Epigenome-wide meta-analysis of DNA methylation and childhood asthma

Sarah E Reese,Anne K Örtqvist,Cilla Söderhäll,Carrie V Breton,Donglei Hu,Anna Bergström,Peter Rzehak,David A Schwartz,Jari Lahti,Lu Gao,Erik Melén,Cathrine Hoyo,Harold Snieder,Catarina Almqvist,Mariona Bustamante,Wilfried Karmaus,Brian D Bennett,Kimberley Burrows,Catherine Laprise,Vilhelmina Ullemar,Herman T Den Dekker,Esteban G Burchard,Katri Räikkönen,Nour Baïz,Syed Hasan Arshad,Eva Corpeleijn,Sinjini Sikdar,Stephanie J London,Eero Kajantie,Juha Kere,Bert Brunekreef,A John Henderson,Leanne K Küpers,Veit Grote,Celeste Eng,Sam S Oh,Vincent W.V Jaddoe,Tianyuan Wang,Janine F Felix,Gerard H Koppelman,Ivana V Yang,Ryan Arathimos,Faisal I Rezwan,Mi Kyeong Lee,Göran Pershagen,Matthias Wielscher,Inger Kull,Berthold Koletzko,Jordi Sunyer,Wenche Nystad,Robert Karlsson,John W Holloway,Shanshan Zhao,Judith M Vonk,Susan K Murphy,Anne-Marie Madore,Phillip E Melton,Andrew H Liu,Nabila Kazmi,Olena Gruzieva,Christian M Page,Elisabeth B Binder,Dereje D Jima,Douglas A Bell,Eva Reischl,Carlos Ruiz‐Arenas ,Maria C Magnus ,Rachel Maguire ,Marjo‐Riitta Järvelin ,Josep M Antó ,Sylvain Sebért ,Rae‐Chi Huang ,Ellen A Nøhr ,Siri Eldevik Håberg ,Elysia M Hollams ,Caroline L Relton ,Gemma C Sharp ,Simon Kebede Merid ,Isabella Annesi‐Maesano ,Cheng‐Jian Xu ,James M Ward ,Adam Richards ,Frank D Gilliland

doi:10.1016/j.jaci.2018.11.043

Abstract

Epigenetic mechanisms, including methylation, can contribute to childhood asthma. Identifying DNA methylation profiles in asthmatic patients can inform disease pathogenesis. We sought to identify differential DNA methylation in newborns and children related to childhood asthma. 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. 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. 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.

Highlights

Epigenetic mechanisms, including methylation, can contribute to childhood asthma
We investigated the association of DNA methylation in blood and asthma at both individual sites and over genomic regions and evaluated the potential functional effect of findings by integrating gene expression, pathway analyses, detailed functional annotation, and the search for druggable targets of differentially methylated loci
We examined the cell-type specificity of significant findings in whole blood in childhood by doing a look-up in 2 data sets, with methylation measured with the Illumina450K in respiratory epithelium collected by means of nasal brushing (455 sixteen-year-old Dutch children [37 with asthma] from the PIAMA study[13] and 72 African-American children [36 asthmatic patients and 38 nonasthmatic subjects],45 as well as a study with methylation measured with the Illumina450K in eosinophils isolated from blood [16 asthmatic patients and 8 nonasthmatic subjects aged 2-56 years from the SaguenayLac-Saint-Jean [SLSJ] region in Canada).[13,46,47]

Summary

Introduction

Epigenetic mechanisms, including methylation, can contribute to childhood asthma. 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. 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. Asthma-related differential methylation in blood in children was substantially replicated in eosinophils and respiratory epithelium. Asthma-related differential methylation in blood in children was substantially replicated in eosinophils and respiratory epithelium. (J Allergy Clin Immunol 2019;143:2062-74.)

Objectives

Methods

Results