Epigenome-wide Meta-analysis of DNA Methylation and Childhood Asthma

BIOS Consortium

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Abstract

Background: Epigenetic mechanisms, including methylation, can contribute to childhood asthma. Identifying DNA methylation profiles in asthmatic patients can inform disease pathogenesis. Objective: We sought to identify differential DNA methylation in newborns and children related to childhood asthma. Methods: Within the Pregnancy And Childhood Epigenetics consortium, we performed epigenome-wide meta-analyses of school-age asthma in relation to CpG methylation (Illumina450K) in blood measured either in newborns, in prospective analyses, or cross-sectionally in school-aged children. We also identified differentially methylated regions. Results: In newborns (8 cohorts, 668 cases), 9 CpGs (and 35 regions) were differentially methylated (epigenome-wide significance, false discovery rate < 0.05) in relation to asthma development. In a cross-sectional meta-analysis of asthma and methylation in children (9 cohorts, 631 cases), we identified 179 CpGs (false discovery rate < 0.05) and 36 differentially methylated regions. In replication studies of methylation in other tissues, most of the 179 CpGs discovered in blood replicated, despite smaller sample sizes, in studies of nasal respiratory epithelium or eosinophils. Pathway analyses highlighted enrichment for asthma-relevant immune processes and overlap in pathways enriched both in newborns and children. Gene expression correlated with methylation at most loci. Functional annotation supports a regulatory effect on gene expression at many asthma-associated CpGs. Several implicated genes are targets for approved or experimental drugs, including IL5RA and KCNH2. Conclusion: Novel loci differentially methylated in newborns represent potential biomarkers of risk of asthma by school age. Cross-sectional associations in children can reflect both risk for and effects of disease. Asthma-related differential methylation in blood in children was substantially replicated in eosinophils and respiratory epithelium.

Original languageEnglish
JournalJournal of Allergy and Clinical Immunology
Volume143
Issue number6
Pages (from-to)2062-2074
ISSN0091-6749
DOIs
Publication statusPublished - Jun 2019

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DNA Methylation
Meta-Analysis
Newborn Infant
Respiratory Mucosa
Eosinophils
Epigenomics
Nasal Mucosa
Sample Size
Cross-Sectional Studies

Keywords

  • Epigenetics
  • asthma
  • childhood
  • drug development
  • methylation
  • newborn

Cite this

@article{ce2565e3701f458a953c5b1ba9a1275a,
title = "Epigenome-wide Meta-analysis of DNA Methylation and Childhood Asthma",
abstract = "Background: Epigenetic mechanisms, including methylation, can contribute to childhood asthma. Identifying DNA methylation profiles in asthmatic patients can inform disease pathogenesis. Objective: We sought to identify differential DNA methylation in newborns and children related to childhood asthma. Methods: Within the Pregnancy And Childhood Epigenetics consortium, we performed epigenome-wide meta-analyses of school-age asthma in relation to CpG methylation (Illumina450K) in blood measured either in newborns, in prospective analyses, or cross-sectionally in school-aged children. We also identified differentially methylated regions. Results: In newborns (8 cohorts, 668 cases), 9 CpGs (and 35 regions) were differentially methylated (epigenome-wide significance, false discovery rate < 0.05) in relation to asthma development. In a cross-sectional meta-analysis of asthma and methylation in children (9 cohorts, 631 cases), we identified 179 CpGs (false discovery rate < 0.05) and 36 differentially methylated regions. In replication studies of methylation in other tissues, most of the 179 CpGs discovered in blood replicated, despite smaller sample sizes, in studies of nasal respiratory epithelium or eosinophils. Pathway analyses highlighted enrichment for asthma-relevant immune processes and overlap in pathways enriched both in newborns and children. Gene expression correlated with methylation at most loci. Functional annotation supports a regulatory effect on gene expression at many asthma-associated CpGs. Several implicated genes are targets for approved or experimental drugs, including IL5RA and KCNH2. Conclusion: Novel loci differentially methylated in newborns represent potential biomarkers of risk of asthma by school age. Cross-sectional associations in children can reflect both risk for and effects of disease. Asthma-related differential methylation in blood in children was substantially replicated in eosinophils and respiratory epithelium.",
keywords = "Epigenetics, asthma, childhood, drug development, methylation, newborn",
author = "Reese, {Sarah E} and Cheng-Jian Xu and {den Dekker}, {Herman T} and Lee, {Mi Kyeong} and Sinjini Sikdar and Carlos Ruiz-Arenas and Merid, {Simon K} and Rezwan, {Faisal I} and Page, {Christian M} and Vilhelmina Ullemar and Melton, {Phillip E} and Oh, {Sam S} and Yang, {Ivana V} and Kimberley Burrows and Cilla S{\"o}derh{\"a}ll and Jima, {Dereje D} and Lu Gao and Ryan Arathimos and K{\"u}pers, {Leanne K} and Matthias Wielscher and Peter Rzehak and Jari Lahti and Catherine Laprise and Anne-Marie Madore and James Ward and Bennett, {Brian D} and Tianyuan Wang and Bell, {Douglas A} and Vonk, {Judith M} and H{\aa}berg, {Siri E} and Shanshan Zhao and Robert Karlsson and Elysia Hollams and Donglei Hu and Richards, {Adam J} and Anna Bergstr{\"o}m and Sharp, {Gemma C} and Felix, {Janine F} and Mariona Bustamante and Olena Gruzieva and Maguire, {Rachel L} and Frank Gilliland and Nour Ba{\"i}z and Nohr, {Ellen A} and Eva Corpeleijn and Sylvain Sebert and Wilfried Karmaus and Veit Grote and Eero Kajantie and Magnus, {Maria C} and {BIOS Consortium}",
note = "Copyright {\circledC} 2018. Published by Elsevier Inc.",
year = "2019",
month = "6",
doi = "10.1016/j.jaci.2018.11.043",
language = "English",
volume = "143",
pages = "2062--2074",
journal = "Journal of Allergy and Clinical Immunology",
issn = "0091-6749",
publisher = "Mosby, Inc.",
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}

Epigenome-wide Meta-analysis of DNA Methylation and Childhood Asthma. / BIOS Consortium.

In: Journal of Allergy and Clinical Immunology, Vol. 143, No. 6, 06.2019, p. 2062-2074.

Research output: Contribution to journalJournal articleResearchpeer-review

TY - JOUR

T1 - Epigenome-wide Meta-analysis of DNA Methylation and Childhood Asthma

AU - Reese, Sarah E

AU - Xu, Cheng-Jian

AU - den Dekker, Herman T

AU - Lee, Mi Kyeong

AU - Sikdar, Sinjini

AU - Ruiz-Arenas, Carlos

AU - Merid, Simon K

AU - Rezwan, Faisal I

AU - Page, Christian M

AU - Ullemar, Vilhelmina

AU - Melton, Phillip E

AU - Oh, Sam S

AU - Yang, Ivana V

AU - Burrows, Kimberley

AU - Söderhäll, Cilla

AU - Jima, Dereje D

AU - Gao, Lu

AU - Arathimos, Ryan

AU - Küpers, Leanne K

AU - Wielscher, Matthias

AU - Rzehak, Peter

AU - Lahti, Jari

AU - Laprise, Catherine

AU - Madore, Anne-Marie

AU - Ward, James

AU - Bennett, Brian D

AU - Wang, Tianyuan

AU - Bell, Douglas A

AU - Vonk, Judith M

AU - Håberg, Siri E

AU - Zhao, Shanshan

AU - Karlsson, Robert

AU - Hollams, Elysia

AU - Hu, Donglei

AU - Richards, Adam J

AU - Bergström, Anna

AU - Sharp, Gemma C

AU - Felix, Janine F

AU - Bustamante, Mariona

AU - Gruzieva, Olena

AU - Maguire, Rachel L

AU - Gilliland, Frank

AU - Baïz, Nour

AU - Nohr, Ellen A

AU - Corpeleijn, Eva

AU - Sebert, Sylvain

AU - Karmaus, Wilfried

AU - Grote, Veit

AU - Kajantie, Eero

AU - Magnus, Maria C

AU - BIOS Consortium

N1 - Copyright © 2018. Published by Elsevier Inc.

PY - 2019/6

Y1 - 2019/6

N2 - Background: Epigenetic mechanisms, including methylation, can contribute to childhood asthma. Identifying DNA methylation profiles in asthmatic patients can inform disease pathogenesis. Objective: We sought to identify differential DNA methylation in newborns and children related to childhood asthma. Methods: Within the Pregnancy And Childhood Epigenetics consortium, we performed epigenome-wide meta-analyses of school-age asthma in relation to CpG methylation (Illumina450K) in blood measured either in newborns, in prospective analyses, or cross-sectionally in school-aged children. We also identified differentially methylated regions. Results: In newborns (8 cohorts, 668 cases), 9 CpGs (and 35 regions) were differentially methylated (epigenome-wide significance, false discovery rate < 0.05) in relation to asthma development. In a cross-sectional meta-analysis of asthma and methylation in children (9 cohorts, 631 cases), we identified 179 CpGs (false discovery rate < 0.05) and 36 differentially methylated regions. In replication studies of methylation in other tissues, most of the 179 CpGs discovered in blood replicated, despite smaller sample sizes, in studies of nasal respiratory epithelium or eosinophils. Pathway analyses highlighted enrichment for asthma-relevant immune processes and overlap in pathways enriched both in newborns and children. Gene expression correlated with methylation at most loci. Functional annotation supports a regulatory effect on gene expression at many asthma-associated CpGs. Several implicated genes are targets for approved or experimental drugs, including IL5RA and KCNH2. Conclusion: Novel loci differentially methylated in newborns represent potential biomarkers of risk of asthma by school age. Cross-sectional associations in children can reflect both risk for and effects of disease. Asthma-related differential methylation in blood in children was substantially replicated in eosinophils and respiratory epithelium.

AB - Background: Epigenetic mechanisms, including methylation, can contribute to childhood asthma. Identifying DNA methylation profiles in asthmatic patients can inform disease pathogenesis. Objective: We sought to identify differential DNA methylation in newborns and children related to childhood asthma. Methods: Within the Pregnancy And Childhood Epigenetics consortium, we performed epigenome-wide meta-analyses of school-age asthma in relation to CpG methylation (Illumina450K) in blood measured either in newborns, in prospective analyses, or cross-sectionally in school-aged children. We also identified differentially methylated regions. Results: In newborns (8 cohorts, 668 cases), 9 CpGs (and 35 regions) were differentially methylated (epigenome-wide significance, false discovery rate < 0.05) in relation to asthma development. In a cross-sectional meta-analysis of asthma and methylation in children (9 cohorts, 631 cases), we identified 179 CpGs (false discovery rate < 0.05) and 36 differentially methylated regions. In replication studies of methylation in other tissues, most of the 179 CpGs discovered in blood replicated, despite smaller sample sizes, in studies of nasal respiratory epithelium or eosinophils. Pathway analyses highlighted enrichment for asthma-relevant immune processes and overlap in pathways enriched both in newborns and children. Gene expression correlated with methylation at most loci. Functional annotation supports a regulatory effect on gene expression at many asthma-associated CpGs. Several implicated genes are targets for approved or experimental drugs, including IL5RA and KCNH2. Conclusion: Novel loci differentially methylated in newborns represent potential biomarkers of risk of asthma by school age. Cross-sectional associations in children can reflect both risk for and effects of disease. Asthma-related differential methylation in blood in children was substantially replicated in eosinophils and respiratory epithelium.

KW - Epigenetics

KW - asthma

KW - childhood

KW - drug development

KW - methylation

KW - newborn

U2 - 10.1016/j.jaci.2018.11.043

DO - 10.1016/j.jaci.2018.11.043

M3 - Journal article

C2 - 30579849

VL - 143

SP - 2062

EP - 2074

JO - Journal of Allergy and Clinical Immunology

JF - Journal of Allergy and Clinical Immunology

SN - 0091-6749

IS - 6

ER -