Background Apical potassium channels regulate ion transport in airway epithelial cells and influence air surface liquid (ASL) hydration and mucociliary clearance (MCC). We sought to identify whether genetic variation within genes encoding airway potassium channels is associated with chronic rhinosinusitis (CRS). Methods Single nucleotide polymorphism (SNP) genotypes for selected potassium channels were derived from data generated on the Illumnia HumanHap550 BeadChip or Illumina Human610-Quad BeadChip for 828 unrelated individuals diagnosed with CRS and 5,083 unrelated healthy controls from the Children's Hospital of Philadelphia (CHOP). Statistical analysis was performed with set-based tests using PLINK, and corrected for multiple testing. Results Set-based case control analysis revealed the gene KCNMA1 was associated with CRS in our Caucasian subset of the cohort (598 CRS cases and 3,489 controls; p = 0.022, based on 10,000 permutations). In addition there was borderline evidence that the gene KCNQ5 (p = 0.0704) was associated with the trait in our African American subset of the cohort (230 CRS cases and 1,594 controls). In addition to the top significant SNPs rs2917454 and rs6907229, imputation analysis uncovered additional genetic variants in KCNMA1 and in KCNQ5 that were associated with CRS. Conclusions We have implicated two airway epithelial potassium channels as novel susceptibility loci in contributing to the pathogenesis of CRS.
References
[1]
Kennedy DW (2004) Pathogenesis of chronic rhinosinusitis. Ann Otol Rhinol Laryngol Suppl 193: 6–9.
[2]
Kennedy DW (2012) As the inflammatory nature of chronic rhinosinusitis (CRS) has become increasingly recognized, the use of steroids, both systemic and topical, as part of the disease management has significantly increased. Int Forum Allergy Rhinol 2: 93–94.
[3]
Tan BK, Schleimer RP, Kern RC (2010) Perspectives on the etiology of chronic rhinosinusitis. Curr Opin Otolaryngol Head Neck Surg 18: 21–26. doi: 10.1097/moo.0b013e3283350053
[4]
Soler ZM, Sauer DA, Mace J, Smith TL (2009) Relationship between clinical measures and histopathologic findings in chronic rhinosinusitis. Otolaryngol Head Neck Surg 141: 454–461. doi: 10.1016/j.otohns.2009.06.085
[5]
Hsu J, Avila PC, Kern RC, Hayes MG, Schleimer RP, et al. (2013) Genetics of chronic rhinosinusitis: State of the field and directions forward. J Allergy Clin Immunol 131: 977–93, 993.e1–5. doi: 10.1016/j.jaci.2013.01.028
[6]
Cohen NA, Widelitz JS, Chiu AG, Palmer JN, Kennedy DW (2006) Familial aggregation of sinonasal polyps correlates with severity of disease. Otolaryngol Head Neck Surg 134: 601–604. doi: 10.1016/j.otohns.2005.11.042
[7]
Lockey RF, Rucknagel DL, Vanselow NA (1973) Familial occurrence of asthma, nasal polyps and aspirin intolerance. Ann Intern Med 78: 57–63. doi: 10.7326/0003-4819-78-1-57
[8]
Delagrand A, Gilbert-Dussardier B, Burg S, Allano G, Gohler-Desmonts C, et al. (2008) Nasal polyposis: Is there an inheritance pattern? A single family study. Rhinology 46: 125–130.
[9]
Greisner WA 3rd, Settipane GA (1996) Hereditary factor for nasal polyps. Allergy Asthma Proc 17: 283–286. doi: 10.2500/108854196778662192
[10]
Wang X, Kim J, McWilliams R, Cutting GR (2005) Increased prevalence of chronic rhinosinusitis in carriers of a cystic fibrosis mutation. Arch Otolaryngol Head Neck Surg 131: 237–240. doi: 10.1001/archotol.131.3.237
[11]
Raman V, Clary R, Siegrist KL, Zehnbauer B, Chatila TA (2002) Increased prevalence of mutations in the cystic fibrosis transmembrane conductance regulator in children with chronic rhinosinusitis. Pediatrics 109: E13. doi: 10.1542/peds.109.1.e13
[12]
Ober C, Yao TC (2011) The genetics of asthma and allergic disease: A 21st century perspective. Immunol Rev 242: 10–30. doi: 10.1111/j.1600-065x.2011.01029.x
[13]
Oomen KP, April MM (2012) Sinonasal manifestations in cystic fibrosis. Int J Otolaryngol 2012: 789572. doi: 10.1155/2012/789572
[14]
Riordan JR, Rommens JM, Kerem B, Alon N, Rozmahel R, et al. (1989) Identification of the cystic fibrosis gene: Cloning and characterization of complementary DNA. Science 245: 1066–1073. doi: 10.1126/science.2475911
[15]
Hollenhorst MI, Richter K, Fronius M (2011) Ion transport by pulmonary epithelia. J Biomed Biotechnol 2011: 174306. doi: 10.1155/2011/174306
[16]
Cook DI, Young JA (1989) Effect of K+ channels in the apical plasma membrane on epithelial secretion based on secondary active cl- transport. J Membr Biol 110: 139–146. doi: 10.1007/bf01869469
[17]
Zhao KQ, Xiong G, Wilber M, Cohen NA, Kreindler JL (2012) A role for two-pore K(+) channels in modulating na(+) absorption and cl(？) secretion in normal human bronchial epithelial cells. Am J Physiol Lung Cell Mol Physiol 302: L4–L12. doi: 10.1152/ajplung.00102.2011
[18]
Ramsey BW, Davies J, McElvaney NG, Tullis E, Bell SC, et al. (2011) A CFTR potentiator in patients with cystic fibrosis and the G551D mutation. N Engl J Med 365: 1663–1672. doi: 10.1056/nejmoa1105185
[19]
Accurso FJ, Rowe SM, Clancy J, Boyle MP, Dunitz JM, et al. (2010) Effect of VX-770 in persons with cystic fibrosis and the G551D-CFTR mutation. N Engl J Med 363: 1991–2003. doi: 10.1056/nejmoa0909825
[20]
Van Goor F, Hadida S, Grootenhuis PD, Burton B, Cao D, et al. (2009) Rescue of CF airway epithelial cell function in vitro by a CFTR potentiator, VX-770. Proc Natl Acad Sci U S A 106: 18825–18830. doi: 10.1073/pnas.0904709106
[21]
Bardou O, Trinh NT, Brochiero E (2009) Molecular diversity and function of K+ channels in airway and alveolar epithelial cells. Am J Physiol Lung Cell Mol Physiol 296: L145–55. doi: 10.1152/ajplung.90525.2008
[22]
Manzanares D, Gonzalez C, Ivonnet P, Chen RS, Valencia-Gattas M, et al. (2011) Functional apical large conductance, Ca2+-activated, and voltage-dependent K+ channels are required for maintenance of airway surface liquid volume. J Biol Chem 286: 19830–19839. doi: 10.1074/jbc.m110.185074
[23]
Leroy C, Prive A, Bourret JC, Berthiaume Y, Ferraro P, et al. (2006) Regulation of ENaC and CFTR expression with K+ channel modulators and effect on fluid absorption across alveolar epithelial cells. Am J Physiol Lung Cell Mol Physiol 291: L1207–19. doi: 10.1152/ajplung.00376.2005
[24]
Price AL, Patterson NJ, Plenge RM, Weinblatt ME, Shadick NA, et al. (2006) Principal components analysis corrects for stratification in genome-wide association studies. Nat Genet 38: 904–909. doi: 10.1038/ng1847
[25]
Lusk RP, Stankiewicz JA (1997) Pediatric rhinosinusitis. Otolaryngol Head Neck Surg 117: S53–7. doi: 10.1016/s0194-5998(97)70008-1
[26]
Purcell S, Neale B, Todd-Brown K, Thomas L, Ferreira MA, et al. (2007) PLINK: A tool set for whole-genome association and population-based linkage analyses. Am J Hum Genet 81: 559–575. doi: 10.1086/519795
[27]
Verschuren JJ, Trompet S, Postmus I, Sampietro ML, Heijmans BT, et al. (2012) Systematic testing of literature reported genetic variation associated with coronary restenosis: Results of the GENDER study. PLoS One 7: e42401. doi: 10.1371/journal.pone.0042401
[28]
Verschuren JJ, Trompet S, Deelen J, Stott DJ, Sattar N, et al. (2013) Non-homologous end-joining pathway associated with occurrence of myocardial infarction: Gene set analysis of genome-wide association study data. PLoS One 8: e56262. doi: 10.1371/journal.pone.0056262
[29]
Marchini J, Howie B, Myers S, McVean G, Donnelly P (2007) A new multipoint method for genome-wide association studies by imputation of genotypes. Nat Genet 39: 906–913. doi: 10.1038/ng2088
[30]
Howie BN, Donnelly P, Marchini J (2009) A flexible and accurate genotype imputation method for the next generation of genome-wide association studies. PLoS Genet 5: e1000529. doi: 10.1371/journal.pgen.1000529
[31]
Yang J, Lee SH, Goddard ME, Visscher PM (2011) GCTA: A tool for genome-wide complex trait analysis. Am J Hum Genet 88: 76–82. doi: 10.1016/j.ajhg.2010.11.011
[32]
Chorev M, Carmel L (2012) The function of introns. Front Genet 3: 55. doi: 10.3389/fgene.2012.00055
[33]
ENCODE Project Consortium (2012) Bernstein BE, Birney E, Dunham I, Green ED, et al. (2012) An integrated encyclopedia of DNA elements in the human genome. Nature 489: 57–74.
[34]
Chadwick LH (2012) The NIH roadmap epigenomics program data resource. Epigenomics 4: 317–324. doi: 10.2217/epi.12.18
[35]
Ward LD, Kellis M (2012) HaploReg: A resource for exploring chromatin states, conservation, and regulatory motif alterations within sets of genetically linked variants. Nucleic Acids Res 40: D930–4. doi: 10.1093/nar/gkr917
[36]
Sakakura Y, Majima Y, Saida S, Ukai K, Miyoshi Y (1985) Reversibility of reduced mucociliary clearance in chronic sinusitis. Clin Otolaryngol Allied Sci 10: 79–83. doi: 10.1111/j.1365-2273.1985.tb01171.x
[37]
Ooi EH, Psaltis AJ, Witterick IJ, Wormald PJ (2010) Innate immunity. Otolaryngol Clin North Am 43: 473–87, vii. doi: 10.1016/j.otc.2010.02.020
[38]
Harvey PR, Tarran R, Garoff S, Myerburg MM (2011) Measurement of the airway surface liquid volume with simple light refraction microscopy. Am J Respir Cell Mol Biol 45: 592–599. doi: 10.1165/rcmb.2010-0484oc
[39]
Derendorf H, Meltzer EO (2008) Molecular and clinical pharmacology of intranasal corticosteroids: Clinical and therapeutic implications. Allergy 63: 1292–1300. doi: 10.1111/j.1398-9995.2008.01750.x
[40]
Sayegh R, Auerbach SD, Li X, Loftus RW, Husted RF, et al. (1999) Glucocorticoid induction of epithelial sodium channel expression in lung and renal epithelia occurs via trans-activation of a hormone response element in the 5′-flanking region of the human epithelial sodium channel alpha subunit gene. J Biol Chem 274: 12431–12437. doi: 10.1074/jbc.274.18.12431
[41]
Deshane J, Kim J, Bolisetty S, Hock TD, Hill-Kapturczak N, et al. (2010) Sp1 regulates chromatin looping between an intronic enhancer and distal promoter of the human heme oxygenase-1 gene in renal cells. J Biol Chem 285: 16476–16486. doi: 10.1074/jbc.m109.058586
[42]
Ott CJ, Suszko M, Blackledge NP, Wright JE, Crawford GE, et al. (2009) A complex intronic enhancer regulates expression of the CFTR gene by direct interaction with the promoter. J Cell Mol Med 13: 680–692. doi: 10.1111/j.1582-4934.2008.00621.x
[43]
Scohy S, Gabant P, Szpirer C, Szpirer J (2000) Identification of an enhancer and an alternative promoter in the first intron of the alpha-fetoprotein gene. Nucleic Acids Res 28: 3743–3751. doi: 10.1093/nar/28.19.3743
[44]
O'Grady SM, Lee SY (2003) Chloride and potassium channel function in alveolar epithelial cells. Am J Physiol Lung Cell Mol Physiol 284: L689–700.
[45]
Coetzee WA, Amarillo Y, Chiu J, Chow A, Lau D, et al. (1999) Molecular diversity of K+ channels. Ann N Y Acad Sci 868: 233–285. doi: 10.1111/j.1749-6632.1999.tb11293.x
[46]
Mall M, Gonska T, Thomas J, Schreiber R, Seydewitz HH, et al. (2003) Modulation of Ca2+-activated cl- secretion by basolateral K+ channels in human normal and cystic fibrosis airway epithelia. Pediatr Res 53: 608–618. doi: 10.1203/01.pdr.0000057204.51420.dc
[47]
Mall M, Wissner A, Schreiber R, Kuehr J, Seydewitz HH, et al. (2000) Role of K(V)LQT1 in cyclic adenosine monophosphate-mediated cl(？) secretion in human airway epithelia. Am J Respir Cell Mol Biol 23: 283–289. doi: 10.1165/ajrcmb.23.3.4060
[48]
Moser SL, Harron SA, Crack J, Fawcett JP, Cowley EA (2008) Multiple KCNQ potassium channel subtypes mediate basal anion secretion from the human airway epithelial cell line calu-3. J Membr Biol 221: 153–163. doi: 10.1007/s00232-008-9093-9
[49]
Cowley EA, Linsdell P (2002) Characterization of basolateral K+ channels underlying anion secretion in the human airway cell line calu-3. J Physiol 538: 747–757. doi: 10.1113/jphysiol.2001.013300
[50]
Teng S, Ma L, Zhen Y, Lin C, Bahring R, et al. (2003) Novel gene hKCNE4 slows the activation of the KCNQ1 channel. Biochem Biophys Res Commun 303: 808–813. doi: 10.1016/s0006-291x(03)00433-9
[51]
Bernard K, Bogliolo S, Soriani O, Ehrenfeld J (2003) Modulation of calcium-dependent chloride secretion by basolateral SK4-like channels in a human bronchial cell line. J Membr Biol 196: 15–31. doi: 10.1007/s00232-003-0621-3
[52]
Jovanovic S, Crawford RM, Ranki HJ, Jovanovic A (2003) Large conductance Ca2+-activated K+ channels sense acute changes in oxygen tension in alveolar epithelial cells. Am J Respir Cell Mol Biol 28: 363–372. doi: 10.1165/rcmb.2002-0101oc
[53]
Ridge FP, Duszyk M, French AS (1997) A large conductance, Ca2+-activated K+ channel in a human lung epithelial cell line (A549). Biochim Biophys Acta 1327: 249–258. doi: 10.1016/s0005-2736(97)00073-4
[54]
Monaghan AS, Baines DL, Kemp PJ, Olver RE (1997) Inwardly rectifying K+ currents of alveolar type II cells isolated from fetal guinea-pig lung: Regulation by G protein- and Mg2+-dependent pathways. Pflugers Arch 433: 294–303. doi: 10.1007/s004240050280
[55]
Plummer HK 3rd, Dhar MS, Cekanova M, Schuller HM (2005) Expression of G-protein inwardly rectifying potassium channels (GIRKs) in lung cancer cell lines. BMC Cancer 5: 104.
[56]
Sakuma T, Takahashi K, Ohya N, Nakada T, Matthay MA (1998) Effects of ATP-sensitive potassium channel opener on potassium transport and alveolar fluid clearance in the resected human lung. Pharmacol Toxicol 83: 16–22. doi: 10.1111/j.1600-0773.1998.tb01436.x
[57]
Doring F, Derst C, Wischmeyer E, Karschin C, Schneggenburger R, et al. (1998) The epithelial inward rectifier channel Kir7.1 displays unusual K+ permeation properties. J Neurosci 18: 8625–8636.
[58]
Inglis SK, Brown SG, Constable MJ, McTavish N, Olver RE, et al. (2007) A Ba2+-resistant, acid-sensitive K+ conductance in na+-absorbing H441 human airway epithelial cells. Am J Physiol Lung Cell Mol Physiol 292: L1304–12. doi: 10.1152/ajplung.00424.2006
