Airway epithelial expression quantitative trait loci reveal genes underlying asthma and other airway diseases

American Journal of Respiratory Cell and Molecular Biology

Volumn 54, Issue 2, 2016, Pages 177-187

  Luo, Wei ^a,b   Obeidat, Ma'en ^c   Di Narzo, Antonio Fabio ^b   Chen, Rong ^b   Sin, Don D ^c   Paré, Peter D ^c   Hao, Ke ^b,d  

^a HUAQIAO UNIVERSITY   (China)

^b MOUNT SINAI SCHOOL OF MEDICINE   (United States)

^c UNIVERSITY OF BRITISH COLUMBIA   (Canada)

^d TONGJI UNIVERSITY   (China)

Author keywords

Airway diseases; Airway epithelium; Asthma; Expression quantitative trait loci

Indexed keywords

INTERLEUKIN 4; GENETIC MARKER;

ARTICLE; ASTHMA; EPITHELIUM CELL; GENE EXPRESSION; GENETIC ASSOCIATION; GENOTYPE; HUMAN; LUNG PARENCHYMA; PHENOTYPE; QUANTITATIVE TRAIT LOCUS; RESPIRATORY EPITHELIUM; RESPIRATORY TRACT DISEASE; SIGNAL TRANSDUCTION; SINGLE NUCLEOTIDE POLYMORPHISM; BIOLOGY; CHEMISTRY; FEMALE; GENE EXPRESSION PROFILING; GENE EXPRESSION REGULATION; GENE REGULATORY NETWORK; GENETIC DATABASE; GENETIC MARKER; GENETIC PREDISPOSITION; GENETICS; GENOME-WIDE ASSOCIATION STUDY; MALE; RESPIRATORY MUCOSA;

ASTHMA; COMPUTATIONAL BIOLOGY; DATABASES, GENETIC; EPITHELIAL CELLS; FEMALE; GENE EXPRESSION PROFILING; GENE EXPRESSION REGULATION; GENE REGULATORY NETWORKS; GENETIC MARKERS; GENETIC PREDISPOSITION TO DISEASE; GENOME-WIDE ASSOCIATION STUDY; HUMANS; MALE; PHENOTYPE; POLYMORPHISM, SINGLE NUCLEOTIDE; QUANTITATIVE TRAIT LOCI; RESPIRATORY MUCOSA;

EID: 84963838559     PISSN: 10441549     EISSN: 15354989     Source Type: Journal    
DOI: 10.1165/rcmb.2014-0381OC     Document Type: Article

References (94)

1. Choudhry S, Taub M, Mei R, Rodriguez-Santana J, Rodriguez-Cintron W, Shriver MD, Ziv E, Risch NJ, Burchard EG. Genome-wide screen for asthma in Puerto Ricans: evidence for association with 5q23 region. Hum Genet 2008;123:455-468.
2. DeWan AT, Triche EW, Xu X, Hsu LI, Zhao C, Belanger K, Hellenbrand K, Willis-Owen SA, Moffatt M, Cookson WO, et al. PDE11A associations with asthma: results of a genome-wide association scan. J Allergy Clin Immunol 2010;126:871-873.
3. Gudbjartsson DF, Bjornsdottir US, Halapi E, Helgadottir A, Sulem P, Jonsdottir GM, Thorleifsson G, Helgadottir H, Steinthorsdottir V, Stefansson H, et al. Sequence variants affecting eosinophil numbers associate with asthma and myocardial infarction. Nat Genet 2009;41:342-347.
4. Hancock DB, Romieu I, Shi M, Sienra-Monge JJ, Wu H, Chiu GY, Li H, del Rio-Navarro BE, Willis-Owen SA, Weiss ST, et al. Genome-wide association study implicates chromosome 9q21.31 as a susceptibility locus for asthma in Mexican children. PLoS Genet 2009;5:e1000623.
5. Himes BE, Hunninghake GM, Baurley JW, Rafaels NM, Sleiman P, Strachan DP, Wilk JB, Willis-Owen SA, Klanderman B, Lasky-Su J, et al. Genome-wide association analysis identifies PDE4D as an asthma-susceptibility gene. Am J Hum Genet 2009;84:581-593.
6. Hui J, Oka A, James A, Palmer LJ, Musk AW, Beilby J, Inoko H. A genome-wide association scan for asthma in a general Australian population. Hum Genet 2008;123:297-306.
7. Kim SH, Cho BY, Park CS, Shin ES, Cho EY, Yang EM, Kim CW, Hong CS, Lee JE, Park HS. Alpha-T-catenin (CTNNA3) gene was identified as a risk variant for toluene diisocyanate-induced asthma by genomewide association analysis. Clin Exp Allergy 2009;39:203-212.
8. Mathias RA, Grant AV, Rafaels N, Hand T, Gao L, Vergara C, Tsai YJ, Yang M, Campbell M, Foster C, et al. A genome-wide association study on African-ancestry populations for asthma. J Allergy Clin Immunol 2010;125:336-346.
9. Moffatt MF, Gut IG, Demenais F, Strachan DP, Bouzigon E, Heath S, von Mutius E, Farrall M, Lathrop M, Cookson WO; GABRIEL Consortium. A large-scale, consortium-based genomewide association study of asthma. N Engl J Med 2010;363:1211-1221.
10. Moffatt MF, Kabesch M, Liang L, Dixon AL, Strachan D, Heath S, Depner M, von Berg A, Bufe A, Rietschel E, et al. Genetic variants regulating ORMDL3 expression contribute to the risk of childhood asthma. Nature 2007;448:470-473.
11. Ober C, Tan Z, Sun Y, Possick JD, Pan L, Nicolae R, Radford S, Parry RR, Heinzmann A, Deichmann KA, et al. Effect of variation in CHI3L1 on serum YKL-40 level, risk of asthma, and lung function. N Engl J Med 2008;358:1682-1691.
12. Sleiman PM, Flory J, Imielinski M, Bradfield JP, Annaiah K, Willis-Owen SA, Wang K, Rafaels NM, Michel S, Bonnelykke K, et al. Variants of DENND1B associated with asthma in children. N Engl J Med 2010;362:36-44.
13. Weidinger S, Gieger C, Rodriguez E, Baurecht H, Mempel M, Klopp N, Gohlke H, Wagenpfeil S, Ollert M, Ring J, et al. Genome-wide scan on total serum IgE levels identifies FCER1A as novel susceptibility locus. PLoS Genet 2008;4:e1000166.
14. Hirota T, Takahashi A, Kubo M, Tsunoda T, Tomita K, Doi S, Fujita K, Miyatake A, Enomoto T, Miyagawa T, et al. Genome-wide association study identifies three new susceptibility loci for adult asthma in the Japanese population. Nat Genet 2011;43:893-896.
15. Torgerson DG, Ampleford EJ, Chiu GY, Gauderman WJ, Gignoux CR, Graves PE, Himes BE, Levin AM, Mathias RA, Hancock DB, et al.; Mexico City Childhood Asthma Study (MCAAS); Children's Health Study (CHS) and HARBORS study; Genetics of Asthma in Latino Americans (GALA) Study, Study of Genes-Environment and Admixture in Latino Americans (GALA2) and Study of African Americans, Asthma, Genes & Environments (SAGE); Childhood Asthma Research and Education (CARE) Network; Childhood Asthma Management Program (CAMP); Study of Asthma Phenotypes and Pharmacogenomic Interactions by Race-Ethnicity (SAPPHIRE); Genetic Research on Asthma in African Diaspora (GRAAD) Study. Meta-analysis of genome-wide association studies of asthma in ethnically diverse North American populations. Nat Genet 2011;43:887-892.
16. Noguchi E, Sakamoto H, Hirota T, Ochiai K, Imoto Y, Sakashita M, Kurosaka F, Akasawa A, Yoshihara S, Kanno N, et al. Genome-wide association study identifies HLA-DP as a susceptibility gene for pediatric asthma in Asian populations. PLoS Genet 2011;7:e1002170.
17. Manolio TA, Collins FS, Cox NJ, Goldstein DB, Hindorff LA, Hunter DJ, McCarthy MI, Ramos EM, Cardon LR, Chakravarti A, et al. Finding the missing heritability of complex diseases. Nature 2009;461:747-753.
18. Emilsson V, Thorleifsson G, Zhang B, Leonardson AS, Zink F, Zhu J, Carlson S, Helgason A, Walters GB, Gunnarsdottir S, et al. Genetics of gene expression and its effect on disease. Nature 2008;452:423-428.
19. Chen Y, Zhu J, Lum PY, Yang X, Pinto S, MacNeil DJ, Zhang C, Lamb J, Edwards S, Sieberts SK, et al. Variations in DNA elucidate molecular networks that cause disease. Nature 2008;452:429-435.
20. Teslovich TM, Musunuru K, Smith AV, Edmondson AC, Stylianou IM, Koseki M, Pirruccello JP, Ripatti S, Chasman DI, Willer CJ, et al. Biological, clinical and population relevance of 95 loci for blood lipids. Nature 2010;466:707-713.
21. Hao K, Bossé Y, Nickle DC, Paré PD, Postma DS, Laviolette M, Sandford A, Hackett TL, Daley D, Hogg JC, et al. Lung eQTLs to help reveal the molecular underpinnings of asthma. PLoS Genet 2012;8:e1003029.
22. Obeidat M, Miller S, Probert K, Billington CK, Henry AP, Hodge E, Nelson CP, Stewart CE, Swan C, Wain LV, et al. GSTCD and INTS12 regulation and expression in the human lung. PLoS One 2013;8:e74630.
23. Lamontagne M, Couture C, Postma DS, Timens W, Sin DD, Paré PD, Hogg JC, Nickle D, Laviolette M, Bossé Y. Refining susceptibility loci of chronic obstructive pulmonary disease with lung eqtls. PLoS One 2013;8:e70220.
24. Dimas AS, Deutsch S, Stranger BE, Montgomery SB, Borel C, Attar-Cohen H, Ingle C, Beazley C, Gutierrez Arcelus M, Sekowska M, et al. Common regulatory variation impacts gene expression in a cell type-dependent manner. Science 2009;325:1246-1250.
25. Tam A, Wadsworth S, Dorscheid D, Man SF, Sin DD. The airway epithelium: more than just a structural barrier. Ther Adv Respir Dis 2011;5:255-273.
26. Holgate ST. The sentinel role of the airway epithelium in asthma pathogenesis. Immunol Rev 2011;242:205-219.
27. Holgate ST, Roberts G, Arshad HS, Howarth PH, Davies DE. The role of the airway epithelium and its interaction with environmental factors in asthma pathogenesis. Proc Am Thorac Soc 2009;6:655-659.
28. Mercer BA, Lemâitre V, Powell CA, D'Armiento J. The epithelial cell in lung health and emphysema pathogenesis. Curr Respir Med Rev 2006;2:101-142.
29. Thorley AJ, Tetley TD. Pulmonary epithelium, cigarette smoke, and chronic obstructive pulmonary disease. Int J Chron Obstruct Pulmon Dis 2007;2:409-428.
30. Carolan BJ, Heguy A, Harvey BG, Leopold PL, Ferris B, Crystal RG. Upregulation of expression of the ubiquitin carboxyl-terminal hydrolase L1 gene in human airway epithelium of cigarette smokers. Cancer Res 2006;66:10729-10740.
31. Gao C, Tignor NL, Salit J, Strulovici-Barel Y, Hackett NR, Crystal RG, Mezey JG. HEFT: eQTL analysis of many thousands of expressed genes while simultaneously controlling for hidden factors. Bioinformatics 2014;30:369-376.
32. Laurie CC, Doheny KF, Mirel DB, Pugh EW, Bierut LJ, Bhangale T, Boehm F, Caporaso NE, Cornelis MC, Edenberg HJ, et al.; GENEVA Investigators. Quality control and quality assurance in genotypic data for genome-wide association studies. Genet Epidemiol 2010;34:591-602.
33. Boyle AP, Hong EL, Hariharan M, Cheng Y, Schaub MA, Kasowski M, Karczewski KJ, Park J, Hitz BC, Weng S, et al. Annotation of functional variation in personal genomes using RegulomeDB. Genome Res 2012;22:1790-1797.
34. Howie B, Fuchsberger C, Stephens M, Marchini J, Abecasis GR. Fast and accurate genotype imputation in genome-wide association studies through pre-phasing. Nat Genet 2012;44:955-959.
35. Schadt EE, Woo S, Hao K. Bayesian method to predict individual SNP genotypes from gene expression data. Nat Genet 2012;44:603-608.
36. Kang HM, Sul JH, Service SK, Zaitlen NA, Kong SY, Freimer NB, Sabatti C, Eskin E. Variance component model to account for sample structure in genome-wide association studies. Nat Genet 2010;42:348-354.
37. Di Narzo AF, Cheng H, Lu J, Hao K. Meta-eQTL: a tool set for flexible eQTL meta-analysis. BMC Bioinformatics 2014;15:392.
38. Lambert JC, Ibrahim-Verbaas CA, Harold D, Naj AC, Sims R, Bellenguez C, DeStafano AL, Bis JC, Beecham GW, Grenier-Boley B, et al.; European Alzheimer's Disease Initiative (EADI); Genetic and Environmental Risk in Alzheimer's Disease; Alzheimer's Disease Genetic Consortium; Cohorts for Heart and Aging Research in Genomic Epidemiology. Meta-analysis of 74, 046 individuals identifies 11 new susceptibility loci for Alzheimer's disease. Nat Genet 2013;45:1452-1458.
39. Morris AP, Voight BF, Teslovich TM, Ferreira T, Segrè AV, Steinthorsdottir V, Strawbridge RJ, Khan H, Grallert H, Mahajan A, et al.; Wellcome Trust Case Control Consortium; Meta-Analyses of Glucose and Insulin-related traits Consortium (MAGIC) Investigators; Genetic Investigation of ANthropometric Traits (GIANT) Consortium; Asian Genetic Epidemiology Network-Type 2 Diabetes (AGEN-T2D) Consortium; South Asian Type 2 Diabetes (SAT2D) Consortium; DIAbetes Genetics Replication And Meta-analysis (DIAGRAM) Consortium. Large-scale association analysis provides insights into the genetic architecture and pathophysiology of type 2 diabetes. Nat Genet 2012;44:981-990.
40. Locke AE, Kahali B, Berndt SI, Justice AE, Pers TH, Day FR, Powell C, Vedantam S, Buchkovich ML, Yang J, et al.; LifeLines Cohort Study; ADIPOGen Consortium; AGEN-BMI Working Group; CARDIOGRAMplusC4D Consortium; CKDGen Consortium; GLGC; ICBP; MAGIC Investigators; MuTHER Consortium; MIGen Consortium; PAGE Consortium; ReproGen Consortium; GENIE Consortium; International Endogene Consortium. Genetic studies of body mass index yield new insights for obesity biology. Nature 2015;518:197-206.
41. Purcell SM, Wray NR, Stone JL, Visscher PM, O'Donovan MC, Sullivan PF, Sklar P; International Schizophrenia Consortium. Common polygenic variation contributes to risk of schizophrenia and bipolar disorder. Nature 2009;460:748-752.
42. Schizophrenia Working Group of the Psychiatric Genomics Consortium. Biological insights from 108 schizophrenia-associated genetic loci. Nature 2014;511:421-427.
43. Ferreira MA, Matheson MC, Duffy DL, Marks GB, Hui J, Le Souëf P, Danoy P, Baltic S, Nyholt DR, Jenkins M, et al.; Australian Asthma Genetics Consortium. Identification of IL6R and chromosome 11q13.5 as risk loci for asthma. Lancet 2011;378:1006-1014.
44. Schadt EE, Molony C, Chudin E, Hao K, Yang X, Lum PY, Kasarskis A, Zhang B, Wang S, Suver C, et al. Mapping the genetic architecture of gene expression in human liver. PLoS Biol 2008;6:e107.
45. Genevar - Welcome Trust Sanger Institute. Search tools and software. Date. [accessed 2015 Feb. 26]. http://www.sanger.ac.uk/resources/software/genevar/
46. Westra HJ, Peters MJ, Esko T, Yaghootkar H, Schurmann C, Kettunen J, Christiansen MW, Fairfax BP, Schramm K, Powell JE, et al. Systematic identification of trans eQTLs as putative drivers of known disease associations. Nat Genet 2013;45:1238-1243.
47. Hindorff LA, Sethupathy P, Junkins HA, Ramos EM, Mehta JP, Collins FS, Manolio TA. Potential etiologic and functional implications of genome-wide association loci for human diseases and traits. Proc Natl Acad Sci USA 2009;106:9362-9367.
48. Flutre T, Wen X, Pritchard J, Stephens M. A statistical framework for joint eQTL analysis in multiple tissues. PLoS Genet 2013;9:e1003486.
49. Greenawalt DM, Dobrin R, Chudin E, Hatoum IJ, Suver C, Beaulaurier J, Zhang B, Castro V, Zhu J, Sieberts SK, et al. A survey of the genetics of stomach, liver, and adipose gene expression from a morbidly obese cohort. Genome Res 2011;21:1008-1016.
50. Dehghan A, Dupuis J, Barbalic M, Bis JC, Eiriksdottir G, Lu C, Pellikka N, Wallaschofski H, Kettunen J, Henneman P, et al. Meta-analysis of genome-wide association studies in >80 000 subjects identifies multiple loci for C-reactive protein levels. Circulation 2011;123:731-738.
51. Imboden M, Bouzigon E, Curjuric I, Ramasamy A, Kumar A, Hancock DB, Wilk JB, Vonk JM, Thun GA, Siroux V, et al. Genome-wide association study of lung function decline in adults with and without asthma. J Allergy Clin Immunol 2012;129:1218-1228.
52. Hancock DB, Artigas MS, Gharib SA, Henry A, Manichaikul A, Ramasamy A, Loth DW, Imboden M, Koch B, McArdle WL, et al. Genome-wide joint meta-analysis of SNP and SNP-by-smoking interaction identifies novel loci for pulmonary function. PLoS Genet 2012;8:e1003098.
53. Bossé Y, Hudson TJ. Toward a comprehensive set of asthma susceptibility genes. Annu Rev Med 2007;58:171-184.
54. Bernstein BE, Birney E, Dunham I, Green ED, Gunter C, Snyder M; ENCODE Project Consortium. An integrated encyclopedia of DNA elements in the human genome. Nature 2012;489:57-74.
55. RegulomeDB. RegulomeDB has been updated to Version 1.1. 2011 [accessed 2015 Feb. 26]. http://regulomedb.org/
56. Wang C, Rose-Zerilli MJ, Koppelman GH, Sandling JK, Holloway JW, Postma DS, Holgate ST, Bours V, Syvänen AC, Dideberg V. Evidence of association between interferon regulatory factor 5 gene polymorphisms and asthma. Gene 2012;504:220-225.
57. RegulomeDB. Data supporting chr7:128589426 (rs10954213). 2011 [accessed 2015 Feb. 26]. http://regulomedb.org/snp/chr7/128589426
58. Bisgaard H, Bønnelykke K, Sleiman PM, Brasholt M, Chawes B, Kreiner-Møller E, Stage M, Kim C, Tavendale R, Baty F, et al. Chromosome 17q21 gene variants are associated with asthma and exacerbations but not atopy in early childhood. Am J Respir Crit Care Med 2009;179:179-185.
59. Ferreira MA, McRae AF, Medland SE, Nyholt DR, Gordon SD, Wright MJ, Henders AK, Madden PA, Visscher PM, Wray NR, et al. Association between ORMDL3, IL1RL1 and a deletion on chromosome 17q21 with asthma risk in Australia. Eur J Hum Genet 2011;19:458-464.
60. Galanter J, Choudhry S, Eng C, Nazario S, Rodríguez-Santana JR, Casal J, Torres-Palacios A, Salas J, Chapela R, Watson HG, et al. ORMDL3 gene is associated with asthma in three ethnically diverse populations. Am J Respir Crit Care Med 2008;177:1194-1200.
61. Halapi E, Gudbjartsson DF, Jonsdottir GM, Bjornsdottir US, Thorleifsson G, Helgadottir H, Williams C, Koppelman GH, Heinzmann A, Boezen HM, et al. A sequence variant on 17q21 is associated with age at onset and severity of asthma. Eur J Hum Genet 2010;18:902-908.
62. Madore AM, Tremblay K, Hudson TJ, Laprise C. Replication of an association between 17q21 SNPs and asthma in a French-Canadian familial collection. Hum Genet 2008;123:93-95.
63. Sleiman PM, Annaiah K, Imielinski M, Bradfield JP, Kim CE, Frackelton EC, Glessner JT, Eckert AW, Otieno FG, Santa E, et al. ORMDL3 variants associated with asthma susceptibility in North Americans of European ancestry. J Allergy Clin Immunol 2008;122:1225-1227.
64. Tavendale R, Macgregor DF, Mukhopadhyay S, Palmer CN. A polymorphism controlling ORMDL3 expression is associated with asthma that is poorly controlled by current medications. J Allergy Clin Immunol 2008;121:860-863.
65. Wu H, Romieu I, Sienra-Monge JJ, Li H, del Rio-Navarro BE, London SJ. Genetic variation in ORM1-like 3 (ORMDL3) and gasdermin-like (GSDML) and childhood asthma. Allergy 2009;64:629-635.
66. Duffin R, Leitch AE, Sheldrake TA, Hallett JM, Meyer C, Fox S, Alessandri AL, Martin MC, Brady HJ, Teixeira MM, et al. The CDK inhibitor, R-roscovitine, promotes eosinophil apoptosis by downregulation of Mcl-1. FEBS Lett 2009;583:2540-2546.
67. Leitch AE, Haslett C, Rossi AG. Cyclin-dependent kinase inhibitor drugs as potential novel anti-inflammatory and pro-resolution agents. Br J Pharmacol 2009;158:1004-1016.
68. Sekigawa T, Tajima A, Hasegawa T, Hasegawa Y, Inoue H, Sano Y, Matsune S, Kurono Y, Inoue I. Gene-expression profiles in human nasal polyp tissues and identification of genetic susceptibility in aspirin-intolerant asthma. Clin Exp Allergy 2009;39:972-981.
69. Daley D, Park JE, He JQ, Yan J, Akhabir L, Stefanowicz D, Becker AB, Chan-Yeung M, Bosse Y, Kozyrskyj AL, et al. Associations and interactions of genetic polymorphisms in innate immunity genes with early viral infections and susceptibility to asthma and asthma-related phenotypes. J Allergy Clin Immunol 2012;130:1284-1293.
70. Colotta F, Re F, Muzio M, Bertini R, Polentarutti N, Sironi M, Giri JG, Dower SK, Sims JE, Mantovani A. Interleukin-1 type II receptor: a decoy target for IL-1 that is regulated by IL-4. Science 1993;261:472-475.
71. Lang D, Knop J, Wesche H, Raffetseder U, Kurrle R, Boraschi D, Martin MU. The type II IL-1 receptor interacts with the IL-1 receptor accessory protein: a novel mechanism of regulation of IL-1 responsiveness. J Immunol 1998;161:6871-6877.
72. Muller B, Peri G, Doni A, Perruchoud AP, Landmann R, Pasqualini F, Mantovani A. High circulating levels of the IL-1 type II decoy receptor in critically ill patients with sepsis: association of high decoy receptor levels with glucocorticoid administration. J Leukoc Biol 2002;72:643-649.
73. Re F, Muzio M, De Rossi M, Polentarutti N, Giri JG, Mantovani A, Colotta F. The type II "receptor" as a decoy target for interleukin 1 in polymorphonuclear leukocytes: characterization of induction by dexamethasone and ligand binding properties of the released decoy receptor. J Exp Med 1994;179:739-743.
74. Colotta F, Saccani S, Giri JG, Dower SK, Sims JE, Introna M, Mantovani A. Regulated expression and release of the IL-1 decoy receptor in human mononuclear phagocytes. J Immunol 1996;156:2534-2541.
75. Penton-Rol G, Orlando S, Polentarutti N, Bernasconi S, Muzio M, Introna M, Mantovani A. Bacterial lipopolysaccharide causes rapid shedding, followed by inhibition of mRNA expression, of the IL-1 type II receptor, with concomitant up-regulation of the type I receptor and induction of incompletely spliced transcripts. J Immunol 1999;162:2931-2938.
76. Brown EA, Dare HA, Marsh CB, Wewers MD. The combination of endotoxin and dexamethasone induces type II interleukin 1 receptor (IL-1r II) in monocytes: a comparison to interleukin 1 beta (IL-1 beta) and interleukin 1 receptor antagonist (IL-1ra). Cytokine 1996;8:828-836.
77. Yu PW, Schuler LA, Kehrli M, Mattocks L, Nonnecke BJ, Czuprynski CJ. Effects of dexamethasone treatment on IL-1 receptor mRNA levels in vivo. J Leukoc Biol 1997;62:401-404.
78. Lin CH, Nai PL, Bien MY, Yu CC, Chen BC. Thrombin-induced CCAAT/enhancer-binding protein β activation and IL-8/CXCL8 expression via MEKK1, ERK, and p90 ribosomal S6 kinase 1 in lung epithelial cells. J Immunol 2014;192:338-348.
79. Hallstrand TS, Lai Y, Henderson WR Jr, Altemeier WA, Gelb MH. Epithelial regulation of eicosanoid production in asthma. Pulm Pharmacol Ther 2012;25:432-437.
80. Imoto Y, Tokunaga T, Matsumoto Y, Hamada Y, Ono M, Yamada T, Ito Y, Arinami T, Okano M, Noguchi E, et al. Cystatin SN upregulation in patients with seasonal allergic rhinitis. PLoS One 2013;8:e67057.
81. Bønnelykke K, Sleiman P, Nielsen K, Kreiner-Møller E, Mercader JM, Belgrave D, den Dekker HT, Husby A, Sevelsted A, Faura-Tellez G, et al. A genome-wide association study identifies CDHR3 as a susceptibility locus for early childhood asthma with severe exacerbations. Nat Genet 2014;46:51-55.
82. Cantin AM, North SL, Hubbard RC, Crystal RG. Normal alveolar epithelial lining fluid contains high levels of glutathione. J Appl Physiol (1985) 1987;63:152-157.
83. Harju T, Mazur W, Merikallio H, Soini Y, Kinnula VL. Glutathione-S-transferases in lung and sputum specimens, effects of smoking and COPD severity. Respir Res 2008;9:80.
84. Zienolddiny S, Campa D, Lind H, Ryberg D, Skaug V, Stangeland LB, Canzian F, Haugen A. A comprehensive analysis of phase I and phase II metabolism gene polymorphisms and risk of non-small cell lung cancer in smokers. Carcinogenesis 2008;29:1164-1169.
85. Qiu W, Cho MH, Riley JH, Anderson WH, Singh D, Bakke P, Gulsvik A, Litonjua AA, Lomas DA, Crapo JD, et al.; ECLIPSE Investigators. Genetics of sputum gene expression in chronic obstructive pulmonary disease. PLoS One 2011;6:e24395.
86. Mägert HJ, Kreutzmann P, Drögemüller K, Ständker L, Adermann K, Walden M, John H, Korting HC, Forssmann WG. The 15-domain serine proteinase inhibitor LEKTI: biochemical properties, genomic organization, and pathophysiological role. Eur J Med Res 2002;7:49-56.
87. Postma DS, Bleecker ER, Amelung PJ, Holroyd KJ, Xu J, Panhuysen CI, Meyers DA, Levitt RC. Genetic susceptibility to asthma: bronchial hyperresponsiveness coinherited with a major gene for atopy. N Engl J Med 1995;333:894-900.
88. Noguchi E, Shibasaki M, Arinami T, Takeda K, Maki T, Miyamoto T, Kawashima T, Kobayashi K, Hamaguchi H. Evidence for linkage between asthma/atopy in childhood and chromosome 5q31-q33 in a Japanese population. Am J Respir Crit Care Med 1997;156:1390-1393.
89. Yokouchi Y, Nukaga Y, Shibasaki M, Noguchi E, Kimura K, Ito S, Nishihara M, Yamakawa-Kobayashi K, Takeda K, Imoto N, et al. Significant evidence for linkage of mite-sensitive childhood asthma to chromosome 5q31-q33 near the interleukin 12 B locus by a genome-wide search in Japanese families. Genomics 2000;66:152-160.
90. Kato A, Fukai K, Oiso N, Hosomi N, Murakami T, Ishii M. Association of SPINK5 gene polymorphisms with atopic dermatitis in the Japanese population. Br J Dermatol 2003;148:665-669.
91. Kabesch M, Carr D, Weiland SK, von Mutius E. Association between polymorphisms in serine protease inhibitor, kazal type 5 and asthma phenotypes in a large German population sample. Clin Exp Allergy 2004;34:340-345.
92. Kusunoki T, Okafuji I, Yoshioka T, Saito M, Nishikomori R, Heike T, Sugai M, Shimizu A, Nakahata T. SPINK5 polymorphism is associated with disease severity and food allergy in children with atopic dermatitis. J Allergy Clin Immunol 2005;115:636-638.
93. Himes BE, Jiang X, Hu R, Wu AC, Lasky-Su JA, Klanderman BJ, Ziniti J, Senter-Sylvia J, Lima JJ, Irvin CG, et al. Genome-wide association analysis in asthma subjects identifies SPATS2L as a novel bronchodilator response gene. PLoS Genet 2012;8:e1002824.
94. Steinke JW, Borish L. Th2 cytokines and asthma. Interleukin-4: its role in the pathogenesis of asthma, and targeting it for asthma treatment with interleukin-4 receptor antagonists. Respir Res 2001;2:66-70.