Association of childhood BMI trajectory with post-adolescent and adult lung function is mediated by pre-adolescent DNA methylation
Association of childhood BMI trajectory with post-adolescent and adult lung function is mediated by pre-adolescent DNA methylation
Background: body mass index (BMI) has been shown to be associated with lung function. Recent findings showed that DNA methylation (DNAm) variation is likely to be a consequence of changes in BMI. However, whether DNAm mediates the association of BMI with lung function is unknown. We examined the mediating role of DNAm on the association of pre-adolescent BMI trajectories with post-adolescent and adulthood lung function (forced expiratory volume (FEV1), forced vital capacity (FVC), and FEV1/FVC).
Methods: analyses were undertaken in the Isle of Wight birth cohort (IOWBC). Group-based trajectory modelling was applied to infer latent BMI trajectories from age 1 to 10 years. An R package, ttscreening, was applied to identify CpGs at 10 years potentially associated with BMI trajectories for each sex. Linear regressions were implemented to further screen CpGs for their association with lung function at 18 years. Path analysis, stratified by sex, was applied to each screened CpG to assess its role of mediation. Internal validation was applied to further examine the mediation consistency of the detected CpGs based on lung function at 26 years. Mendelian randomization (MR-base) was used to test possible causal effects of the identified CpGs.
Results: two BMI trajectories (high vs. low) were identified. Of the 442,475 CpG sites, 18 CpGs in males and 33 in females passed screening. Eight CpGs in males and 16 CpGs in females (none overlapping) were identified as mediators. For subjects with high BMI trajectory, high DNAm at all CpGs in males were associated with decreased lung function, while 8 CpGs in females were associated with increased lung function at 18 years. At 26 years, 6 CpGs in males and 14 CpGs in females showed the same direction of indirect effects as those at 18 years. DNAm at CpGs cg19088553 (GRIK2) and cg00612625 (HPSE2) showed a potential causal effect on FEV1.
Conclusions: the effects of BMI trajectory in early childhood on post-adolescence lung function were likely to be mediated by pre-adolescence DNAm in both males and females, but such mediation effects were likely to diminish over time.
Adolescent, Adult, Body Mass Index, Body-Weight Trajectory, Child, Child, Preschool, DNA Methylation/physiology, Female, Forced Expiratory Volume/physiology, Humans, Infant, Lung/physiology, Male, Vital Capacity/physiology
Rathod, Rutu
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Zhang, Hongmei
9f774048-54d6-4321-a252-3887b2c76db0
Karmaus, Wilfried
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Ewart, Susan
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Mzayek, Fawaz
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Arshad, S. Hasan
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Holloway, John W.
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29 July 2022
Rathod, Rutu
4d0f6483-9248-4468-8d51-1e0e378b9cc4
Zhang, Hongmei
9f774048-54d6-4321-a252-3887b2c76db0
Karmaus, Wilfried
281d0e53-6b5d-4d38-9732-3981b07cd853
Ewart, Susan
28667421-3cf7-43d7-b1c3-ca27564938f7
Mzayek, Fawaz
0e635b70-c9f4-4cb0-a334-c75bb401559c
Arshad, S. Hasan
917e246d-2e60-472f-8d30-94b01ef28958
Holloway, John W.
4bbd77e6-c095-445d-a36b-a50a72f6fe1a
Rathod, Rutu, Zhang, Hongmei, Karmaus, Wilfried, Ewart, Susan, Mzayek, Fawaz, Arshad, S. Hasan and Holloway, John W.
(2022)
Association of childhood BMI trajectory with post-adolescent and adult lung function is mediated by pre-adolescent DNA methylation.
Respiratory Research, 23 (1), [194].
(doi:10.1186/s12931-022-02089-4).
Abstract
Background: body mass index (BMI) has been shown to be associated with lung function. Recent findings showed that DNA methylation (DNAm) variation is likely to be a consequence of changes in BMI. However, whether DNAm mediates the association of BMI with lung function is unknown. We examined the mediating role of DNAm on the association of pre-adolescent BMI trajectories with post-adolescent and adulthood lung function (forced expiratory volume (FEV1), forced vital capacity (FVC), and FEV1/FVC).
Methods: analyses were undertaken in the Isle of Wight birth cohort (IOWBC). Group-based trajectory modelling was applied to infer latent BMI trajectories from age 1 to 10 years. An R package, ttscreening, was applied to identify CpGs at 10 years potentially associated with BMI trajectories for each sex. Linear regressions were implemented to further screen CpGs for their association with lung function at 18 years. Path analysis, stratified by sex, was applied to each screened CpG to assess its role of mediation. Internal validation was applied to further examine the mediation consistency of the detected CpGs based on lung function at 26 years. Mendelian randomization (MR-base) was used to test possible causal effects of the identified CpGs.
Results: two BMI trajectories (high vs. low) were identified. Of the 442,475 CpG sites, 18 CpGs in males and 33 in females passed screening. Eight CpGs in males and 16 CpGs in females (none overlapping) were identified as mediators. For subjects with high BMI trajectory, high DNAm at all CpGs in males were associated with decreased lung function, while 8 CpGs in females were associated with increased lung function at 18 years. At 26 years, 6 CpGs in males and 14 CpGs in females showed the same direction of indirect effects as those at 18 years. DNAm at CpGs cg19088553 (GRIK2) and cg00612625 (HPSE2) showed a potential causal effect on FEV1.
Conclusions: the effects of BMI trajectory in early childhood on post-adolescence lung function were likely to be mediated by pre-adolescence DNAm in both males and females, but such mediation effects were likely to diminish over time.
Text
s12931-022-02089-4
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Accepted/In Press date: 14 June 2022
Published date: 29 July 2022
Additional Information:
Funding
This study was supported by the National Institutes of Health research fund R01AI121226 (MPI: H Zhang and JW Holloway). Part of the methylation data generation was supported by R01AI091905 (PI: W Karmaus). The Isle of Wight Birth Cohort assessments have been supported by the National Institutes of Health USA (Grant no. R01 HL082925, H. Arshad), Asthma UK (Grant no. 364. S.H. Arshad) and the David Hide Asthma and Allergy Research Trust.
Keywords:
Adolescent, Adult, Body Mass Index, Body-Weight Trajectory, Child, Child, Preschool, DNA Methylation/physiology, Female, Forced Expiratory Volume/physiology, Humans, Infant, Lung/physiology, Male, Vital Capacity/physiology
Identifiers
Local EPrints ID: 470036
URI: http://eprints.soton.ac.uk/id/eprint/470036
ISSN: 1465-9921
PURE UUID: f2b0e23d-7db5-4454-957b-e429c14ff273
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Date deposited: 30 Sep 2022 16:51
Last modified: 17 Mar 2024 02:45
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Contributors
Author:
Rutu Rathod
Author:
Hongmei Zhang
Author:
Wilfried Karmaus
Author:
Susan Ewart
Author:
Fawaz Mzayek
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