DNA methylation at birth is associated with lung function development until age 26 years

Nandini Mukherjee, Ryan Arathimos, Su Chen, Parnian Kheirkhah Rahimabad, Luhang Han, Hongmei Zhang, John W Holloway, Caroline Relton, A John Henderson, Syed Hasan Arshad, Susan Ewart, Wilfried Karmaus*

*Corresponding author for this work

Research output: Contribution to journalArticle (Academic Journal)peer-review

7 Citations (Scopus)
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Abstract

Little is known about whether DNA methylation (DNAm) of cytosine-phosphate-guanine (CpG) sites at birth predicts patterns of lung function development. We used heel prick DNAm from the F1-generation of Isle of Wight birth cohort (IOWBC-F1) for discovery of CpGs associated with lung function trajectories (Forced Expiratory Volume, Forced Vital Capacity, their ratio, and Forced Expiratory Flow at 25-75%) over the first 26 years, stratified by sex. We replicated the findings in the Avon Longitudinal Study of Parents and Children (ALSPAC) using cord blood DNAm.

Epigenome-wide screening was applied to identify CpGs associated with lung function trajectories in 396 boys, and 390 girls of IOWBC-F1. Replication in ALSPAC focused on lung function at ages 8, 15 and 24 years. Statistically significantly replicated CpGs were investigated for consistency in direction of association between cohorts, stability of DNAm over time in IOWBC-F1, relevant biological processes, and for association with gene expression (n=161) in IOWBC F2-generation (IOWBC-F2).

Differential DNAm of 8 CpGs on genes GLUL, MYCN, HLX, LHX1, COBL, COL18A1,
STRA6, and WNT11 involved in developmental processes, were significantly associated with lung function in the same direction in IOWBC-F1 and ALSPAC, and showed stable patterns at birth, age 10 and 18 years between high and low lung function trajectories in IOWBC-F1. CpGs on LHX1 and COL18A1 were linked to gene expression in IOWBCF2.

In two large cohorts, novel DNAm at birth were associated with patterns of lung function in adolescence and early adulthood providing possible targets for preventative interventions against adverse pulmonary function development.
Original languageEnglish
Article number2003505
JournalEuropean Respiratory Journal
Volume57
Issue number4
DOIs
Publication statusPublished - 15 Apr 2021

Bibliographical note

Funding Information:
The authors gratefully acknowledge the participation and cooperation of the children and parents of Isle of Wight and appreciate the hard work of Sharon Matthews and the Isle of Wight research team in collecting data and Nikki Graham for technical support. We thank the High-Throughput Genomics Group at the Wellcome Trust Centre for Human Genetics (funded by Wellcome Trust grant reference 090532/Z/09/Z) for the generation of the methylation data. We are extremely grateful to all the families who took part in this study, the midwives for their help in recruiting them, and the whole ALSPAC team, which includes interviewers, computer and laboratory technicians, clerical workers, research scientists, volunteers, managers, receptionists and nurses. We would like to thank Gemma Sharp for her contribution towards the quality control of the ARIES data. This work has been supported by National Institutes of Health/National Institute of Allergy and Infectious Diseases (R01 AI091905 and R01HL132321 to W.K., R01 AI121226 to H.Z. and J.W.H.); National Asthma Campaign, UK (364); and the National Institutes of Health/National Heart, Lung, and Blood Institute (R01 HL082925 to S.H.A.). The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health, USA, and National Asthma Campaign, UK. The Accessible Resource for Integrated Epigenomics Studies (ARIES) which generated large scale methylation data was funded by the UK Biotechnology and Biological Sciences Research Council (BB/I025751/1 and BB/I025263/1). Additional epigenetic profiling on the ALSPAC cohort was supported by the UK Medical Research Council Integrative Epidemiology Unit and the University of Bristol (MC_UU_12013_1, MC_UU_12013_2, MC_UU_12013_5 and MC_UU_12013_8), the Wellcome Trust (WT088806) and the United States National Institute of Diabetes and Digestive and Kidney Diseases (R01 DK10324). The UK Medical Research Council and Wellcome (Grant ref: 102215/2/13/2) and the University of Bristol provide core support for ALSPAC. Funding information for this article has been deposited with the Crossref Funder Registry.

Funding Information:
Support statement: This work has been supported by National Institutes of Health/National Institute of Allergy and Infectious Diseases (R01 AI091905 and R01HL132321 to W.K., R01 AI121226 to H.Z. and J.W.H.); National Asthma Campaign, UK (364); and the National Institutes of Health/National Heart, Lung, and Blood Institute (R01 HL082925 to S.H.A.). The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health, USA, and National Asthma Campaign, UK. The Accessible Resource for Integrated Epigenomics Studies (ARIES) which generated large scale methylation data was funded by the UK Biotechnology and Biological Sciences Research Council (BB/I025751/1 and BB/I025263/1). Additional epigenetic profiling on the ALSPAC cohort was supported by the UK Medical Research Council Integrative Epidemiology Unit and the University of Bristol (MC_UU_12013_1, MC_UU_12013_2, MC_UU_12013_5 and MC_UU_12013_8), the Wellcome Trust (WT088806) and the United States National Institute of Diabetes and Digestive and Kidney Diseases (R01 DK10324). The UK Medical Research Council and Wellcome (Grant ref: 102215/2/13/2) and the University of Bristol provide core support for ALSPAC. Funding information for this article has been deposited with the Crossref Funder Registry.

Funding Information:
Acknowledgements: The authors gratefully acknowledge the participation and cooperation of the children and parents of Isle of Wight and appreciate the hard work of Sharon Matthews and the Isle of Wight research team in collecting data and Nikki Graham for technical support. We thank the High-Throughput Genomics Group at the Wellcome Trust Centre for Human Genetics (funded by Wellcome Trust grant reference 090532/Z/09/Z) for the generation of the methylation data. We are extremely grateful to all the families who took part in this study, the midwives for their help in recruiting them, and the whole ALSPAC team, which includes interviewers, computer and laboratory technicians, clerical workers, research scientists, volunteers, managers, receptionists and nurses. We would like to thank Gemma Sharp for her contribution towards the quality control of the ARIES data.

Publisher Copyright:
© ERS 2021

Keywords

  • DNA-methylation pattern
  • epigenome-wide
  • lung function trajectories
  • prospective
  • cohort study

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