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

Avery DeVries, Gabriela Wlasiuk, Susan J. Miller, Anthony Bosco, Debra A. Stern, I. Carla Lohman, Janet L Rothers, Anya C. Jones, Jessie Nicodemus-Johnson, Monica M. Vasquez, John A. Curtin, Angela Simpson, Adnan Custovic, Daniel J. Jackson, James E. Gern, Robert F. Lemanske, Stefano Guerra, Anne L Wright, Carole Ober, Marilyn HalonenDonata Vercelli

Research output: Contribution to journalArticle

27 Citations (Scopus)

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.

Original languageEnglish (US)
JournalJournal of Allergy and Clinical Immunology
DOIs
StateAccepted/In press - Feb 26 2016

Fingerprint

Methylation
Asthma
Mothers
Parturition
Epigenomics
DNA Methylation
Fetal Blood
Interleukin-1
Blood Cells
CpG Islands
Hypersensitivity
Enzyme-Linked Immunosorbent Assay
Newborn Infant

Keywords

  • Childhood asthma
  • DNA methylation
  • Epigenetics
  • SMAD3

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology

Cite this

Epigenome-wide analysis links SMAD3 methylation at birth to asthma in children of asthmatic mothers. / DeVries, Avery; Wlasiuk, Gabriela; Miller, Susan J.; Bosco, Anthony; Stern, Debra A.; Lohman, I. Carla; Rothers, Janet L; Jones, Anya C.; Nicodemus-Johnson, Jessie; Vasquez, Monica M.; Curtin, John A.; Simpson, Angela; Custovic, Adnan; Jackson, Daniel J.; Gern, James E.; Lemanske, Robert F.; Guerra, Stefano; Wright, Anne L; Ober, Carole; Halonen, Marilyn; Vercelli, Donata.

In: Journal of Allergy and Clinical Immunology, 26.02.2016.

Research output: Contribution to journalArticle

DeVries, A, Wlasiuk, G, Miller, SJ, Bosco, A, Stern, DA, Lohman, IC, Rothers, JL, Jones, AC, Nicodemus-Johnson, J, Vasquez, MM, Curtin, JA, Simpson, A, Custovic, A, Jackson, DJ, Gern, JE, Lemanske, RF, Guerra, S, Wright, AL, Ober, C, Halonen, M & Vercelli, D 2016, 'Epigenome-wide analysis links SMAD3 methylation at birth to asthma in children of asthmatic mothers', Journal of Allergy and Clinical Immunology. https://doi.org/10.1016/j.jaci.2016.10.041
DeVries, Avery ; Wlasiuk, Gabriela ; Miller, Susan J. ; Bosco, Anthony ; Stern, Debra A. ; Lohman, I. Carla ; Rothers, Janet L ; Jones, Anya C. ; Nicodemus-Johnson, Jessie ; Vasquez, Monica M. ; Curtin, John A. ; Simpson, Angela ; Custovic, Adnan ; Jackson, Daniel J. ; Gern, James E. ; Lemanske, Robert F. ; Guerra, Stefano ; Wright, Anne L ; Ober, Carole ; Halonen, Marilyn ; Vercelli, Donata. / Epigenome-wide analysis links SMAD3 methylation at birth to asthma in children of asthmatic mothers. In: Journal of Allergy and Clinical Immunology. 2016.
@article{c6622805fa684e59b033cc50165e9066,
title = "Epigenome-wide analysis links SMAD3 methylation at birth to asthma in children of asthmatic mothers",
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 = "Childhood asthma, DNA methylation, Epigenetics, SMAD3",
author = "Avery DeVries and Gabriela Wlasiuk and Miller, {Susan J.} and Anthony Bosco and Stern, {Debra A.} and Lohman, {I. Carla} and Rothers, {Janet L} and Jones, {Anya C.} and Jessie Nicodemus-Johnson and Vasquez, {Monica M.} and Curtin, {John A.} and Angela Simpson and Adnan Custovic and Jackson, {Daniel J.} and Gern, {James E.} and Lemanske, {Robert F.} and Stefano Guerra and Wright, {Anne L} and Carole Ober and Marilyn Halonen and Donata Vercelli",
year = "2016",
month = "2",
day = "26",
doi = "10.1016/j.jaci.2016.10.041",
language = "English (US)",
journal = "Journal of Allergy and Clinical Immunology",
issn = "0091-6749",
publisher = "Mosby Inc.",

}

TY - JOUR

T1 - Epigenome-wide analysis links SMAD3 methylation at birth to asthma in children of asthmatic mothers

AU - DeVries, Avery

AU - Wlasiuk, Gabriela

AU - Miller, Susan J.

AU - Bosco, Anthony

AU - Stern, Debra A.

AU - Lohman, I. Carla

AU - Rothers, Janet L

AU - Jones, Anya C.

AU - Nicodemus-Johnson, Jessie

AU - Vasquez, Monica M.

AU - Curtin, John A.

AU - Simpson, Angela

AU - Custovic, Adnan

AU - Jackson, Daniel J.

AU - Gern, James E.

AU - Lemanske, Robert F.

AU - Guerra, Stefano

AU - Wright, Anne L

AU - Ober, Carole

AU - Halonen, Marilyn

AU - Vercelli, Donata

PY - 2016/2/26

Y1 - 2016/2/26

N2 - 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.

AB - 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.

KW - Childhood asthma

KW - DNA methylation

KW - Epigenetics

KW - SMAD3

UR - http://www.scopus.com/inward/record.url?scp=85009733754&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85009733754&partnerID=8YFLogxK

U2 - 10.1016/j.jaci.2016.10.041

DO - 10.1016/j.jaci.2016.10.041

M3 - Article

C2 - 28011059

AN - SCOPUS:85009733754

JO - Journal of Allergy and Clinical Immunology

JF - Journal of Allergy and Clinical Immunology

SN - 0091-6749

ER -