Phenotypic and functional translation of IL33 genetics in asthma

Ketelaar, Marjolijn; Portelli, Michael A.; Dijk, F. Nicole; Shrine, Nick; Faiz, Alen; Vermeulen, C; Cheng, Xu; Hankinson, Jenny; Bhaker, Sangita; Henry, Amanda; Billington, C.K.; Shaw, Dominick; Johnson, Simon R.; Benest, Andrew V.; Pang, Vincent; Bates, David O.; Pogson, Zara; Fogarty, Andrew; McKeever, Tricia M.; Singapuri, Amisha; Heaney, Liam G.; Mansur, Adel; Chaudhuri, Rekha; Thomson, Neil C.; Holloway, John W.; Lockett, Gabrielle A.; Howarth, Peter H.; Niven, Robert; Simpson, Angela; Tobin, Martin D.; Hall, Ian P.; Wain, Louise V.; Blakey, John; Brightling, Christopher E.; Obeidat, Ma’en; Sin, Don D.; Nickle, David C.; Bossé, Yohan; Vonk, Judith M.; Berge, Maarten van den; Koppelman, Gerard H.; Sayers, Ian; Nawijn, Martijn C.

doi:10.1016/j.jaci.2020.04.051

Cited by 36 publications

(35 citation statements)

References 54 publications

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“…For example, the A-allele of rs992969, which is associated with an increased risk of AR in the present study, was also significantly associated with higher IL-33 expression in bronchial epithelial cells (P=1.3x10 -6 ) in a previous study (74). 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).…”

Section: Discussionsupporting

confidence: 60%

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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Section: Discussionsupporting

confidence: 60%

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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“…53Recent GWASs have convincingly identified associations of the genetic variants at the IL33 with adult-onset asthma and nasal polyps 38,39,41,42. Genetic signals at the IL33 predominantly associated with blood eosinophil levels in the general population and with an eosinophilic asthma phenotype and also influenced IL33 levels in the airway epithelium, with the risk allele associating with increased IL33 in vivo 54. An epigenetic analysis of human naïve ILC2s activated with IL-25 and IL-33 in vitro revealed that a number of asthma-associated genetic variants localized to ILC2-specific regulatory elements 55.…”

mentioning

confidence: 99%

Adult‐onset eosinophilic airway diseases

Asano

Ueki

Tamari

et al. 2020

Allergy

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Allergic diseases in the upper and the lower airways such as allergic rhinitis and atopic asthma are usually accompanied by local eosinophilia and sometimes by peripheral blood eosinophilia. Chronic rhinosinusitis with nasal polyps (CRSwNP) and nonatopic asthma are also characterized by local and systemic eosinophilia; however, there are substantial differences in the age of onset and the presence of atopy. Atopic asthma and allergic rhinitis develop during childhood in most cases and mediated by type 1 hypersensitivity reactions to allergen(s), as are other childhood-onset allergic diseases such as food allergies and eczema. Patients often develop these diseases consecutively as an allergic march (Figure 1), suggesting the presence of common genetic backgrounds and pathophysiology. In contrast to childhood-onset disease, adult-onset asthma frequently presents as a nonatopic and eosinophilic condition, 1-6

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“…Recently, the IL-33 pathway has been specifically tied to eosinophilic asthma [144]. Therefore, a key area of interest for clinicians is the possibility of a genetic test to identify severe asthma patients with https://doi.org/10.1183/16000617.0183-2021…”

Section: Comorbiditiesmentioning

confidence: 99%

Holy Grail: the journey towards disease modification in asthma

Busse

Menzies‐Gow

2022

Eur Respir Rev

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At present, there is no cure for asthma, and treatment typically involves therapies that prevent or reduce asthma symptoms, without modifying the underlying disease. A “disease-modifying” treatment can be classed as able to address the pathogenesis of a disease, preventing progression or leading to a long-term reduction in symptoms. Such therapies have been investigated and approved in other indications, e.g. rheumatoid arthritis and immunoglobulin E-mediated allergic disease. Asthma's heterogeneous nature has made the discovery of similar therapies in asthma more difficult, although novel therapies (e.g. biologics) may have the potential to exhibit disease-modifying properties. To investigate the disease-modifying potential of a treatment, study design considerations can be made, including: appropriate end-point selection, length of trial, age of study population (key differences between adults/children in physiology, pathology and drug metabolism) and comorbidities in the patient population. Potential future focus areas for disease-modifying treatments in asthma include early assessments (e.g. to detect patterns of remodelling) and interventions for patients genetically susceptible to asthma, interventions to prevent virally induced asthma and therapies to promote a healthy microbiome. This review explores the pathophysiology of asthma, the disease-modifying potential of current asthma therapies and the direction future research may take to achieve full disease remission or prevention.

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Phenotypic and functional translation of IL33 genetics in asthma

Cited by 36 publications

References 54 publications

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

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

Adult‐onset eosinophilic airway diseases

Holy Grail: the journey towards disease modification in asthma

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