The Risk G Allele of the Single-Nucleotide Polymorphism rs928413 Creates a CREB1-Binding Site That Activates IL33 Promoter in Lung Epithelial Cells

Gorbacheva, Alisa M.; Korneev, Kirill V.; Kuprash, Dmitry V.; Mitkin, Nikita A.

doi:10.3390/ijms19102911

Cited by 19 publications

(19 citation statements)

References 78 publications

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“…This eQTL signal A also comprised an SNP (rs928413, in LD r 2 5 0.96 with rs992969) where the phenotype-risk allele was recently found to form a CREB1 binding site, functionally activating the IL33 promotor in lung epithelial cells. 41 This allele associates with higher level of eosinophils, higher risk of (eosinophilic) asthma, and increased IL33 expression in brushes in our cohorts. As lung tissue resection samples mainly consist of parenchymal lung tissue with minor contributions of airway epithelial cells, while bronchial brushes contain more than 90% bronchial epithelial cells, 48 we interpret these data as evidence for regulation of IL33 expression in bronchial epithelium.…”

Section: Functional Effects Of Phenotype-associated Il33 Polymorphismmentioning

confidence: 59%

“…To investigate potential functionality of signals A and E, QTL analyses were performed in lung tissue, bronchial epithelial brushes, and cultured BECs (Table III, Fig 5, and Table E5). 23,24,35,[39][40][41] In lung tissue samples, no eQTLs for IL33 were found (see Table E18 and Fig Table E19 in this article's Online Repository at www. jacionline.org), the tagSNP of signal A was a significant and strong eQTL for IL33, with the disease-associated allele Table II.…”

Section: Qtl/functional Investigation Of Il33 Genetic Variationmentioning

confidence: 99%

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Phenotypic and functional translation of IL33 genetics in asthma

Ketelaar

Portelli

Dijk

et al. 2021

Journal of Allergy and Clinical Immunology

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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 FEV 1 , FEV 1 / 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. (J Allergy Clin Immunol 2020;nnn:nnn-nnn.)

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Section: Functional Effects Of Phenotype-associated Il33 Polymorphismmentioning

confidence: 59%

Section: Qtl/functional Investigation Of Il33 Genetic Variationmentioning

confidence: 99%

Phenotypic and functional translation of IL33 genetics in asthma

Ketelaar

Portelli

Dijk

et al. 2021

Journal of Allergy and Clinical Immunology

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“…Single-nucleotide polymorphism rs4742170 is located in the second intron of the human IL33 gene, more than 27 kb from the distal IL33 promoter characterized in our previous work [24] and +27244 bp from the TSS. Based on the available epigenetic data [25], the 5′ part of intron 2 of the IL33 gene containing rs4742170 has a number of features typical for regulatory elements (Supplementary Figure S1).…”

Section: Resultsmentioning

confidence: 99%

“…For functional evaluation, we designated the region from +26297 to +28033 bp from TSS a putative enhancer and cloned it into a luciferase reporter vector (Figure 1A). We supplemented the luciferase reporter vector already containing the IL33 promoter [24] with different variants of a downstream enhancer: an irrelevant control fragment without enhancer properties; enhancer with protective (C) allele of rs4742170; and enhancer with risk (T) allele of rs4742170. The activities of these constructs were compared in NCIH-196 human lung carcinoma cell line [24].…”

Section: Resultsmentioning

confidence: 99%

Glucocorticoid Receptor Binding Inhibits an Intronic IL33 Enhancer and is Disrupted by rs4742170 (T) Allele Associated with Specific Wheezing Phenotype in Early Childhood

Gorbacheva

Kuprash

Mitkin

2018

IJMS

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Interleukin 33 (IL-33) is a cytokine constitutively expressed by various cells of barrier tissues that contribute to the development of inflammatory immune responses. According to its function as an alarmin secreted by lung and airway epithelium, IL-33 plays a significant role in pathogenesis of allergic disorders. IL-33 is strongly involved in the pathogenesis of asthma, anaphylaxis, allergy and dermatitis, and genetic variations in IL33 locus are associated with increased susceptibility to asthma. Genome-wide association studies have identified risk “T” allele of the single-nucleotide polymorphism rs4742170 located in putative IL33 enhancer area as susceptible variant for development of specific wheezing phenotype in early childhood. Here, we demonstrate that risk “T” rs4742170 allele disrupts binding of glucocorticoid receptor (GR) transcription factor to IL33 putative enhancer. The IL33 promoter/enhancer constructs containing either 4742170 (T) allele or point mutations in the GR-binding site, were significantly more active and did not respond to cortisol in a pulmonary epithelial cell line. At the same time, the constructs containing rs4742170 (C) allele with a functional GR-binding site were less active and further inhibitable by cortisol. The latter effect was GR-dependent as it was completely abolished by GR-specific siRNA. This mechanism may explain the negative effect of the rs4742170 (T) risk allele on the development of wheezing phenotype that strongly correlates with allergic sensitization in childhood.

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“…A recent study has indicated that the A-allele of rs992969 was significantly associated with a higher mRNA level of IL-33 in bronchial brushes (P=8.3x10 -12 ) (75). In addition, a functional study has revealed that the G-allele of rs928413 was associated with higher IL-33 promoter activity compared with the A-allele in lung cancer cells, and the G-allele of rs928413 included a binding site for cyclic AMP-responsive element-binding protein 1, which is likely an activator of IL-33 transcription in the presence of this allele (76). These studies have demonstrated the potential regulatory effects of these SNPs on the transcription of IL-33.…”

Section: Discussionmentioning

confidence: 99%

Single‑nucleotide polymorphisms and haplotypes in the interleukin‑33 gene are associated with a risk of allergic rhinitis in the Chinese population

Zhou

Guo

et al. 2020

Exp Ther Med

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Allergic rhinitis (AR) is a common upper airway disease attributed to a variety of risk factors, such as environmental exposures and genetic susceptibility. The commonly observed comorbidity of asthma and AR in the clinic suggests the presence of shared genetic risk factors and biological mechanisms between these diseases. Interleukin (IL)-33 has been indicated to be an important factor driving asthma susceptibility and pathogenesis using both genome-wide association studies and functional studies in model animals. Although previous studies have reported the putative association of this gene with AR, evidence for the association of genetic variations of IL-33 with the disease is still missing. To examine whether variations in the IL-33 gene confer a genetic risk of AR, a total of 769 patients with AR and 769 age-and sex-matched healthy controls were recruited among Han Chinese residents in the Hubei province, and 14 single-nucleotide polymorphisms (SNPs) spanning the IL-33 gene were examined for their association with the risk of AR. The results indicated that five SNPs, which were in a moderate linkage disequilibrium and were located in the 5'-flanking region of IL-33, exhibited significant associations with the risk of AR, and these associations were additionally supported by genotypic and haplotypic analyses. Notably, three of the five IL-33 SNPs have been previously reported to exhibit genome-wide associations with asthma, and their alleles were also revealed to confer an increased risk of AR in the present study. In summary, the results of the current study suggested that certain variations in the IL-33 gene represent a potential risk for AR, and indicated a shared genetic basis between AR and asthma.

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The Risk G Allele of the Single-Nucleotide Polymorphism rs928413 Creates a CREB1-Binding Site That Activates IL33 Promoter in Lung Epithelial Cells

Cited by 19 publications

References 78 publications

Phenotypic and functional translation of IL33 genetics in asthma

Phenotypic and functional translation of IL33 genetics in asthma

Glucocorticoid Receptor Binding Inhibits an Intronic IL33 Enhancer and is Disrupted by rs4742170 (T) Allele Associated with Specific Wheezing Phenotype in Early Childhood

Single‑nucleotide polymorphisms and haplotypes in the interleukin‑33 gene are associated with a risk of allergic rhinitis in the Chinese population

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