TY - JOUR T1 - Sex-specific longitudinal association of DNA methylation with lung function JF - ERJ Open Research JO - erjor DO - 10.1183/23120541.00127-2021 SP - 00127-2021 AU - Shadia Khan Sunny AU - Hongmei Zhang AU - Caroline L. Relton AU - Susan Ring AU - Latha Kadalayil AU - Fawaz Mzayek AU - Susan Ewart AU - John W. Holloway AU - S. Hasan Arshad Y1 - 2021/01/01 UR - http://openres.ersjournals.com/content/early/2021/04/22/23120541.00127-2021.abstract N2 - 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.FootnotesThis 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. ER -