Genome wide association studies (GWASs) have revealed several airway disease-associated risk loci. Their role in the onset of asthma, allergic rhinitis (AR) or chronic rhinosinusitis (CRS), however, is not yet fully understood. The aim of this review is to evaluate the airway relevance of loci and genes identified in GWAS studies. GWASs were searched from databases, and a list of loci associating significantly (p < 10-8) with asthma, AR and CRS was created. This yielded a total of 267 significantly asthma/AR-associated loci from 31 GWASs. No significant CRS -associated loci were found in this search. A total of 170 protein coding genes were connected to these loci. Of these, 76/170 (44%) showed bronchial epithelial protein expression in stained microscopic figures of Human Protein Atlas (HPA), and 61/170 (36%) had a literature report of having airway epithelial function. Gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) annotation analyses were performed, and 19 functional protein categories were found as significantly (p < 0.05) enriched among these genes. These were related to cytokine production, cell activation and adaptive immune response, and all were strongly connected in network analysis. We also identified 15 protein pathways that were significantly (p < 0.05) enriched in these genes, related to T-helper cell differentiation, virus infection, JAK-STAT signaling pathway, and asthma. A third of GWAS-level risk loci genes of asthma or AR seemed to have airway epithelial functions according to our database and literature searches. In addition, many of the risk loci genes were immunity related. Some risk loci genes also related to metabolism, neuro-musculoskeletal or other functions. Functions overlapped and formed a strong network in our pathway analyses and are worth future studies of biomarker and therapeutics.

Corporate Member of Freie Universität Berlin Humboldt Universität Zu Berlin and Berlin Institute of Health Comprehensive Allergy Center Department of Dermatology and Allergy Charité Universitätsmedizin Berlin Berlin Germany

Department of Otorhinolaryngology Head and Neck Surgery University of Helsinki and Helsinki University Hospital Kasarmikatu 11 13 P O Box 263 00029 HUS Helsinki Finland

Department of Pediatrics and Adolescent Medicine Turku University Hospital and University of Turku Turku Finland

Haartman Institute University of Helsinki Helsinki Finland

Hematology Research Unit Helsinki Department of Hematology Helsinki University Hospital Comprehensive Cancer Center Helsinki Finland

HUS Diagnostic Center Helsinki University Hospital Helsinki Finland

Laboratory of Cellular and Molecular Immunology Institute of Microbiology of the Czech Academy of Sciences Prague Czech Republic

MACVIA France Montpellier France

Skin and Allergy Hospital University of Helsinki and Helsinki University Hospital Helsinki Finland

Translational Immunology Research Program and Department of Clinical Chemistry University of Helsinki Helsinki Finland

Université Montpellier Montpellier France

Zobrazit více v PubMed

Wang D‐Y. Risk factors of allergic rhinitis: genetic or environmental? Ther Clin Risk Manag. 2005; 1(2): 115–123. PubMed PMC

Fokkens WJ, Lund VJ, Mullol J, Bachert C, Alobid I, Baroody F, et al. EPOS 2012: European position paper on rhinosinusitis and nasal polyps 2012. A summary for otorhinolaryngologists Rhinology. 2012; 50(1): 1–12 PubMed

de Loos DD, Lourijsen ES, Wildeman MAM, Freling NJM, Wolvers MDJ, Reitsma S, et al. Prevalence of chronic rhinosinusitis in the general population based on sinus radiology and symptomatology. J Allergy Clin Immunol. 2019; 143(3): 1207–14. PubMed

Hirsch AG, Nordberg C, Bandeen‐Roche K, Tan BK, Schleimer RP, Kern RC, et al. Radiologic sinus inflammation and symptoms of chronic rhinosinusitis in a population‐based sample. Allergy. 2019;all.14106. PubMed PMC

Fokkens WJ, Lund VJ, Hopkins C, Hellings PW, Kern R, Reitsma S, et al. European Position Paper on Rhinosinusitis and Nasal Polyps, vol 103. Dieudonné Nyenbue Tshipukane. 2020.

Wikstén J, Toppila‐Salmi S, Mäkelä M. Primary prevention of airway allergy. Curr Treat Options Allergy. 2018; 5(4): 347–355. PubMed PMC

Dharmage SC, Perret JL, Custovic A. Epidemiology of asthma in children and adults. Front Pediatrics. 2019, 7: 246 PubMed PMC

Bashiardes S, Zilberman‐Schapira G, Elinav E. Use of metatranscriptomics in microbiome research. Bioinform Biol Insights. 2016, 10: 19–25. PubMed PMC

Laulajainen‐Hongisto A, Toppila‐Salmi S, Luukkainen A, Kern R. Airway Epithelial Dynamics in Allergy and Related Chronic Inflammatory Airway Diseases. Front Cell Dev Biol. 2020;8(204). PubMed PMC

Ober C. Asthma genetics in the post‐GWAS Era. In: Annals of the American Thoracic Society. American Thoracic Society; 2016. p. S85–90. PubMed PMC

Mattila P, Renkonen J, Toppila‐Salmi S, Parviainen V, Joenväärä S, Alff‐Tuomala S, et al. Time‐series nasal epithelial transcriptomics during natural pollen exposure in healthy subjects and allergic patients. Allergy Eur J Allergy Clin Immunol. 2010; 65(2): 175–183. PubMed

Dickson RP, Erb‐Downward JR, Huffnagle GB. The role of the bacterial microbiome in lung disease. Expert Review of Respiratory Medicine. 2013, 7: 245–257. PubMed PMC

Busse WW, Lemanske RF, Gern JE. Role of viral respiratory infections in asthma and asthma exacerbations. Lancet. 2010, 376: 826–834. PubMed PMC

Li N, Peters AT. Chronic rhinosinusitis management beyond intranasal steroids and saline solution irrigations. Allergy Asthma Proc. 2015; 36(5): 339–343. PubMed PMC

Just J, Pierre SP, Amat F, Gouvis‐Echraghi R, Lambert‐Guillemot N, Guiddir T, et al. What lessons can be learned about asthma phenotypes in children from cohort studies? Pediatric Allergy Immunol. 2015, 26: 300–5. PubMed

Lemmetyinen RE, Karjalainen JV, But A, Renkonen RLO, Pekkanen JR, Toppila‐Salmi SK, et al. Higher mortality of adults with asthma: a 15‐year follow‐up of a population‐based cohort. Allergy. 2018; 73(7): 1479–1488. PubMed

Hanif T, Dhaygude K, Kankainen M, Renkonen J, Mattila P, Ojala T, et al. Birch pollen allergen immunotherapy reprograms nasal epithelial transcriptome and recovers microbial diversity. J Allergy Clin Immunol. 2019; 143(6): 2293–2296.e11. PubMed

Lampi J, Koskela H, Hartikainen A‐L, Ramasamy A, Couto Alves A, Järvelin M‐R, et al. Farm environment during infancy and lung function at the age of 31: a prospective birth cohort study in Finland. BMJ Open. 2015; 5(7): e007350 PubMed PMC

Demenais F, Margaritte‐Jeannin P, Barnes KC, Cookson WOC, Altmüller J, Ang W, et al. Multiancestry association study identifies new asthma risk loci that colocalize with immune‐cell enhancer marks. Nat Genet. 2018; 50(1): 42–50. PubMed PMC

Ober C, Yao T‐C. The genetics of asthma and allergic disease: a 21st century perspective. Immunol Rev. 2011; 242(1): 10–30. PubMed PMC

Oakley GM, Curtin K, Orb Q, Schaefer C, Orlandi RR, Alt JA. Familial risk of chronic rhinosinusitis with and without nasal polyposis: genetics or environment. Int Forum Allergy Rhinol. 2015; 5(4): 276–282. PubMed

Kim KW, Ober C. Lessons learned from GWAS of asthma. Allergy, asthma and immunology research. Korean Acad Asthma Allergy Clin Immunol. 2019, 11: 170–87. PubMed PMC

Willis‐Owen SAG, Cookson WOC, Moffatt MF. The genetics and genomics of asthma. Annu Rev Genomics Hum Genet. 2018; 19(1): 223–246. PubMed

Schoettler N, Rodríguez E, Weidinger S, Ober C. Advances in asthma and allergic disease genetics: Is bigger always better? J Allergy Clin Immunol. 2019; 144(6): 1495–1506. PubMed PMC

Yu G, Wang LG, Han Y, He QY. ClusterProfiler: An R package for comparing biological themes among gene clusters. Omi A J Integr Biol. 2012; 16(5): 284–287. PubMed PMC

Chupp GL, Lee CG, Jarjour N, Shim YM, Holm CT, He S, et al. A chitinase‐like protein in the lung and circulation of patients with severe asthma. N Engl J Med. 2007; 357(20): 2016–2027. PubMed

Ober C, Tan Z, Sun Y, Possick JD, Pan L, Nicolae R, et al. Effect of variation in CHI3L1 on serum YKL‐40 level, risk of asthma, and lung function. N Engl J Med. 2008; 358(16): 1682–1691. PubMed PMC

Lemanske RF. The Childhood Origins of Asthma (COAST) study. In: Pediatric Allergy and Immunology, Supplement. 2002. p. 38–43. PubMed

Hulpiau P, van Roy F. Molecular evolution of the cadherin superfamily. Int J Biochem Cell Biol. 2009, 41: 349–369. PubMed

Griggs TF, Bochkov YA, Basnet S, Pasic TR, Brockman‐Schneider RA, Palmenberg AC, et al. Rhinovirus C targets ciliated airway epithelial cells. Respir Res. 2017; 18(1): 84 PubMed PMC

Bønnelykke K, Sleiman P, Nielsen K, Kreiner‐Møller E, Mercader JM, Belgrave D, et al. A genome‐wide association study identifies CDHR3 as a susceptibility locus for early childhood asthma with severe exacerbations. Nat Genet. 2014; 46(1): 51–55. PubMed

Stein MM, Thompson EE, Schoettler N, Helling BA, Magnaye KM, Stanhope C, et al. A decade of research on the 17q12‐21 asthma locus: piecing together the puzzle. J Allergy Clin Immunol. 2018; 142(3): 749–764.e3. PubMed PMC

Das S, Miller M, Broide DH. Chromosome 17q21 Genes ORMDL3 and GSDMB in Asthma and Immune Diseases. In: Advances in Immunology. Academic Press Inc.; 2017. p. 1–52. PubMed

Broz P, Pelegrín P, Shao F. The gasdermins, a protein family executing cell death and inflammation. 2019, Nature Reviews Immunology: Nature Publishing Group. PubMed

Panganiban RA, Sun M, Dahlin A, Park HR, Kan M, Himes BE, et al. A functional splice variant associated with decreased asthma risk abolishes the ability of gasdermin B to induce epithelial cell pyroptosis. J Allergy Clin Immunol. 2018; 142(5): 1469–1478.e2. PubMed PMC

Moffatt MF, Gut IG, Demenais F, Strachan DP, Bouzigon E, Heath S, et al. A large‐scale, consortium‐based genomewide association study of asthma. N Engl J Med. 2010; 363(13): 1211–1221. PubMed PMC

Ferreira MAR, Matheson MC, Tang CS, Granell R, Ang W, Hui J, et al. Genome‐wide association analysis identifies 11 risk variants associated with the asthma with hay fever phenotype. J Allergy Clin Immunol. 2014; 133(6): 1564–1571. PubMed PMC

Torgerson DG, Ampleford EJ, Chiu GY, Gauderman WJ, Gignoux CR, Graves PE, et al. Meta‐analysis of genome‐wide association studies of asthma in ethnically diverse North American populations. Nat Genet. 2011; 43(9): 887–892. PubMed PMC

Bønnelykke K, Matheson MC, Pers TH, Granell R, Strachan DP, Alves AC, et al. Meta‐analysis of genome‐wide association studies identifies ten loci influencing allergic sensitization. Nat Genet. 2013; 45(8): 902–906. PubMed PMC

Ferreira MA, Vonk JM, Baurecht H, Marenholz I, Tian C, Hoffman JD, et al. Shared genetic origin of asthma, hay fever and eczema elucidates allergic disease biology. Nat Genet. 2017; 49(12): 1752–1757. PubMed PMC

Hinds DA, McMahon G, Kiefer AK, Do CB, Eriksson N, Evans DM, et al. A genome‐wide association meta‐analysis of self‐reported allergy identifies shared and allergy‐specific susceptibility loci. Nat Genet. 2013; 45(8): 907–911. PubMed PMC

Yan Q, Brehm J, Pino‐Yanes M, Forno E, Lin J, Oh SS, et al. A meta‐analysis of genome‐wide association studies of asthma in Puerto Ricans. Eur Respir J. 2017;49(5). PubMed PMC

Poole A, Urbanek C, Eng C, Schageman J, Jacobson S, O'Connor BP, et al. Dissecting childhood asthma with nasal transcriptomics distinguishes subphenotypes of disease. J Allergy Clin Immunol. 2014; 133(3): 670 PubMed PMC

Das S, Miller M, Beppu AK, Mueller J, McGeough MD, Vuong C, et al. GSDMB induces an asthma phenotype characterized by increased airway responsiveness and remodeling without lung inflammation. Proc Natl Acad Sci U S A. 2016; 113(46): 13132–13137. PubMed PMC

Nieuwenhuis MA, Siedlinski M, van den Berge M, Granell R, Li X, Niens M, et al. Combining genomewide association study and lung eQTL analysis provides evidence for novel genes associated with asthma. Allergy Eur J Allergy Clin Immunol. 2016; 71(12): 1712–1720. PubMed PMC

Awwad MHS, Kriegsmann K, Plaumann J, Benn M, Hillengass J, Raab MS, et al. The prognostic and predictive value of IKZF1 and IKZF3 expression in T‐cells in patients with multiple myeloma. Oncoimmunology. 2018; 7(10): e1486356 PubMed PMC

Uhlén M, Fagerberg L, Hallström BM, Lindskog C, Oksvold P, Mardinoglu A, et al. Tissue‐based map of the human proteome. Science. 2015; 347(6220): 1260419 PubMed

Vandevenne M, Jacques DA, Artuz C, Nguyen CD, Kwan AHY, Segal DJ, et al. New insights into DNA recognition by zinc fingers revealed by structural analysis of the oncoprotein ZNF217. J Biol Chem. 2013; 288(15): 10616–10627. PubMed PMC

Cohen PA, Donini CF, Nguyen NT, Lincet H, Vendrell JA. The dark side of ZNF217, a key regulator of tumorigenesis with powerful biomarker value. Oncotarget. 2015; 6(39): 41566–41581. PubMed PMC

Cassandri M, Smirnov A, Novelli F, Pitolli C, Agostini M, Malewicz M, et al. Zinc‐finger proteins in health and disease. 2017, Springer Nature: Cell Death Discovery. PubMed PMC

Wu AC, Himes BE, Lasky‐Su J, Litonjua A, Peters SP, Lima J, et al. Inhaled corticosteroid treatment modulates ZNF432 gene variant's effect on bronchodilator response in asthmatics. J Allergy Clin Immunol. 2014; 133(3): 723–728. PubMed PMC

O'Regan GM, Sandilands A, McLean WHI, Irvine AD. Filaggrin in atopic dermatitis. J Allergy Clin Immunol. 2009,124(3 SUPPL. 2). PubMed

Van Den Oord RAHM, Sheikh A. Filaggrin gene defects and risk of developing allergic sensitisation and allergic disorders: systematic review and meta‐analysis. BMJ. 2009; 339(7712): 86–88 PubMed PMC

Bin L, Leung DYM. Genetic and epigenetic studies of atopic dermatitis. Allergy, Asthma and Clinical Immunology. 2016, 12: 52 PubMed PMC

Weidinger S, Willis‐Owen SAG, Kamatani Y, Baurecht H, Morar N, Liang L, et al. A genome‐wide association study of atopic dermatitis identifies loci with overlapping effects on asthma and psoriasis. Hum Mol Genet. 2013; 22(23): 4841–4856. PubMed PMC

Tsuji G, Hashimoto‐Hachiya A, Kiyomatsu‐Oda M, Takemura M, Ohno F, Ito T, et al. Aryl hydrocarbon receptor activation restores filaggrin expression via OVOL1 in atopic dermatitis. Cell Death Dis. 2017; 8(7): e2931 PubMed PMC

Hashimoto‐Hachiya A, Tsuji G, Murai M, Yan X, Furue M. Upregulation of FLG, LOR, and IVL expression by rhodiola crenulata root extract via aryl hydrocarbon receptor: Differential involvement of OVOL1. Int J Mol Sci. 2018; 19(6): 1654 PubMed PMC

De Benedetto A, Qualia CM, Baroody FM, Beck LA. Filaggrin expression in oral, nasal, and esophageal mucosa. J Investigative Dermatol. 2008, 128: 1594–7. PubMed

Renkonen J, Toppila‐Salmi S, Joenväärä S, Mattila P, Parviainen V, Hagström J, et al. Expression of Toll‐like receptors in nasal epithelium in allergic rhinitis. APMIS. 2015; 123(8): 716–725. PubMed PMC

Anthoni M, Wang G, Leino MS, Lauerma AI, Alenius HT, Wolff HJ. Smad3 ‐signalling and Th2 cytokines in normal mouse airways and in a mouse model of asthma. Int J Biol Sci. 2007; 3(7): 477–485. PubMed PMC

Yasukawa A, Hosoki K, Toda M, Miyake Y, Matsushima Y, Matsumoto T, et al. Eosinophils promote epithelial to mesenchymal transition of bronchial epithelial cells. Chu HW, editor. PLoS One. 2013;8(5):e64281. PubMed PMC

Kitamura H, Cambier S, Somanath S, Barker T, Minagawa S, Markovics J, et al. Mouse and human lung fibroblasts regulate dendritic cell trafficking, airway inflammation, and fibrosis through integrin αvβ8 ‐ Mediated activation of TGF‐β. J Clin Invest. 2011; 121(7): 2863–2875. PubMed PMC

Fernando MMA, Stevens CR, Walsh EC, De Jager PL, Goyette P, Plenge RM, et al. Defining the role of the MHC in autoimmunity: a review and pooled analysis. PLoS Genetics. 2008, 4: e1000024 PubMed PMC

Fawzy MS, Elgazzaz MG, Ibrahim A, Hussein MH, Khashana MS, Toraih EA. Association of group‐specific component exon 11 polymorphisms with bronchial asthma in children and adolescents. Scand J Immunol. 2019; 89(3): e12740 PubMed

Global strategy for asthma management and prevention . (cited 2020 Apr 20). www.ginasthma.org

Boonpiyathad T, Sözener ZC, Satitsuksanoa P, Akdis CA. Immunologic mechanisms in asthma. Seminars in Immunology. 2019, 46: 101333 PubMed

Fahy JV. Type 2 inflammation in asthma‐present in most, absent in many. Nature Rev Immunol. 2015, 15: 57–65. PubMed PMC

Lloyd CM. IL‐33 family members and asthma ‐ bridging innate and adaptive immune responses. Curr Opin Immunol. 2010, 22: 800–806. PubMed PMC

Takatori H, Makita S, Ito T, Matsuki A, Nakajima H. Regulatory mechanisms of IL‐33‐ST2‐mediated allergic inflammation. Front Immunol. 2018, 9: 2004 PubMed PMC

Cayrol C, Girard JP. IL‐33: An alarmin cytokine with crucial roles in innate immunity, inflammation and allergy. Curr Opin Immunol. 2014, 31: 31–37. PubMed

Papadopoulos NG, Barnes P, Canonica GW, Gaga M, Heaney L, Menzies‐Gow A, et al. The Evolving Algorithm of Biological Selection in Severe Asthma. Allergy. 2020; 14256. PubMed

Nadif R, Siroux V, Boudier A, Le Moual N, Just J, Gormand F, et al. Blood granulocyte patterns as predictors of asthma phenotypes in adults from the EGEA study. Eur Respir J. 2016; 48(4): 1040–1051. PubMed

Préfontaine D, Nadigel J, Chouiali F, Audusseau S, Semlali A, Chakir J, et al. Increased IL‐33 expression by epithelial cells in bronchial asthma. J Allergy Clin Immunol. 2010, 125: 752–754. PubMed

Smith D, Helgason H, Sulem P, Bjornsdottir US, Lim AC, Sveinbjornsson G, et al. A rare IL33 loss‐of‐function mutation reduces blood eosinophil counts and protects from asthma. PLoS Genet. 2017; 13(3): e1006659 PubMed PMC

Holgado A, Braun H, Van Nuffel E, Detry S, Schuijs MJ, Deswarte K, et al. IL‐33trap is a novel IL‐33–neutralizing biologic that inhibits allergic airway inflammation. J Allergy Clin Immunol. 2019; 144(1): 204–215. PubMed PMC

Braun H, Afonina IS, Mueller C, Beyaert R. Dichotomous function of IL‐33 in health and disease: From biology to clinical implications. Biochem Pharmacol. 2018, 148: 238–252. PubMed

Khurana Hershey GK. IL‐13 receptors and signaling pathways: An evolving web. J Allergy Clin Immunol. 2003, 111: 677–690. PubMed

Sastre J, Dávila I. Dupilumab: A new paradigm for the treatment of allergic diseases. J Investig Allergol Clin Immunol. 2018, 28: 139–150. PubMed

Bachert C, Han JK, Desrosiers M, Hellings PW, Amin N, Lee SE, et al. Efficacy and safety of dupilumab in patients with severe chronic rhinosinusitis with nasal polyps (LIBERTY NP SINUS‐24 and LIBERTY NP SINUS‐52): results from two multicentre, randomised, double‐blind, placebo‐controlled, parallel‐group phase 3 trials. Lancet. 2019; 394(10209): 1638–1650. PubMed

Zhu Z, Homer RJ, Wang Z, Chen Q, Geba GP, Wang J, et al. Pulmonary expression of interleukin‐13 causes inflammation, mucus hypersecretion, subepithelial fibrosis, physiologic abnormalities, and eotaxin production. J Clin Invest. 1999; 103(6): 779–788. PubMed PMC

Zheng T, Zhu Z, Wang Z, Homer RJ, Ma B, Riese RJ, et al. Inducible targeting of IL‐13 to the adult lung causes matrix metalloproteinase‐ and cathepsin‐dependent emphysema. J Clin Invest. 2000; 106(9): 1081–1093. PubMed PMC

Accordini S, Calciano L, Bombieri C, Malerba G, Belpinati F, Lo Presti AR, et al. An Interleukin 13 polymorphism is associated with symptom severity in adult subjects with ever asthma. PLoS ONE. 2016; 11(3): e0151292 PubMed PMC

Ito T, Liu YJ, Arima K. Cellular and molecular mechanisms of TSLP function in human allergic disorders ‐ TSLP programs the “Th2 code” in dendritic cells. Allergol Int. 2012, 61: 35–43. PubMed PMC

Corren J, Parnes JR, Wang L, Mo M, Roseti SL, Griffiths JM, et al. Tezepelumab in adults with uncontrolled asthma. N Engl J Med. 2017; 377(10): 936–946. PubMed

Ray A, Cohn L. Th2 cells and GATA‐3 in asthma: New insights into the regulation of airway inflammation. J Clin Investigation. 1999, 104: 985–93. PubMed PMC

Bergqvist A, Andersson CK, Hoffmann HJ, Mori M, Shikhagaie M, Krohn IK, et al. Marked epithelial cell pathology and leukocyte paucity in persistently symptomatic severe asthma. Am J Resp Crit Care Med. 2013, 188: 1475–7. PubMed

KleinJan A, Klein Wolterink RGJ, Levani Y, de Bruijn MJW, Hoogsteden HC, van Nimwegen M, et al. Enforced expression of Gata3 in T cells and group 2 innate lymphoid cells increases susceptibility to allergic airway inflammation in mice. J Immunol. 2014; 192(4): 1385–1394. PubMed

Krug N, Hohlfeld JM, Kirsten A‐M, Kornmann O, Beeh KM, Kappeler D, et al. Allergen‐induced asthmatic responses modified by a GATA3‐specific DNAzyme. N Engl J Med. 2015; 372(21): 1987–1995. PubMed

Czimmerer Z, Daniel B, Horvath A, Rückerl D, Nagy G, Kiss M, et al. The Transcription factor STAT6 mediates direct repression of inflammatory enhancers and limits activation of alternatively polarized macrophages. Immunity. 2018; 48(1): 75–90.e6. PubMed PMC

Walford HH, Doherty TA. STAT6 and lung inflammation. JAK‐STAT. 2013; 2(4): e25301 PubMed PMC

Förster R, Davalos‐Misslitz AC, Rot A. CCR7 and its ligands: Balancing immunity and tolerance. Nat Rev Immunol. 2008, 8: 362–371. PubMed

Wei G, Jie Y, Haibo L, Chaoneng W, Dong H, Jianbing Z, et al. Dendritic cells derived exosomes migration to spleen and induction of inflammation are regulated by CCR7. Sci Rep. 2017, 7: 42996 PubMed PMC

Li Y, Du Y, Zhang A, Jiang R, Nie X, Xiong X. Role of CCR7 on dendritic cell‐mediated immune tolerance in the airways of allergy‐induced asthmatic rats. Mol Med Rep. 2019; 20(5): 4425–4432. PubMed PMC

Weidinger S, Gieger C, Rodriguez E, Baurecht H, Mempel M, Klopp N, et al. Genome‐wide scan on total serum IgE levels identifies FCER1A as novel susceptibility locus. PLoS Genet. 2008; 4(8): e1000166 PubMed PMC

Granada M, Wilk JB, Tuzova M, Strachan DP, Weidinger S, Albrecht E, et al. A genome‐wide association study of plasma total IgE concentrations in the Framingham Heart Study. J Allergy Clin Immunol. 2012; 129(3): 840–845.e21. PubMed PMC

Dar SA, Rai G, Ansari MA, Akhter N, Gupta N, Sharma S, et al. FcɛR1α gene polymorphism shows association with high IgE and anti‐FcɛR1α in Chronic Rhinosinusitis with Nasal Polyposis. J Cell Biochem. 2018; 119(5): 4142–4149. PubMed

Shin JS, Greer AM. The role of FcεRI expressed in dendritic cells and monocytes. Cell Mol Life Sci. 2015, 72: 2349–60. PubMed PMC

Ramasamy A, Curjuric I, Coin LJ, Kumar A, McArdle WL, Imboden M, et al. A genome‐wide meta‐analysis of genetic variants associated with allergic rhinitis and grass sensitization and their interaction with birth order. J Allergy Clin Immunol. 2011; 128(5): 996–1005. PubMed

Vogelzang A, McGuire HM, Yu D, Sprent J, Mackay CR, King C. A fundamental role for interleukin‐21 in the generation of T follicular helper cells. Immunity. 2008; 29(1): 127–137. PubMed

Liao W, Lin JX, Wang L, Li P, Leonard WJ. Modulation of cytokine receptors by IL‐2 broadly regulates differentiation into helper T cell lineages. Nat Immunol. 2011; 12(6): 551–559. PubMed PMC

Liénart S, Merceron R, Vanderaa C, Lambert F, Colau D, Stockis J, et al. Structural basis of latent TGF‐β1 presentation and activation by GARP on human regulatory T cells. Science. 2018; 362(6417): 952–956. PubMed

Fahey LM, Guzek R, Ruffner MA, Sullivan KE, Spergel J, Cianferoni A. EMSY is increased and activates TSLP & CCL5 expression in eosinophilic esophagitis. Pediatr Allergy Immunol. 2018, 29: 565–568. PubMed

Amaral AFS, Minelli C, Guerra S, Wjst M, Probst‐Hensch N, Pin I, et al. The locus C11orf30 increases susceptibility to poly‐sensitization. Allergy Eur J Allergy Clin Immunol. 2015; 70(3): 328–333. PubMed

Toppila‐Salmi S, Huhtala H, Karjalainen J, Renkonen R, Mäkelä MJ, Wang DY, et al. Sensitization pattern affects the asthma risk in Finnish adult population. Allergy Eur J Allergy Clin Immunol. 2015; 70(9): 1112–1120. PubMed

Asai Y, Eslami A, van Ginkel CD, Akhabir L, Wan M, Ellis G, et al. Genome‐wide association study and meta‐analysis in multiple populations identifies new loci for peanut allergy and establishes C11orf30/EMSY as a genetic risk factor for food allergy. J Allergy Clin Immunol. 2018; 141(3): 991–1001. PubMed

Ohanian M, Rozovski U, Kanagal‐Shamanna R, Abruzzo LV, Loghavi S, Kadia T, et al. MYC protein expression is an important prognostic factor in acute myeloid leukemia. Leuk Lymphoma. 2019; 60(1): 37–48. PubMed PMC

Ye L, Pan J, Liang M, Pasha MA, Shen X, D'Souza SS, et al. A critical role for c‐Myc in group 2 innate lymphoid cell activation. Allergy Eur J Allergy Clin Immunol. 2019; 75(4): 841–852. PubMed PMC

Volckaert T, Campbell A, De Langhe S. c‐Myc regulates proliferation and Fgf10 expression in airway smooth muscle after airway epithelial injury in mouse. PLoS ONE. 2013; 8(8): e71426 PubMed PMC

Rogers NK, Clements D, Dongre A, Harrison TW, Shaw D, Johnson SR. Extra‐cellular matrix proteins induce matrix metalloproteinase‐1 (MMP‐1) activity and increase airway smooth muscle contraction in asthma. PLoS ONE. 2014; 9(2): e90565 PubMed PMC

Zhao Y, Zhang Y, Zhang L. Variant of PBX2 gene in the 6p21.3 asthma susceptibility locus is associated with allergic rhinitis in Chinese subjects. Int Forum Allergy Rhinol. 2016; 6(5): 537–43. PubMed

Clark H, Granell R, Curtin JA, Belgrave D, Simpson A, Murray C, et al. Differential associations of allergic disease genetic variants with developmental profiles of eczema, wheeze and rhinitis. Clin Exp Allergy. 2019; 49(11): 1475–1486. PubMed PMC

Namkung JH, Lee JE, Kim E, Kim HJ, Seo EY, Jang HY, et al. Association of polymorphisms in genes encoding IL‐4, IL‐13 and their receptors with atopic dermatitis in a Korean population. Exp Dermatol. 2011; 20(11): 915–919. PubMed

Li X, Hawkins GA, Moore WC, Hastie AT, Ampleford EJ, Milosevic J, et al. Expression of asthma susceptibility genes in bronchial epithelial cells and bronchial alveolar lavage in the Severe Asthma Research Program (SARP) cohort. J Asthma. 2016; 53(8): 775–782. PubMed PMC

Daya M, Rafaels N, Brunetti TM, Chavan S, Levin AM, Shetty A, et al. Association study in African‐admixed populations across the Americas recapitulates asthma risk loci in non‐African populations. Nat Commun. 2019; 10(1): 1 PubMed PMC

Acevedo N, Sääf A, Söderhäll C, Melén E, Mandelin J, Pietras CO, et al. Interaction between Retinoid Acid Receptor‐Related Orphan Receptor Alpha (RORA) and Neuropeptide S Receptor 1 (NPSR1) in Asthma. PLoS ONE. 2013; 8(4): e60111 PubMed PMC

Pulkkinen V, Acevedo N, Söderhäll C, Melen E, Orsmark‐Pietras C, Ezer S, et al. Interaction of retinoid acid receptor‐related orphan receptor alpha (RORA) and neuropeptide S receptor 1 (NPSR1) in asthma. Eur Respir J. 2012;40(Suppl 56). PubMed PMC

Yang IV, Pedersen BS, Liu A, O'Connor GT, Teach SJ, Kattan M, et al. DNA methylation and childhood asthma in the inner city. J Allergy Clin Immunol. 2015; 136(1): 69–80. PubMed PMC

Sood R, Kamikubo Y, Liu P. Role of RUNX1 in hematological malignancies. Blood Am Soc Hematol. 2017, 129: 2070–2082. PubMed PMC

Toppila‐Salmi S, Luukkainen A, Xu B, Lampi J, Auvinen J, Dhaygude K, et al. Maternal smoking during pregnancy affects adult onset of asthma in offspring: a follow up from birth to age 46 years. Eur Respir J. 2020;in press. PubMed

Gudbjartsson DF, Bjornsdottir US, Halapi E, Helgadottir A, Sulem P, Jonsdottir GM, et al. Sequence variants affecting eosinophil numbers associate with asthma and myocardial infarction. Nat Genet. 2009; 41(3): 342–347. PubMed

Hirota T, Takahashi A, Kubo M, Tsunoda T, Tomita K, Doi S, et al. Genome‐wide association study identifies three new susceptibility loci for adult asthma in the Japanese population. Nat Genet. 2011; 43(9): 893–896. PubMed PMC

Zhu Z, Lee PH, Chaffin MD, Chung W, Loh PR, Lu Q, et al. A genome‐wide cross‐trait analysis from UK Biobank highlights the shared genetic architecture of asthma and allergic diseases. Nat Genet. 2018; 50(6): 857–864. PubMed PMC

Gao Y, Li J, Zhang Y, Zhang L. Replication study of susceptibility variants associated with allergic rhinitis and allergy in Han Chinese. Allergy, Asthma Clin Immunol. 2020; 16(1): 13 PubMed PMC

Blankenbach KV, Bruno G, Wondra E, Spohner AK, Aster NJ, Vienken H, et al. The WD40 repeat protein, WDR36, orchestrates sphingosine kinase‐1 recruitment and phospholipase C‐β activation by Gq ‐coupled receptors. Biochim Biophys Acta Mol Cell Biol Lipids. 2020;158704. PubMed

Palmieri F. The mitochondrial transporter family SLC25: Identification, properties and physiopathology. Mol Aspects Med. 2013, 34: 465–484. PubMed

Noguchi E, Sakamoto H, Hirota T, Ochiai K, Imoto Y, Sakashita M, et al. Genome‐wide association study identifies HLA‐DP as a susceptibility gene for pediatric asthma in Asian populations. PLoS Genet. 2011; 7(7): e1002170 PubMed PMC

Ngan E, Stoletov K, Smith HW, Common J, Muller WJ, Lewis JD, et al. LPP is a Src substrate required for invadopodia formation & efficient breast cancer lung metastasis. Nat Commun. 2017, 8: 1 PubMed PMC

Qiu W, Cho MH, Riley JH, Anderson WH, Singh D, Bakke P, et al. Genetics of Sputum Gene Expression in Chronic Obstructive Pulmonary Disease. Wurfel MM, editor. PLoS One. 2011;6(9):e24395. PubMed PMC

Haque A, Koide N, Odkhuu E, Tsolmongyn B, Naiki Y, Komatsu T, et al. Mouse pyrin and HIN domain family member 1 (pyhin1) protein positively regulates LPS‐induced IFN‐β and NO production in macrophages. Innate Immun. 2014; 20(1): 40–48. PubMed

Wang M, Sun Y, Zheng F, Gao Y, Zhang S, Wei Y, et al. Changes of respiratory function on urine volume, renal AQP1, and AQP2 in mice with bronchial asthma and effects of lung‐diffusing herb Platycodon grandiflorus (JACQ.) A.D.C. J Tradit Chinese Med Sci. 2018; 5(1): 72–79

Hu Y, Shmygelska A, Tran D, Eriksson N, Tung JY, Hinds DA. GWAS of 89,283 individuals identifies genetic variants associated with self‐reporting of being a morning person. Nat Commun. 2016, 7: 1 PubMed PMC

Delfín DA, DeAguero JL, McKown EN. The extracellular matrix protein ABI3BP in cardiovascular health and disease. Front Cardiovasc Med. 2019, 6: 23 PubMed PMC

Radder JE, Gregory AD, Leme AS, Cho MH, Chu Y, Kelly NJ, et al. Variable susceptibility to cigarette smoke‐induced emphysema in 34 inbred strains of mice implicates Abi3bp in emphysema susceptibility. Am J Respir Cell Mol Biol. 2017; 57(3): 367–375. PubMed PMC

Yang H, Chen W, Shi J, Huang D, Li J, Hu B, et al. Knockout of Abi3bp in mice does not affect their olfactory function, mental state and NNK‐induced lung tumorigenesis. Acta Biochim Biophys Sin (Shanghai). 2016; 48(9): 820–826. PubMed

Khundadze M, Kollmann K, Koch N, Biskup C, Nietzsche S, Zimmer G, et al. A hereditary spastic paraplegia mouse model supports a role of ZFYVE26/SPASTIZIN for the Endolysosomal system. PLoS Genet. 2013; 9(12): e1003988 PubMed PMC

Conde L, Bracci PM, Richardson R, Montgomery SB, Skibola CF. Integrating GWAS and expression data for functional characterization of disease‐associated SNPs: an application to follicular lymphoma. Am J Hum Genet. 2013; 92(1): 126–130. PubMed PMC

Bunyavanich S, Schadt EE, Himes BE, Lasky‐Su J, Qiu W, Lazarus R, et al. Integrated genome‐wide association, coexpression network, and expression single nucleotide polymorphism analysis identifies novel pathway in allergic rhinitis. BMC Med Genomics. 2014; 7(1): 48 PubMed PMC

Kristjansson RP, Benonisdottir S, Davidsson OB, Oddsson A, Tragante V, Sigurdsson JK, et al. A loss‐of‐function variant in ALOX15 protects against nasal polyps and chronic rhinosinusitis. Nat Genet. 2019; 51(2): 267–276. PubMed

Lemonnier N, Melén E, Jiang Y, Joly S, Ménard C, Aguilar D, et al. A novel whole blood gene expression signature for asthma, dermatitis, and rhinitis multimorbidity in children and adolescents. Allergy Eur J Allergy Clin Immunol. 2020. PubMed PMC

Comer DM, Elborn JS, Ennis M. Comparison of nasal and bronchial epithelial cells obtained from patients with COPD. PLoS ONE. 2012; 7(3): e32924 PubMed PMC

Pandey G, Pandey OP, Rogers AJ, Ahsen ME, Hoffman GE, Raby BA, et al. A nasal brush‐based classifier of asthma identified by machine learning analysis of nasal RNA sequence data. Sci Rep. 2018; 8(1): 1 PubMed PMC

Edris A, De Feyter S, Maes T, Joos G, Lahousse L. Monoclonal antibodies in type 2 asthma: a systematic review and network meta‐analysis. Respir Res. 2019, 20: 179 PubMed PMC

Olafsdottir TA, Theodors F, Bjarnadottir K, Bjornsdottir US, Agustsdottir AB, Stefansson OA, et al. Eighty‐eight variants highlight the role of T cell regulation and airway remodeling in asthma pathogenesis. Nat Commun. 2020; 11(1): 1 PubMed PMC

Duvall MG, Krishnamoorthy N, Levy BD. Non‐type 2 inflammation in severe asthma is propelled by neutrophil cytoplasts and maintained by defective resolution. Allergol Int. 2019, 68: 143–149. PubMed

Revez JA, Bain L, Chapman B, Powell JE, Jansen R, Duffy DL, et al. A new regulatory variant in the interleukin‐6 receptor gene associates with asthma risk. Genes Immun. 2013; 14(7): 441–446. PubMed PMC

Anwar MA, Shah M, Kim J, Choi S. Recent clinical trends in Toll‐like receptor targeting therapeutics. Med Res Rev. 2019, 39: 1053–1090. PubMed PMC

Zhu Z, Guo Y, Shi H, Liu CL, Panganiban RA, Chung W, et al. Shared genetic and experimental links between obesity‐related traits and asthma subtypes in UK Biobank. J Allergy Clin Immunol. 2020; 145(2): 537–549. PubMed PMC