolaryngol Relat Spec 67:289–293. doi:10.1159/000089410

  13. 13.

    Campbell CA, Della Santina CC, Meyer NC et al (2010) Polymorphisms in KCNE1 or KCNE3 are not associated with Ménière disease in the Caucasian population. Am J Med Genet A 152:67–74. doi:10.1002/ajmg.a.33114

  14. 14.

    Teggi R, Lanzani C, Zagato L, Delli Carpini S, Manunta P, Bianchi G, Bussi M (2008) Gly460Trp alpha-adducin mutation as a possible mechanism leading to endolymphatic hydrops in Ménière’s syndrome. Otol Neurotol 29:824–828. doi:10.1097/MAO.0b013e318180a4b1

  15. 15.

    Teggi R, Zagato L, Delli Carpini S, Messaggio E, Casamassima N, Lanzani C, Manunta P, Bussi M (2010) Endogenous ouabain in Ménière’s disease. Otol Neurotol 31:153–156. doi:10.1097/MAO.0b013e3181c0eaba

  16. 16.

    Hietikko E, Kotimaki J, Okuloff A, Sorri M, Mannikko M (2012) A replication study on proposed candidate genes in Ménière’s disease, and a review of the current status of genetic studies. Int J Audiol 51:841–845. doi:10.3109/14992027.2012.705900

  17. 17.

    Kim SH, Park HY, Choi HS et al (2009) Functional and molecular expression of epithelial sodium channels in cultured human endolymphatic sac epithelial cells. Otol Neurotol 30:529–534. doi:10.1097/MAO.0b013e31819a8e0e

  18. 18.

    Committee on Hearing and Equilibrium (1995) Guidelines for the diagnosis and evaluation of therapy in Ménière’s disease. Otolaryngol Head Neck Surg 113:181–185. doi:10.1016/s0194-5998(95)70102-8

  19. 19.

    Headache Classification Subcommittee of the International Headache Society (2013) The international classification of headache disorders: 3rd edn. Cephalalgia 33:629–680. doi:10.1177/0333102413485658

  20. 20.

    Liu YP, Gu YM, Thijs L, Knapen MH, Salvi E, Citterio L, Petit T, Delli Carpini S, Zhang Z, Jacobs L, Jin Y, Barlassina C, Manunta P, Kuznetsova T, Verhamme P, Struijker-Boudier HA, Cusi D, Vermeer C, Staessen JA (2015) Inactive matrix Gla protein is causally related to adverse health outcomes: a Mendelian randomization study in a Flemish population. Hypertension 65:463–470. doi:10.1161/HYPERTENSIONAHA.114.04494

  21. 21.

    Livak KJ (1999) Allelic discrimination using fluorogenic probes and the 5′ nuclease assay. Genet Anal 14:143–149. doi:10.1016/s1050-3862(98),00019-9

  22. 22.

    Citterio L, Simonini M, Zagato L, Salvi E, Delli Carpini S, Lanzani C, Messaggio E, Casamassima N, Frau F, D’Avila F, Cusi D, Barlassina C, Manunta (2011) Genes involved in vasoconstriction and vasodilation system affect salt-sensitive hypertension. PLoS One 6:e19620. doi:10.1371/journal.pone.0019620

  23. 23.

    Lanzani C, Citterio L, Glorioso N, Manunta P, Tripodi G, Salvi E, Carpini SD, Ferrandi M, Messaggio E, Staessen JA, Cusi D, Macciardi F, Argiolas G, Valentini G, Ferrari P, Bianchi G (2010) Adducin- and ouabain-related gene variants predict the antihypertensive activity of rostafuroxin, part 2: clinical studies. Sci Transl Med 2:59ra87. doi:10.1126/scitranslmed.3001814

  24. 24.

    Lanzani C, Gatti G, Citterio L, Messaggio E, Delli Carpini S, Simonini M, Casamassima N, Zagato L, Brioni E, Hamlyn JM, Manunta P (2016) Lanosterol synthase gene polymorphisms and changes in endogenous ouabain in the response to low sodium intake. Hypertension 67:342–348. doi:10.1161/HYPERTENSIONAHA.115.06415

  25. 25.

    Salvi E, Kutalik Z, Glorioso N, Benaglio P, Frau F et al (2012) Genomewide association study using a high-density single nucleotide polymorphism array and case–control design identifies a novel essential hypertension susceptibility locus in the promoter region of endothelial NO synthase. Hypertension 59:248–255. doi:10.1161/HYPERTENSIONAHA.111.181990

  26. 26.

    On C, Marshall CR, Chen N, Moyes CD, Tibbits GF (2008) Gene structure evolution of the Na+–Ca2+ exchanger (NCX) family. BMC Evol Biol 8:127–142. doi:10.1186/1471-2148-8-127

  27. 27.

    Khananshvili D (2013) The SLC8 gene family of sodium–calcium exchangers (NCX)—structure, function, and regulation in health and disease. Mol Aspects Med 34:220–235. doi:10.1016/j.mam.2012.07.003

  28. 28.

    Iwamoto T, Kita S, Zhang J, Blaustein MP, Arai Y, Yoshida S, Wakimoto K, Komuro I, Katsuragi T (2004) Salt-sensitive hypertension is triggered by Ca2+ entry via Na+/Ca2+ exchanger type-1 in vascular smooth muscle. Nat Med 10:1193–1199. doi:10.1038/nm1118

  29. 29.

    Zhang J, Ren C, Chen L, Navedo MF, Antos LK, Kinsey SP, Iwamoto T, Philipson KD, Kotlikoff MI, Santana LF, Wier WG, Matteson DR, Blaustein MP (2010) Knockout of Na+/Ca2+ exchanger in smooth muscle attenuates vasoconstriction and L-type Ca2+ channel current and lowers blood pressure. Am J Physiol Heart Circ Physiol 298:H1472–H1483. doi:10.1152/ajpheart.00964.2009

  30. 30.

    Boscia F, Gala R, Pignataro G, de Bartolomeis A, Cicale M, Ambesi-Impiombato A, Di Renzo G, Annunziato L (2006) Permanent focal brain ischemia induces isoform-dependent changes in the pattern of Na+/Ca2+ exchanger gene expression in the ischemic core, periinfarct area, and intact brain regions. J Cereb Blood Flow Metab 26:502–517. doi:10.1038/sj.jcbfm.9600207

  31. 31.

    Pignataro G, Gala R, Cuomo O, Tortiglione A, Giaccio L, Castaldo P, Sirabella R, Matrone C, Canitano A, Amoroso S, Di Renzo G, Annunziato L (2004) Two sodium/calcium exchanger gene products, NCX1 and NCX3, play a major role in the development of permanent focal cerebral ischemia. Stroke 35:2566–2570. doi:10.1161/01.str.0000143730.29964.93

  32. 32.

    Staiano RI, Granata F, Secondo A, Petraroli A, Loffredo S, Frattini A, Annunziato L, Marone G, Triggiani M (2009) Expression and function of Na+/Ca2+ exchangers 1 and 3 in human macrophages and monocytes. Eur J Immunol 39:1405–1418. doi:10.1002/eji.200838792

  33. 33.

    Popov S, Silveira A, Wågsäter D, Takemori H, Oguro R, Matsumoto S, Sugimoto K, Kamide K, Hirose T, Satoh M et al (2011) Salt-inducible kinase 1 influences Na, K-ATPase activity in vascular smooth muscle cells and associates with variations in blood pressure. J Hypertens 29:2395–2403. doi:10.1097/HJH.0b013e32834d3d55

  34. 34.

    Stenstrom K, Takemori H, Bianchi G, Katz AI, Bertorello AM (2009) Blocking the salt-inducible kinase 1 network prevents the increases in cell sodium transport caused by a hypertension-linked mutation in human α-adducin. J Hypertens 27:2452–2457. doi:10.1097/HJH.0b013e328330cf15

  35. 35.

    Hietakangas V, Cohen SM (2008) TORCing up metabolic control in the brain. Cell Metab 7:357–358. doi:10.1016/j.cmet.2008.04.006

  36. 36.

    Hu Z, Hu J, Shen WJ, Kraemer FB, Azhar S (2015) A novel role of Salt-Inducible Kinase 1 (SIK1) in the post-translational regulation of scavenger receptor class B type 1 activity. Biochemistry 54:6917–6930. doi:10.1021/acs.biochem.5b00147

  37. 37.

    Degerman E, Rauch U, Göransson O, Lindberg S, Hultgårdh A, Magnusson M (2011) Identification of new signaling components in the sensory epithelium of human saccule. Front Neurol 2:e48. doi:10.3389/fneur.2011.00048

  38. 38.

    Illarionova NB, Gunnarson E, Li Y, Brismar H, Bondar A, Zelenin S, Aperia A (2010) Functional and molecular interactions between aquaporins and Na, K-ATPase. Neuroscience 168:915–925. doi:10.1016/j.neuroscience.2009.11.062

  39. 39.

    Radtke A, Lempert T, Gresty MA, Brookes GB, Bronstein AM, Neuhauser H (2002) Migraine and Ménière’s disease: is there a link? Neurology 59:1700–1704. doi:10.1212/01.wnl.0000036903.22461.39

  40. 40.

    Lopez-Escamez JA, Dlugaiczyk J, Jacobs J, Lempert T, Teggi R, von Brevern M, Bisdorff A (2014) Accompanying symptoms overlap during attacks in Menière’s Disease and vestibular migraine. Front Neurol 5:265. doi:10.3389/fneur.2014.00265

  41. 41.

    Lempert T, Olesen J, Furman J, Waterston J, Seemungal B, Carey J, Bisdorff A, Versino M, Evers S, Newman-Toker D (2012) Vestibular migraine: diagnostic criteria. J Vestib Res 22:167–172. doi:10.3233/VES-2012-0453

  42. 42.

    Lang F, Vallon V, Knipper M, Wangemann P (2007) Functional significance of channels and transporters expressed in the inner ear and kidney. Am J Physiol Cell Physiol 293:1187–1208. doi:10.1152/ajpcell.00024.2007

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Correspondence to Roberto Teggi.

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The authors declare they did not receive grants for the work and they have no competing interests. All procedures were in accordance with the ethical standards of the 1964 Helsinki declaration. The research has been approved by our Ethics Committee and all subjects signed informed consent.

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Teggi, R., Zagato, L., Delli Carpini, S. et al. Genetics of ion homeostasis in Ménière’s Disease. Eur Arch Otorhinolaryngol 274, 757–763 (2017).

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  • Ménière’s Disease
  • Genetics
  • Ionic transporters
  • Salt inducible kinase 1 (SIK1)
  • Na+-Ca++ exchanger 1 (SLC8A1)