Eleven loci with new reproducible genetic associations with allergic disease risk

Ferreira, Manuel; Vonk, Judith M.; Baurecht, Hansjörg; Marenholz, Ingo; Tian, Chao; Hoffman, Joshua; Helmer, Quinta; Tillander, Annika; Ullemar, Vilhelmina; Lu, Yi; Rüschendorf, Franz; Hinds, David A.; Hübner, Norbert; Weidinger, Stephan; Magnusson, Patrik K. E.; Jorgenson, Eric; Lee, Youngae; Boomsma, Dorret I.; Karlsson, Robert; Almqvist, Catarina; Koppelman, Gerard H.; Paternoster, Lavinia

doi:10.1016/j.jaci.2018.03.012

Cited by 56 publications

(68 citation statements)

References 60 publications

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“…Ferreira et al report eleven loci having new reproducible genetic associations with allergic disease risk [8]. Of these, diminished FOSL2, APOBR and NCF4 RNA expression are significantly associated with increased glioma survival.…”

Section: Resultsmentioning

confidence: 99%

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Allergy may confer better survival on patients with gliomas

Lehrer

Rheinstein

Rosenzweig

2019

Clinical Neurology and Neurosurgery

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Objectives: Glioma susceptibility is inversely related to a history of allergies and atopy. Lung allergies are associated with 30% lower glioma susceptibility, compared to no lung allergies. Asthma and eczema also reduce the chance of glioma. However, the effect of allergy on glioma survival is not well characterized. Because of the allergy-glioma inverse relationship we examined the association of allergy with glioma survival in The Cancer Genome Atlas (TCGA). Patients and methods: We evaluated the association between allergy and overall survival in TCGA Glioma (LGG) dataset. In order to have a sample of sufficient size to analyze, we classified as allergic any patient who answered yes to any of the manifestations of allergy that were queried. Results: We analyzed data from 526 patients with glioma. History of allergy conferred a survival advantage on glioma patients, when stratified by tumor histologic grade (p = 0.049). Because allergy confers a favorable prognosis, we performed Cox regression. The effect of allergy on survival was significant (p = 0.025, HR 0.525, 95% CI 0.299–0.924), independent of the effect of chromosome 1p (p < 0.001, HR 93.4, 95% CI 16–546) and 19q (p = 0.801, HR 1.2, 95% CI 0.23–6.9) codeletion or TP53 mutation (p = 0.015, HR 2.7, 95% CI 1.2–5.9), unrelated to TERT expression (p = 0.365, HR 1.1, 95% CI 0.89–1.4) or ATRX mutation (p = 0.904, HR 1.04, 95% CI 0.51–2.14), independent of tumor grade (grade 2 versus grade 3, p = 0.004, HR 2.2, 95% CI 1.3–3.8), not independent of histology (oligodendroglioma and oligoastrocytoma, NOS versus astrocytoma, p = 0.08, HR 0.62, 95% CI 0.36–1.1). Diminished RNA expression of three loci, having reproducible genetic associations with allergic disease risk, are significantly associated with increased survival in glioma: FOSL2, APOBR, and NCF4. Diminished NCF4 copy number is significantly associated with reduced survival (D). Conclusion: Our finding of the improved prognosis that allergy confers on glioma increases the potential importance of understanding the allergy-glioma inverse association. If the mechanism could be more clearly elucidated, new, more effective treatments and preventive measures may be developed. Further studies are warranted.

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Section: Resultsmentioning

confidence: 99%

“…Genetic loci examined were chosen if they were associated with glioma (1p, 19q, TERT, ATRX) or allergy (FOSL2, APOBR and NCF4) [8]. …”

Section: Methodsmentioning

confidence: 99%

Allergy may confer better survival on patients with gliomas

Lehrer

Rheinstein

Rosenzweig

2019

Clinical Neurology and Neurosurgery

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“…Another level of complexity is that both mIL‐6R and sIL‐6R also bind the p28 subunit of IL‐27, with the sIL‐6R/p28 complex having antiviral activity . IL‐27 has been implicated in the aetiology of allergic disease, both by functional and genetic association studies . Therefore, a role for IL‐6R inhibition in IL‐27‐dependent allergic responses should also be considered in future studies.…”

Section: Discussionmentioning

confidence: 99%

“…89 IL-27 has been implicated in the aetiology of allergic disease, both by functional 90 and genetic association studies. 91,92 Therefore, a role for IL-6R inhibition in IL-27-dependent allergic responses should also be considered in future studies.…”

Section: Discussionmentioning

confidence: 99%

Effects of interleukin‐6 receptor blockade on allergen‐induced airway responses in mild asthmatics

et al. 2019

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Background Interleukin (IL)‐6 signalling has been implicated in allergic asthma by animal, genetic association and clinical studies. In this study, we tested the hypothesis that tocilizumab (TCZ), a human monoclonal antibody that blocks IL‐6 signalling, can prevent the development of allergen‐induced bronchoconstriction in humans. Methods We performed a randomised, double‐blind, placebo‐controlled study, with eligible participants completing two allergen inhalation challenge tests, conducted before and after treatment with a single dose of TCZ or placebo. The primary efficacy endpoint was the magnitude of the late asthmatic response recorded between 3 and 7 after allergen challenge. The secondary efficacy endpoint was the early asthmatic response, measured 20 min to 2 h after allergen challenge. Results A total of 66 patients enrolled between September 2014 and August 2017, when the trial was stopped for futility based on results from an interim analysis. Eleven patients fulfilled all eligibility criteria assessed at baseline and were subsequently randomised to the TCZ ( n = 6) or placebo ( n = 5) groups. Both the primary and secondary efficacy endpoints were not significantly different between the two groups. Five patients reported adverse events (AEs), three in the TCZ group (11 AEs) and two in the placebo group (four AEs). Only one AE was TCZ‐related (mild neutropenia), and there were no serious AEs. Significant treatment effects were observed for serum levels of C‐reactive protein, IL‐6 and soluble IL‐6R levels. Conclusion In a small proof‐of‐concept clinical trial, we found no evidence that a single dose of tocilizumab was able to prevent allergen‐induced bronchoconstriction. (Trial registered in the Australian New Zealand Clinical Trials Registry, number ACTRN12614000123640).

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“…So far, 31 risk loci for AD have been identified, and most susceptibility loci are related to (auto-)immune regulation, in particular, innate signaling and T-cell activation [47]. Moreover, genome-wide association studies have revealed that asthma, hay fever, and eczema share 136 risk variants in 99 loci that dysregulate the expression of immune-related genes [48]. …”

Section: Pathogenenic Mechanismsmentioning

confidence: 99%

Atopic Dermatitis: Collegium Internationale Allergologicum (CIA) Update 2019

Simon

Wollenberg

Renz

et al. 2019

Int Arch Allergy Immunol

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Atopic dermatitis (AD) is a chronic inflammatory skin disease presenting with recurrent eczematous lesions and intense pruritus. It is common and affects both children and adults, often beginning in infancy. Due to the unpredictable disease course, its visible skin lesions, itching and scratching followed by sleeplessness, other associated atopic diseases, and behavioral and psychiatric disorders, AD is an immense burden for patients and caregivers. AD is determined by a genetic predisposition characterized by an impaired skin barrier and a T-helper-2-predominant inflammation. Restoration of the skin barrier is the main approach for treating and preventing AD. In order to cope with acute flares, usually topical corticosteroids (TCS) are applied, while topical calcineurin inhibitors (TCI) are used mainly for maintenance therapy. There is a small group of patients who are refractory to TCS and TCI and require systemic immunosuppressive drugs such as ciclosporin. Novel, targeted therapies are under clinical investigation, among which an anti-IL-4/IL-13 receptor antibody has recently been approved in several countries. As we learn to understand the pathomechanisms of AD, the characteristics of the different patient subgroups, and the effectiveness of various targeted therapies, a personalized treatment ensuring the best efficacy and safety and, probably, a disease-modifying effect will result.

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Eleven loci with new reproducible genetic associations with allergic disease risk

Cited by 56 publications

References 60 publications

Allergy may confer better survival on patients with gliomas

Allergy may confer better survival on patients with gliomas

Effects of interleukin‐6 receptor blockade on allergen‐induced airway responses in mild asthmatics

Atopic Dermatitis: Collegium Internationale Allergologicum (CIA) Update 2019

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