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Sex-specific longitudinal association of DNA methylation with lung function

Sex-specific longitudinal association of DNA methylation with lung function
Sex-specific longitudinal association of DNA methylation with lung function

Investigating whether DNA methylation (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 using gene expression data. DNA-M at eight CpGs (five CpGs with forced expiratory volume in 1 s (FEV 1) and three CpGs with FEV 1/forced vital capacity (FVC)) at an earlier age was associated with lung function at a later age regardless of sex, while at 13 CpGs (five CpGs with FVC, three with FEV 1 and five with FEV 1/FVC), the associations were sex-specific (p FDR <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.

2312-0541
00127-2021
Sunny, Shadia Khan
a77127e5-1281-445d-b8cb-dd58fab1b63e
Zhang, Hongmei
9f774048-54d6-4321-a252-3887b2c76db0
Relton, Caroline L.
7a9fe7f7-d14b-4bb7-be71-a3afa6ff8538
Ring, Susan
79941daa-7ae8-47f1-beb4-e8560ce12fd8
Perunthadambil Kadalayil, Latha
e620b801-844a-45d9-acaf-e0a58acd7cf2
Mzayek, Fawaz
0e635b70-c9f4-4cb0-a334-c75bb401559c
Ewart, Susan
28667421-3cf7-43d7-b1c3-ca27564938f7
Holloway, John W.
4bbd77e6-c095-445d-a36b-a50a72f6fe1a
Arshad, Syed
917e246d-2e60-472f-8d30-94b01ef28958
Sunny, Shadia Khan
a77127e5-1281-445d-b8cb-dd58fab1b63e
Zhang, Hongmei
9f774048-54d6-4321-a252-3887b2c76db0
Relton, Caroline L.
7a9fe7f7-d14b-4bb7-be71-a3afa6ff8538
Ring, Susan
79941daa-7ae8-47f1-beb4-e8560ce12fd8
Perunthadambil Kadalayil, Latha
e620b801-844a-45d9-acaf-e0a58acd7cf2
Mzayek, Fawaz
0e635b70-c9f4-4cb0-a334-c75bb401559c
Ewart, Susan
28667421-3cf7-43d7-b1c3-ca27564938f7
Holloway, John W.
4bbd77e6-c095-445d-a36b-a50a72f6fe1a
Arshad, Syed
917e246d-2e60-472f-8d30-94b01ef28958

Sunny, Shadia Khan, Zhang, Hongmei, Relton, Caroline L., Ring, Susan, Perunthadambil Kadalayil, Latha, Mzayek, Fawaz, Ewart, Susan, Holloway, John W. and Arshad, Syed (2021) Sex-specific longitudinal association of DNA methylation with lung function. ERJ Open Research, 7 (3), 00127-2021. (doi:10.1183/23120541.00127-2021).

Record type: Article

Abstract

Investigating whether DNA methylation (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 using gene expression data. DNA-M at eight CpGs (five CpGs with forced expiratory volume in 1 s (FEV 1) and three CpGs with FEV 1/forced vital capacity (FVC)) at an earlier age was associated with lung function at a later age regardless of sex, while at 13 CpGs (five CpGs with FVC, three with FEV 1 and five with FEV 1/FVC), the associations were sex-specific (p FDR <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.

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More information

Accepted/In Press date: 16 April 2021
Published date: 5 July 2021
Additional Information: Acknowledgements The authors gratefully acknowledge the cooperation of the children and parents who participated in this study and appreciate the hard work of the Isle of Wight research team in collecting data. We thank the High-Throughput Genomics Group at the Wellcome Trust Centre for Human Genetics (funded by Wellcome Trust grant ref. 090532/Z/09/Z and MRC Hub grant G0900747 91070) for the generation of the methylation data. The authors are thankful to the High-Performance Computing facility at the University of Memphis. For the ALSPAC cohort, 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.

Identifiers

Local EPrints ID: 450319
URI: http://eprints.soton.ac.uk/id/eprint/450319
ISSN: 2312-0541
PURE UUID: 230b80b3-2603-4cb9-a378-2a3cb83223de
ORCID for John W. Holloway: ORCID iD orcid.org/0000-0001-9998-0464

Catalogue record

Date deposited: 22 Jul 2021 16:33
Last modified: 12 Nov 2021 02:37

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Contributors

Author: Shadia Khan Sunny
Author: Hongmei Zhang
Author: Caroline L. Relton
Author: Susan Ring
Author: Fawaz Mzayek
Author: Susan Ewart
Author: Syed Arshad

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