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J Allergy Clin Immunol. 2017 Aug;140(2):534-542. doi: 10.1016/j.jaci.2016.10.041. Epub 2016 Dec 21.

Epigenome-wide analysis links SMAD3 methylation at birth to asthma in children of asthmatic mothers.

Author information

1
Asthma and Airway Disease Research Center, University of Arizona, Tucson, Ariz; Department of Cellular and Molecular Medicine, University of Arizona, Tucson, Ariz.
2
Asthma and Airway Disease Research Center, University of Arizona, Tucson, Ariz.
3
Arizona Research Laboratories, University of Arizona, Tucson, Ariz.
4
Telethon Kids Institute, University of Western Australia, Perth, Australia.
5
College of Nursing, University of Arizona, Tucson, Ariz.
6
Department of Human Genetics, University of Chicago, Chicago, Ill.
7
Centre for Respiratory Medicine and Allergy, Institute of Inflammation and Repair, Manchester Academic Health Science Centre, University of Manchester and University Hospital of South Manchester NHS Foundation Trust, Manchester, United Kingdom.
8
Department of Pediatrics, University of Wisconsin School of Medicine and Public Health, Madison, Wis.
9
Asthma and Airway Disease Research Center, University of Arizona, Tucson, Ariz; CREAL, University Pompeu Fabra, Barcelona, Spain.
10
Asthma and Airway Disease Research Center, University of Arizona, Tucson, Ariz; Department of Pediatrics, University of Arizona, Tucson, Ariz.
11
Asthma and Airway Disease Research Center, University of Arizona, Tucson, Ariz; Department of Pharmacology, University of Arizona, Tucson, Ariz; Arizona Center for the Biology of Complex Diseases, University of Arizona, Tucson, Ariz; Bio5 Institute, University of Arizona, Tucson, Ariz.
12
Asthma and Airway Disease Research Center, University of Arizona, Tucson, Ariz; Department of Cellular and Molecular Medicine, University of Arizona, Tucson, Ariz; Arizona Center for the Biology of Complex Diseases, University of Arizona, Tucson, Ariz; Bio5 Institute, University of Arizona, Tucson, Ariz. Electronic address: donata@email.arizona.edu.

Abstract

BACKGROUND:

The timing and mechanisms of asthma inception remain imprecisely defined. Although epigenetic mechanisms likely contribute to asthma pathogenesis, little is known about their role in asthma inception.

OBJECTIVE:

We sought to assess whether the trajectory to asthma begins already at birth and whether epigenetic mechanisms, specifically DNA methylation, contribute to asthma inception.

METHODS:

We used the Methylated CpG Island Recovery Assay chip to survey DNA methylation in cord blood mononuclear cells from 36 children (18 nonasthmatic and 18 asthmatic subjects by age 9 years) from the Infant Immune Study (IIS), an unselected birth cohort closely monitored for asthma for a decade. SMAD3 methylation in IIS (n = 60) and in 2 replication cohorts (the Manchester Asthma and Allergy Study [n = 30] and the Childhood Origins of Asthma Study [n = 28]) was analyzed by using bisulfite sequencing or Illumina 450K arrays. Cord blood mononuclear cell-derived IL-1β levels were measured by means of ELISA.

RESULTS:

Neonatal immune cells harbored 589 differentially methylated regions that distinguished IIS children who did and did not have asthma by age 9 years. In all 3 cohorts methylation in SMAD3, the most connected node within the network of asthma-associated, differentially methylated regions, was selectively increased in asthmatic children of asthmatic mothers and was associated with childhood asthma risk. Moreover, SMAD3 methylation in IIS neonates with maternal asthma was strongly and positively associated with neonatal production of IL-1β, an innate inflammatory mediator.

CONCLUSIONS:

The trajectory to childhood asthma begins at birth and involves epigenetic modifications in immunoregulatory and proinflammatory pathways. Maternal asthma influences epigenetic mechanisms that contribute to the inception of this trajectory.

KEYWORDS:

DNA methylation; Epigenetics; SMAD3; childhood asthma

PMID:
28011059
PMCID:
PMC5479765
DOI:
10.1016/j.jaci.2016.10.041
[Indexed for MEDLINE]
Free PMC Article

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