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J Allergy Clin Immunol. 2016 Sep;138(3):748-753. doi: 10.1016/j.jaci.2015.12.1341. Epub 2016 Mar 30.

DNA methylation within melatonin receptor 1A (MTNR1A) mediates paternally transmitted genetic variant effect on asthma plus rhinitis.

Author information

1
INSERM, UMR946, Genetic Variation and Human Diseases Unit, Paris, France; Université Paris Diderot, Sorbonne Paris Cité, Institut Universitaire d'Hématologie, Paris, France.
2
Université du Québec, à Chicoutimi, Québec, Canada.
3
Section of Biology and Genetics, Department of Mother and Child, and Biology-Genetics, University of Verona, Verona, Italy.
4
National Heart and Lung Institute, Imperial College London, London, United Kingdom.
5
Université du Québec, à Chicoutimi, Québec, Canada; McGill University and Génome Québec Innovation Centre, Montreal, Québec, Canada.
6
Laboratory of Human Genetics of Infectious Diseases, Necker Branch, INSERM, UMR1163, Paris, France; Université Paris Descartes, Imagine Institute, Paris, France.
7
Max-Delbrück-Center for Molecular Medicine (MDC), Berlin, Germany.
8
Max-Delbrück-Center for Molecular Medicine (MDC), Berlin, Germany; Clinic for Pediatric Allergy, Experimental and Clinical Research Centre, Charité Universitätsmedizin Berlin, Berlin, Germany.
9
Department of Epidemiology, Harvard School of Public Health, Boston, Mass.
10
Hôpital Arnaud de Villeneuve, Service des Maladies Respiratoires, Montpellier, France.
11
Université Grenoble Alpes, IAB, Team of Environmental Epidemiology Applied to Reproduction and Respiratory Health, Grenoble, France; INSERM, IAB, Team of Environmental Epidemiology Applied to Reproduction and Respiratory Health, Grenoble, France; CHU de Grenoble, IAB, Team of Environmental Epidemiology Applied to Reproduction and Respiratory Health, Grenoble, France.
12
McGill University and Génome Québec Innovation Centre, Montreal, Québec, Canada.
13
INSERM, UMR946, Genetic Variation and Human Diseases Unit, Paris, France; Université Paris Diderot, Sorbonne Paris Cité, Institut Universitaire d'Hématologie, Paris, France. Electronic address: emmanuelle.bouzigon@inserm.fr.

Abstract

BACKGROUND:

Asthma and allergic rhinitis (AR) are common allergic comorbidities with a strong genetic component in which epigenetic mechanisms might be involved.

OBJECTIVE:

We aimed to identify novel risk loci for asthma and AR while accounting for parent-of-origin effect.

METHODS:

We performed a series of genetic analyses, taking into account the parent-of-origin effect in families ascertained through asthma: (1) genome-wide linkage scan of asthma and AR in 615 European families, (2) association analysis with 1233 single nucleotide polymorphisms (SNPs) covering the significant linkage region in 162 French Epidemiological Study on the Genetics and Environment of Asthma families with replication in 154 Canadian Saguenay-Lac-Saint-Jean asthma study families, and (3) association analysis of disease and significant SNPs with DNA methylation (DNAm) at CpG sites in 40 Saguenay-Lac-Saint-Jean asthma study families.

RESULTS:

We detected a significant paternal linkage of the 4q35 region to asthma and allergic rhinitis comorbidity (AAR; P = 7.2 × 10(-5)). Association analysis in this region showed strong evidence for the effect of the paternally inherited G allele of rs10009104 on AAR (P = 1.1 × 10(-5), reaching the multiple-testing corrected threshold). This paternally inherited allele was also significantly associated with DNAm levels at the cg02303933 site (P = 1.7 × 10(-4)). Differential DNAm at this site was found to mediate the identified SNP-AAR association.

CONCLUSION:

By integrating genetic and epigenetic data, we identified that a differentially methylated CpG site within the melatonin receptor 1A (MTNR1A) gene mediates the effect of a paternally transmitted genetic variant on the comorbidity of asthma and AR. This study provides a novel insight into the role of epigenetic mechanisms in patients with allergic respiratory diseases.

KEYWORDS:

DNA methylation; Linkage analysis; allergic rhinitis; asthma; genetic association study; parent-of-origin effect; positional cloning

PMID:
27038909
DOI:
10.1016/j.jaci.2015.12.1341
[Indexed for MEDLINE]

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