TABLE 1.

Selected genes identified through genetic studies of asthma implicated in airway epithelial cell homeostasis which may impact barrier properties and inflammation

Chrs	Gene Reported variants	Main Asthma Phenotype(s)	Suggested role in HBEC homeostasis/epithelial gene expression	References
2q12.1	a IL1RL1 rs3771166	Asthma, Asthma + Exacerbation, moderate‐severe asthma	IL33 receptor, regulates inflammation. Important in innate immune responses including responses to viruses and Type 2 inflammation. Expressed in HBEC	74, 76, 138, 139
5q22.1	a TSLP rs1043828	Asthma, Asthma + Hay fever, moderate‐severe asthma	Can drive induction of allergic responses by effects on several cell types including dendritic cells. Regulates an IL‐13–dependent increase in bronchial epithelial cell proliferation	138, 140, 141, 142, 143
5q31.1	KIF3A rs17690965	Atopic Dermatitis followed by Asthma	Molecular motor that transports molecules along microtubules, role in ciliary function. Role in epithelial apoptosis and inflammation	70, 71, 144
5q31.3	PCDH1 rs3797054 rs3822357	Airway hyper‐responsiveness	Epithelial adhesion, differentiation, barrier formation	78, 79, 145
6p12.2	EFHC1 rs9357733	Atopic Dermatitis followed by Asthma	Contains an EF‐hand motif which is able to bind Ca2+ ions. Involved in ciliary function	70, 72, 73
7q22.3	a CDHR3 rs6967330	Asthma + Exacerbation	Epithelial polarity and cell‐cell interactions. Receptor for Rhinovirus C, the most common respiratory virus associated with exacerbations in asthma. Cys529Tyr regulates viral entry	76, 77, 146
9p24.1	a IL33 rs1342326	Asthma, Asthma + Exacerbation, moderate‐severe asthma	Epithelium‐derived cytokine alarmin, regulates inflammation via interactions with ST2/IL1RL1 on several inflammatory cells. Type 2 inflammation, viral exacerbation. Also activates HBEC via ST2/IL1RL1	74, 76, 138, 147, 148
11p15.5	a MUC5AC rs11603634	Moderate‐Severe asthma	Oligomeric mucus/gel‐forming, a pathogenic mucin linked to allergic airway hyper‐reactivity. Elevated in bronchial epithelial cell brushing from severe asthma patients	74, 75
15q22.33	SMAD3 rs744910	Asthma, Asthma + Hay fever	Signalling intermediate in the TGF‐β1 induced epithelial–mesenchymal transition	69, 74, 75, 139, 149, 150
17q21.1	a GSDMB rs7216389	Asthma, childhood asthma + exacerbations, Asthma + Hay fever, childhood asthma, moderate–severe asthma	Member of gasdermin‐domain containing protein family, elevated in the airway epithelium in asthma and in mice increased expression led to spontaneous, remodelling and airway hyper‐responsiveness. Epithelial cell pyroptosis	76, 82, 83, 140, 151
17q21.1	ORMDL3 rs7216389	Asthma, childhood asthma + exacerbations, Asthma + Hay fever, childhood asthma, moderate–severe asthma	Orosomucoid‑like protein isoform 3, regulates endoplasmic reticulum (ER) stress. Implicated in epithelial barrier formation, pro‐remodelling phenotype in vivo and in vitro. Sphingolipid regulation	69, 76, 138, 151, 152, 153, 154, 155, 156
19q23	PLAUR rs4493171 rs2356338 rs2239372	Asthma, decline in lung function	Regulates activation of urokinase plasminogen activator (uPA), triggering the plasminogen/plasmin activation cycle. Epithelial repair, proliferation, pro‐remodeling phenotype	157, 158, 159, 160

For a comprehensive review of asthma related phenotypes, these loci have been associated with see recent reviews. ⁵⁴ , ¹⁴²

Abbreviations: CDHR3 cadherin‐related family member 3; EFHC1, EF‐hand domain containing protein 1; IL1RL1, Interleukin 1 Receptor Like 1; IL33, Interleukin 33; KIF3A, Kinesin Family Member 3A; MUC5AC, Mucin 5AC, Oligomeric Mucus/Gel‐Forming; ORMDL3, ORMDL sphingolipid biosynthesis regulator 3; PCDH1, Protocadherin 1; PLAUR, plasminogen activator, urokinase receptor; SMAD3, GSDMB, gasdermin B; TSLP, Thymic stromal lymphopoietin.

^aIdentified in eQTL studies using asthma risk alleles in airway epithelium.