Phenotypic and functional translation of IL33 genetics in asthma.

Ketelaar, ME; Portelli, MA; Dijk, FN; Shrine, N; Faiz, A; Vermeulen, CJ; Xu, CJ; Hankinson, J; Bhaker, S; Henry, AP; Billington, CK; Shaw, DE; Johnson, SR; Benest, AV; Pang, V; Bates, DO; Pogson, ZEK; Fogarty, A; McKeever, TM; Singapuri, A; Heaney, LG; Mansur, AH; Chaudhuri, R; Thomson, NC; Holloway, JW; Lockett, GA; Howarth, PH; Niven, R; Simpson, A; Tobin, MD; Hall, IP; Wain, LV; Blakey, JD; Brightling, CE; Obeidat, M; Sin, DD; Nickle, DC; Bossé, Y; Vonk, JM; van den Berge, M; Koppelman, GH; Sayers, I; Nawijn, MC

Phenotypic and functional translation of IL33 genetics in asthma.

Ketelaar, ME Portelli, MA Dijk, FN Shrine, N Faiz, A

Vermeulen, CJ Xu, CJ Hankinson, J Bhaker, S Henry, AP Billington, CK Shaw, DE Johnson, SR Benest, AV Pang, V Bates, DO Pogson, ZEK Fogarty, A McKeever, TM Singapuri, A Heaney, LG Mansur, AH Chaudhuri, R Thomson, NC Holloway, JW Lockett, GA Howarth, PH Niven, R Simpson, A Tobin, MD Hall, IP Wain, LV Blakey, JD Brightling, CE Obeidat, M Sin, DD Nickle, DC Bossé, Y Vonk, JM van den Berge, M Koppelman, GH Sayers, I Nawijn, MC

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Publisher:: Elsevier BV
Publication Type:: Journal Article
Citation:: The Journal of allergy and clinical immunology, 2020, 147, (1), pp. 144-157
Issue Date:: 2020-05-19

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Field	Value	Language
dc.contributor.author	Ketelaar, ME
dc.contributor.author	Portelli, MA
dc.contributor.author	Dijk, FN
dc.contributor.author	Shrine, N
dc.contributor.author	Faiz, A https://orcid.org/0000-0003-1740-3538
dc.contributor.author	Vermeulen, CJ
dc.contributor.author	Xu, CJ
dc.contributor.author	Hankinson, J
dc.contributor.author	Bhaker, S
dc.contributor.author	Henry, AP
dc.contributor.author	Billington, CK
dc.contributor.author	Shaw, DE
dc.contributor.author	Johnson, SR
dc.contributor.author	Benest, AV
dc.contributor.author	Pang, V
dc.contributor.author	Bates, DO
dc.contributor.author	Pogson, ZEK
dc.contributor.author	Fogarty, A
dc.contributor.author	McKeever, TM
dc.contributor.author	Singapuri, A
dc.contributor.author	Heaney, LG
dc.contributor.author	Mansur, AH
dc.contributor.author	Chaudhuri, R
dc.contributor.author	Thomson, NC
dc.contributor.author	Holloway, JW
dc.contributor.author	Lockett, GA
dc.contributor.author	Howarth, PH
dc.contributor.author	Niven, R
dc.contributor.author	Simpson, A
dc.contributor.author	Tobin, MD
dc.contributor.author	Hall, IP
dc.contributor.author	Wain, LV
dc.contributor.author	Blakey, JD
dc.contributor.author	Brightling, CE
dc.contributor.author	Obeidat, M
dc.contributor.author	Sin, DD
dc.contributor.author	Nickle, DC
dc.contributor.author	Bossé, Y
dc.contributor.author	Vonk, JM
dc.contributor.author	van den Berge, M
dc.contributor.author	Koppelman, GH
dc.contributor.author	Sayers, I
dc.contributor.author	Nawijn, MC
dc.date.accessioned	2021-01-12T04:39:03Z
dc.date.available	2020-04-14
dc.date.available	2021-01-12T04:39:03Z
dc.date.issued	2020-05-19
dc.identifier.citation	The Journal of allergy and clinical immunology, 2020, 147, (1), pp. 144-157
dc.identifier.issn	0091-6749
dc.identifier.issn	1097-6825
dc.identifier.uri	http://hdl.handle.net/10453/145331
dc.description.abstract	BACKGROUND:Asthma is a complex disease with multiple phenotypes that may differ in disease pathobiology and treatment response. IL33 single nucleotide polymorphisms (SNPs) have been reproducibly associated with asthma. IL33 levels are elevated in sputum and bronchial biopsies of patients with asthma. The functional consequences of IL33 asthma SNPs remain unknown. OBJECTIVE:This study sought to determine whether IL33 SNPs associate with asthma-related phenotypes and with IL33 expression in lung or bronchial epithelium. This study investigated the effect of increased IL33 expression on human bronchial epithelial cell (HBEC) function. METHODS:Association between IL33 SNPs (Chr9: 5,815,786-6,657,983) and asthma phenotypes (Lifelines/DAG [Dutch Asthma GWAS]/GASP [Genetics of Asthma Severity & Phenotypes] cohorts) and between SNPs and expression (lung tissue, bronchial brushes, HBECs) was done using regression modeling. Lentiviral overexpression was used to study IL33 effects on HBECs. RESULTS:We found that 161 SNPs spanning the IL33 region associated with 1 or more asthma phenotypes after correction for multiple testing. We report a main independent signal tagged by rs992969 associating with blood eosinophil levels, asthma, and eosinophilic asthma. A second, independent signal tagged by rs4008366 presented modest association with eosinophilic asthma. Neither signal associated with FEV1, FEV1/forced vital capacity, atopy, and age of asthma onset. The 2 IL33 signals are expression quantitative loci in bronchial brushes and cultured HBECs, but not in lung tissue. IL33 overexpression in vitro resulted in reduced viability and reactive oxygen species-capturing of HBECs, without influencing epithelial cell count, metabolic activity, or barrier function. CONCLUSIONS:We identify IL33 as an epithelial susceptibility gene for eosinophilia and asthma, provide mechanistic insight, and implicate targeting of the IL33 pathway specifically in eosinophilic asthma.
dc.format	Print-Electronic
dc.language	eng
dc.publisher	Elsevier BV
dc.relation.ispartof	The Journal of allergy and clinical immunology
dc.relation.isbasedon	10.1016/j.jaci.2020.04.051
dc.rights	info:eu-repo/semantics/restrictedAccess
dc.subject	1107 Immunology
dc.subject.classification	Allergy
dc.title	Phenotypic and functional translation of IL33 genetics in asthma.
dc.type	Journal Article
utslib.citation.volume	147
utslib.location.activity	United States
utslib.for	1107 Immunology
pubs.organisational-group	/University of Technology Sydney/Faculty of Science
pubs.organisational-group	/University of Technology Sydney/Faculty of Science/School of Life Sciences
pubs.organisational-group	/University of Technology Sydney
utslib.copyright.status	closed_access	*
dc.date.updated	2021-01-12T04:38:50Z
pubs.issue	1
pubs.publication-status	Published
pubs.volume	147
utslib.citation.issue	1

Abstract:

BACKGROUND:Asthma is a complex disease with multiple phenotypes that may differ in disease pathobiology and treatment response. IL33 single nucleotide polymorphisms (SNPs) have been reproducibly associated with asthma. IL33 levels are elevated in sputum and bronchial biopsies of patients with asthma. The functional consequences of IL33 asthma SNPs remain unknown. OBJECTIVE:This study sought to determine whether IL33 SNPs associate with asthma-related phenotypes and with IL33 expression in lung or bronchial epithelium. This study investigated the effect of increased IL33 expression on human bronchial epithelial cell (HBEC) function. METHODS:Association between IL33 SNPs (Chr9: 5,815,786-6,657,983) and asthma phenotypes (Lifelines/DAG [Dutch Asthma GWAS]/GASP [Genetics of Asthma Severity & Phenotypes] cohorts) and between SNPs and expression (lung tissue, bronchial brushes, HBECs) was done using regression modeling. Lentiviral overexpression was used to study IL33 effects on HBECs. RESULTS:We found that 161 SNPs spanning the IL33 region associated with 1 or more asthma phenotypes after correction for multiple testing. We report a main independent signal tagged by rs992969 associating with blood eosinophil levels, asthma, and eosinophilic asthma. A second, independent signal tagged by rs4008366 presented modest association with eosinophilic asthma. Neither signal associated with FEV1, FEV1/forced vital capacity, atopy, and age of asthma onset. The 2 IL33 signals are expression quantitative loci in bronchial brushes and cultured HBECs, but not in lung tissue. IL33 overexpression in vitro resulted in reduced viability and reactive oxygen species-capturing of HBECs, without influencing epithelial cell count, metabolic activity, or barrier function. CONCLUSIONS:We identify IL33 as an epithelial susceptibility gene for eosinophilia and asthma, provide mechanistic insight, and implicate targeting of the IL33 pathway specifically in eosinophilic asthma.

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http://hdl.handle.net/10453/145331