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Research project

Effect of Prenatal Compounds on Adult Lung Function via Neonatal DNA-Methylation

Project overview

Prenatal exposure to gestational smoking and use of vitamins during pregnancy can predict deficits in lung function, which is a feature of asthma and chronic obstructive pulmonary disease. Recent studies suggest that the fetus adapts to prenatal conditions by changing its epigenetic make-up thus linking the prenatal conditions to lung function and adverse pulmonary outcomes later in life. The addition of methyl groups at cytosine- phosphate-guanine sites (CpGs) is one such epigenetic mechanism which is influenced by prenatal conditions. However, it is not known yet which specific CpGs are associated with lung function. It is also unknown which metabolites, nutrients, and toxins (MNTs) during gestation influence the methylation of specific CpGs, which in turn predict lung function. To improve our mechanistic understanding the proposed pathways will be investigated in three aims. The study uses two consecutive birth cohorts (F0 grandparents, F1 parents, and F2 children), established on the Isle of Wight, UK.
In Aim 1, using the statistical methods of recursive Random Forest, we will identify differently methylated CpGs that are related to a deficit in lung function in the F1 generation. The findings will be replicated in an independent sample, the Avon Longitudinal Study of Parents and Children (ALSPAC) birth cohort.
Aim 2 will utilize liquid chromatography-mass spectrometry to conduct an un-targeted chemical screening of unknown MNTs in maternal serum collected at birth of the F1 and F2 generations. This will be followed by a statistical screening via recursive Random Forest for MNTs significantly related to the differently methylated CpGs. Associations between MNTs and CpGs will be replicated using data of a Swedish and a Japanese cohort.
In Aim 1 and 2 we analyze associations in a backward approach: (1) from lung function at age 10 and 18 years to CpGs at birth and (2) from CpGs at birth to MNTs during gestation. In contrast, in Aim 3 we will analyze the data of the F2 generation in a forward manner.
Aim 3 is to develop path-analytical models explaining a differential methylation of specific CpGs in response to prenatal MNTs and consequently predicting a deficit in lung function. We will measure lung function markers with Impulse Oscillometry at age 3 years and IOS and spirometry at 5-7 years of age in the F2 generation. Structural equation models will be implemented to link maternal MNTs and CpG sites to lung function markers in the F1 generation and will be replicated in F2. Our research team has a long track record of successful collaboration and associates epidemiological and biostatistical knowledge and metabolomic and epigenetic expertise with clinical/pulmonary partners. The proposal is of high importance since it has the potential to change the way pulmonary diseases are managed, being proactive during pregnancy and early childhood, rather than waiting for the individual to develop lung function deficit and symptoms later in life.

Staff

Lead researcher

Professor John Holloway PhD, FHEA

Associate V-P Interdisciplinary Research

Research interests

  • Human genetics
  • Epigenetics

Connect with John

Research outputs

Dilini M. Kothalawala,
Veronique B. N. Weiss,
Latha Kadalayil,
Raquel Granell,
John A. Curtin,
Clare S. Murray,
Angela Simpson,
Adnan Custovic,
William J. Tapper,
Faisal I. Rezwan,
, 2022 , Pediatric Allergy and Immunology , 33 (4) , e13777
Type: letterEditorial
Olivia Solomon,
Karen Huen,
Paul Yousefi,
Leanne K. Küpers,
Juan R. Gonzalez,
Matthew Suderman,
Sarah E. Reese,
Christian M. Page,
Olena Gruzieva,
Peter Rzehak,
Lu Gao,
Kelly M. Bakulski,
Alexei Novoloaca,
Catherine Allard,
Irene Pappa,
Maria Llambrich,
Marta Vives,
Dereje D. Jima,
Tuomas Kvist,
Andrea A. Baccarelli,
Cory White,
Faisal I Rezwan,
Gemma C. Sharp,
Gwen Tindula,
Anna Bergström,
Veit Grote,
John F Dou,
Elena Isaevska,
Maria C. Magnus,
Eva Corpeleijn,
Patrice Perron,
Vincent W V Jaddoe,
Ellen A. Nohr,
Lea Maitre,
Maria Foraster,
Cathrine Hoyo,
Siri E. Håberg,
Jari Lahti,
Dawn L. DeMeo,
Hongmei Zhang,
Wilfried Karmaus,
Inger Kull,
Berthold Koletzko,
Jason I Feinberg,
Luigi Gagliardi,
Luigi Bouchard,
Cecilia Host Ramlau-Hansen,
Henning Tiemeier,
Gillian Santorelli,
Rachel L. Maguire,
Darina Czamara,
Augusto A. Litonjua,
Jean-Paul Langhendries,
Michelle Plusquin,
Johanna Lepeule,
Elisabeth B. Binder,
Elvira Verduci,
Terence Dwyer,
Angel Carracedo,
Natalia Ferre,
Brenda Eskenazi,
Manolis Kogevinas,
Tim S. Nawrot,
Monica Cheng Munthe-Kaas,
Zdenko Herceg,
Caroline L. Relton,
Erik Melen,
Dariusz Gruszfeld,
Carrie Breton,
M D Fallin,
Akram Ghantous,
Wenche Nystad,
Barbara Heude,
Harold Snieder,
Marie-France Hivert,
Janine F. Felix,
Thorkild I. A. Sørensen,
Mariona Bustamante,
Susan K. Murphy,
Katri Raikkonen,
Emily Oken,
Syed Arshad,
Stephanie London,
& Nina Holland
, 2022 , Mutation Research - Reviews in Mutation Research , 789
Type: article
Dilini M. Kothalawala,
Latha Kadalayil,
John A. Curtin,
Clare S. Murray,
Angela Simpson,
Adnan Custovic,
William J. Tapper,
Faisal I. Rezwan,
, 2022 , Journal of Personalized Medicine , 12 (1) , 75
Type: article
Nandini Mukherjee,
Thomas R. Sutter,
Hongmei Zhang,
& Wilfried Karmaus
, 2018 , Clinical & Experimental Allergy , 48 (12) , 1688--1697
Type: article
Wilfried Karmaus,
Hongmei Zhang,
Susan Ewart,
Linda Mansfield,
Sharon Matthews,
Claire Hodgekiss,
, 2018 , International Journal of Epidemiology , 47 (4) , 1043--1044i
Type: article
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