17q21 variants modify the association between early respiratory infections and asthma

Smit, Lidwien A M; Bouzigon, Emmanuelle; Pin, Isabelle; Siroux, Valérie; Monier, Florent; Aschard, Hugues; Bousquet, Jean; Gormand, F.; Just, Jocelyne; Moual, Nicole Le; Nadif, Rachel; Scheinmann, P.; Vervloët, D.; Lathrop, Mark; Demenais, Florence; Kauffmann, F.

doi:10.1183/09031936.00154509

Cited by 96 publications

(60 citation statements)

References 33 publications

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“…During this time window, intensive maturation of the adaptive immunity occurs, in addition to substantial lung growth with a faster increase in lung volume than in airway caliber (30). The notion of hampered lung development is supported by the previously reported three-way interaction (29,31) of genotype, viral infections, and ETS, which in itself impairs lung development. Beyond infancy and before school age, wheeze may gradually become more independent of viral triggers and may reflect a response characteristic of an airway system primed for asthma possibly promoted by atopic sensitization (6).…”

Section: Discussionsupporting

confidence: 62%

The Early Development of Wheeze. Environmental Determinants and Genetic Susceptibility at 17q21

Loss

Depner

Hose

et al. 2016

Am J Respir Crit Care Med

143

117

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RATIONALE: Growing up on a farm protects from childhood asthma and early wheeze. Virustriggered wheeze in infancy predicts asthma in individuals with a genetic asthma risk associated with chromosome 17q21. OBJECTIVES: To test environmental determinants of infections and wheeze in the first year of life, potential modifications of these associations by 17q21, and the implications for different trajectories of wheeze. METHODS: We followed 983 children in rural areas of Europe from birth until age 6 years. Symptoms of wheeze, rhinitis, fever, and environmental exposures were documented with weekly diaries during year 1. Asthma at age 6 was defined as ever having a reported doctor's diagnosis. Single-nucleotide polymorphisms related to ORMDL3 (rs8076131) and GSDMB (rs7216389, rs2290400) at 17q21 were genotyped. MEASUREMENTS AND MAIN RESULTS: Early wheeze was positively associated with presence of older siblings among carriers of known asthma risk alleles at 17q21 (e.g., rs8076131) (adjusted odds ratio [aOR], 1.53; 95% confidence interval [CI], 1.16-2.01). Exposure to farm animal sheds was inversely related to wheeze (aOR, 0.44; 95% CI, 0.33-0.60). Both effects were similarly observed in children with transient wheeze up to age 3 years without subsequent development of asthma (aOR, 1.71 [95% CI, 1.09-2.67]; and aOR, 0.48 [95% CI, 0.30-0.76], respectively). CONCLUSIONS: These findings suggest that the chromosome 17q21 locus relates to episodes of acute airway obstruction common to both transient wheeze and asthma. The previously identified asthma risk alleles are the ones susceptible to environmental influences. Thus, this gene-environment interaction reveals two faces of 17q21: The same genotype constitutes genetic risk and allows for environmental protection, thereby providing options for prospective prevention strategies. AbstractRationale: Growing up on a farm protects from childhood asthma and early wheeze. Virus-triggered wheeze in infancy predicts asthma in individuals with a genetic asthma risk associated with chromosome 17q21.

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Section: Discussionsupporting

confidence: 62%

The Early Development of Wheeze. Environmental Determinants and Genetic Susceptibility at 17q21

Loss

Depner

Hose

et al. 2016

Am J Respir Crit Care Med

143

117

View full text Add to dashboard Cite

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“…Our study reports several additional observations suggesting a direct association of this gene with the abnormalities affecting the paediatric asthmatic epithelium: first, the existence of several response elements for IFN regulatory factors in its promoter region; secondly, its transcriptional induction by epithelial IFN in HNECs; and thirdly, its protein expression in airway epithelial cells. This is in line with the fact that one of its SNPs (rs7216389) has been associated with early onset of asthma, acute severe exacerbations (80% of which are virus-induced in children) and asthma severity [11,35,36]. MOFFATT et al [37] initially noted an association of childhood asthma risk with modified expression of ORDML3, located in the immediate vicinity of GSDML.…”

Section: Discussionmentioning

confidence: 54%

Distinct epithelial gene expression phenotypes in childhood respiratory allergy

Giovannini‐Chami¹,

Marcet²,

Moreilhon³

et al. 2011

Eur Respir J

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Epithelial cell contribution to the natural history of childhood allergic respiratory disease remains poorly understood. Our aims were to identify epithelial pathways that are dysregulated in different phenotypes of respiratory allergy.We established gene expression signatures of nasal brushings from children with dust miteallergic rhinitis, associated or not associated with controlled or uncontrolled asthma. Supervised learning and unsupervised clustering were used to predict the different subgroups of patients and define altered signalling pathways. These profiles were compared with those of primary cultures of human nasal epithelial cells stimulated with either interleukin (IL)-4, IL-13, interferon (IFN)-a, IFN-b or IFN-c, or during in vitro differentiation.A supervised method discriminated children with allergic rhinitis from healthy controls (prediction accuracy 91%), based on 61 transcripts, including 21 T-helper cell (Th) type 2-responsive genes. This method was then applied to predict children with controlled or uncontrolled asthma (prediction accuracy 75%), based on 41 transcripts: nine of them, which were down-regulated in uncontrolled asthma, are directly linked to IFN. This group also included GSDML, which is genetically associated with asthma.Our data revealed a Th2-driven epithelial phenotype common to all children with dust mite allergic rhinitis. It highlights the influence of epithelially expressed molecules on the control of asthma, in association with atopy and impaired viral response.

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“…This highlights the interaction between genetic susceptibility and a common environmental risk factor. The increased risk for early-onset asthma conferred by the 17q21 locus was further increased by early exposure to tobacco smoke (18) and also confirmed in a study analyzing the relationship between early-onset asthma, viral infection, and tobacco smoke exposure (71).…”

Section: Environmental Influence and Genetic Susceptibilitymentioning

confidence: 61%