Sex-specific longitudinal association of DNA methylation with lung function
- Shadia Khan Sunny1,
- Hongmei Zhang1⇑,
- Caroline L. Relton2,
- Susan Ring2,3,
- Latha Kadalayil4,
- Fawaz Mzayek1,
- Susan Ewart5,
- John W. Holloway4,6 and
- S. Hasan Arshad6,7,8
- 1Division of Epidemiology, Biostatistics, and Environmental Health, School of Public Health, University of Memphis, Memphis, TN, USA
- 2MRC Integrative Epidemiology Unit, University of Bristol, Bristol, UK
- 3Population Health Sciences, University of Bristol, Bristol, UK
- 4Human Development and Health, Faculty of Medicine, University of Southampton, Southampton, UK
- 5Large Animal Clinical Sciences, Michigan State University, East Lansing, MI
- 6NIHR Southampton Biomedical Research Centre, University Hospital Southampton, Southampton, UK
- 7Clinical and Experimental Sciences, Faculty of Medicine, University of Southampton, Southampton, UK
- 8The David Hide Asthma and Allergy Research Centre, St Mary's Hospital, Isle of Wight, UK
- Hongmei Zhang, Division of Epidemiology, Biostatistics, and Environmental Health Sciences, School of Public Health, University of Memphis, Memphis, TN 38152, USA. E-mail: hzhang6{at}memphis.edu
Abstract
Investigating whether DNA-M at an earlier age is associated with lung function at a later age and whether this relationship differs by sex could enable prediction of future lung function deficit.
A training/testing-based technique was used to screen 402 714 cytosine-phosphate-guanine dinucleotide sites (CpGs) to assess the longitudinal association of blood-based DNA-M at ages 10 and 18-years with lung function at 18 and 26-years, respectively, in the Isle of Wight birth cohort (IOWBC). Multivariable linear mixed models were applied to the CpGs that passed screening. To detect differentially methylated regions (DMRs), DMR enrichment analysis was conducted. Findings were further examined in the Avon Longitudinal Study of Parents and Children (ALSPAC). Biological relevance of the identified CpGs was assessed utilizing gene expression data.
DNA-M at 8 CpGs (FEV1: 5 and FEV1/FVC: 3 CpGs) at an earlier age was associated with lung function at a later age regardless of sex, while at 13 CpGs (FVC: 5, FEV1:3, and FEV1/FVC: 5 CpGs), the associations were sex-specific (pFDR<0.05) in IOWBC with consistent directions of association in ALSPAC (IOWBC-ALSPAC consistent CpGs). cg16582803 (WNT10A) and cg14083603 (ZGPAT) were replicated in ALSPAC for main and sex-specific effects, respectively. Among IOWBC-ALSPAC consistent CpGs, DNA-M at cg01376079 (SSH3) and cg07557690 (TGFBR3) was associated with gene expression both longitudinally and cross-sectionally. In total, 57 and 170 DMRs were linked to lung function longitudinally in males and females, respectively.
CpGs showing longitudinal associations with lung function have the potential to serve as candidate markers in future studies on lung function deficit prediction.
Footnotes
This manuscript has recently been accepted for publication in the ERJ Open Research. It is published here in its accepted form prior to copyediting and typesetting by our production team. After these production processes are complete and the authors have approved the resulting proofs, the article will move to the latest issue of the ERJOR online. Please open or download the PDF to view this article.
Conflict of interest: Dr. Sunny has nothing to disclose.
Conflict of interest: Dr. Zhang has nothing to disclose.
Conflict of interest: Prof. Relton has nothing to disclose.
Conflict of interest: Dr. Ring has nothing to disclose.
Conflict of interest: Dr. Kadalayil has nothing to disclose.
Conflict of interest: Dr. Mzayek has nothing to disclose.
Conflict of interest: Dr. Ewart has nothing to disclose.
Conflict of interest: Dr. Holloway reports grants from National Institutes of Health (USA), during the conduct of the study.
Conflict of interest: Dr. Arshad has nothing to disclose.
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- Received February 23, 2021.
- Accepted April 16, 2021.
- Copyright ©The authors 2021
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