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Maternal dysglycaemia, changes in the infant's epigenome modified with a diet and physical activity intervention in pregnancy: Secondary analysis of a randomised control trial

Maternal dysglycaemia, changes in the infant's epigenome modified with a diet and physical activity intervention in pregnancy: Secondary analysis of a randomised control trial
Maternal dysglycaemia, changes in the infant's epigenome modified with a diet and physical activity intervention in pregnancy: Secondary analysis of a randomised control trial

BACKGROUND: Higher maternal plasma glucose (PG) concentrations, even below gestational diabetes mellitus (GDM) thresholds, are associated with adverse offspring outcomes, with DNA methylation proposed as a mediating mechanism. Here, we examined the relationships between maternal dysglycaemia at 24 to 28 weeks' gestation and DNA methylation in neonates and whether a dietary and physical activity intervention in pregnant women with obesity modified the methylation signatures associated with maternal dysglycaemia.

METHODS AND FINDINGS: We investigated 557 women, recruited between 2009 and 2014 from the UK Pregnancies Better Eating and Activity Trial (UPBEAT), a randomised controlled trial (RCT), of a lifestyle intervention (low glycaemic index (GI) diet plus physical activity) in pregnant women with obesity (294 contol, 263 intervention). Between 27 and 28 weeks of pregnancy, participants had an oral glucose (75 g) tolerance test (OGTT), and GDM diagnosis was based on diagnostic criteria recommended by the International Association of Diabetes and Pregnancy Study Groups (IADPSG), with 159 women having a diagnosis of GDM. Cord blood DNA samples from the infants were interrogated for genome-wide DNA methylation levels using the Infinium Human MethylationEPIC BeadChip array. Robust regression was carried out, adjusting for maternal age, smoking, parity, ethnicity, neonate sex, and predicted cell-type composition. Maternal GDM, fasting glucose, 1-h, and 2-h glucose concentrations following an OGTT were associated with 242, 1, 592, and 17 differentially methylated cytosine-phosphate-guanine (dmCpG) sites (false discovery rate (FDR) ≤ 0.05), respectively, in the infant's cord blood DNA. The most significantly GDM-associated CpG was cg03566881 located within the leucine-rich repeat-containing G-protein coupled receptor 6 (LGR6) (FDR = 0.0002). Moreover, we show that the GDM and 1-h glucose-associated methylation signatures in the cord blood of the infant appeared to be attenuated by the dietary and physical activity intervention during pregnancy; in the intervention arm, there were no GDM and two 1-h glucose-associated dmCpGs, whereas in the standard care arm, there were 41 GDM and 160 1-h glucose-associated dmCpGs. A total of 87% of the GDM and 77% of the 1-h glucose-associated dmCpGs had smaller effect sizes in the intervention compared to the standard care arm; the adjusted r2 for the association of LGR6 cg03566881 with GDM was 0.317 (95% confidence interval (CI) 0.012, 0.022) in the standard care and 0.240 (95% CI 0.001, 0.015) in the intervention arm. Limitations included measurement of DNA methylation in cord blood, where the functional significance of such changes are unclear, and because of the strong collinearity between treatment modality and severity of hyperglycaemia, we cannot exclude that treatment-related differences are potential confounders.

CONCLUSIONS: Maternal dysglycaemia was associated with significant changes in the epigenome of the infants. Moreover, we found that the epigenetic impact of a dysglycaemic prenatal maternal environment appeared to be modified by a lifestyle intervention in pregnancy. Further research will be needed to investigate possible medical implications of the findings.

TRIAL REGISTRATION: ISRCTN89971375.

1549-1277
Antoun, Elie
10fc5678-b33c-4410-977d-b11234031791
Kitaba, Negusse T.
5e35ae4a-edaa-4b78-bcb6-00628c3b6e83
Titcombe, Philip
a84c9fad-0580-42f9-8bb6-db0fe20435aa
Dalrymple, Kathryn V.
8ef94198-4e90-44a9-b77d-19d35d013cde
Garratt, Emma S.
66ddd4cb-19a2-4d08-889b-12f418e6878b
Barton, Sheila J.
4f674382-ca0b-44ad-9670-e71a0b134ef0
Murray, Robert
c3e973b5-525c-49b3-96ee-af60a666a0f4
Seed, Paul T.
d3eda3f4-0e4c-4c17-9efd-dc75b583e79a
Holbrook, Joanna D.
69989b79-2710-4f12-946e-c6214e1b6513
Kobor, Michael S.
e387ab6f-d060-4d39-95c6-acf0c3b9687b
Lin, David Ts
7349d763-63ed-4e08-8a49-657138fadb3d
Macisaac, Julia L.
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Burdge, Graham C.
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White, Sara L.
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Poston, Lucilla
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Godfrey, Keith M.
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Lillycrop, Karen A.
eeaaa78d-0c4d-4033-a178-60ce7345a2cc
Antoun, Elie
10fc5678-b33c-4410-977d-b11234031791
Kitaba, Negusse T.
5e35ae4a-edaa-4b78-bcb6-00628c3b6e83
Titcombe, Philip
a84c9fad-0580-42f9-8bb6-db0fe20435aa
Dalrymple, Kathryn V.
8ef94198-4e90-44a9-b77d-19d35d013cde
Garratt, Emma S.
66ddd4cb-19a2-4d08-889b-12f418e6878b
Barton, Sheila J.
4f674382-ca0b-44ad-9670-e71a0b134ef0
Murray, Robert
c3e973b5-525c-49b3-96ee-af60a666a0f4
Seed, Paul T.
d3eda3f4-0e4c-4c17-9efd-dc75b583e79a
Holbrook, Joanna D.
69989b79-2710-4f12-946e-c6214e1b6513
Kobor, Michael S.
e387ab6f-d060-4d39-95c6-acf0c3b9687b
Lin, David Ts
7349d763-63ed-4e08-8a49-657138fadb3d
Macisaac, Julia L.
4e74f97f-0016-4bfd-9154-25fa22e2a4b6
Burdge, Graham C.
09d60a07-8ca1-4351-9bf1-de6ffcfb2159
White, Sara L.
7c2d382b-89ff-4535-9f86-b542f0e7d20e
Poston, Lucilla
916aced2-462e-445f-9efa-83ed4b7b3a9f
Godfrey, Keith M.
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Lillycrop, Karen A.
eeaaa78d-0c4d-4033-a178-60ce7345a2cc

Antoun, Elie, Kitaba, Negusse T., Titcombe, Philip, Dalrymple, Kathryn V., Garratt, Emma S., Barton, Sheila J., Murray, Robert, Seed, Paul T., Holbrook, Joanna D., Kobor, Michael S., Lin, David Ts, Macisaac, Julia L., Burdge, Graham C., White, Sara L., Poston, Lucilla, Godfrey, Keith M. and Lillycrop, Karen A. (2020) Maternal dysglycaemia, changes in the infant's epigenome modified with a diet and physical activity intervention in pregnancy: Secondary analysis of a randomised control trial. PLoS Medicine, 17 (11), [e1003229]. (doi:10.1371/journal.pmed.1003229).

Record type: Article

Abstract

BACKGROUND: Higher maternal plasma glucose (PG) concentrations, even below gestational diabetes mellitus (GDM) thresholds, are associated with adverse offspring outcomes, with DNA methylation proposed as a mediating mechanism. Here, we examined the relationships between maternal dysglycaemia at 24 to 28 weeks' gestation and DNA methylation in neonates and whether a dietary and physical activity intervention in pregnant women with obesity modified the methylation signatures associated with maternal dysglycaemia.

METHODS AND FINDINGS: We investigated 557 women, recruited between 2009 and 2014 from the UK Pregnancies Better Eating and Activity Trial (UPBEAT), a randomised controlled trial (RCT), of a lifestyle intervention (low glycaemic index (GI) diet plus physical activity) in pregnant women with obesity (294 contol, 263 intervention). Between 27 and 28 weeks of pregnancy, participants had an oral glucose (75 g) tolerance test (OGTT), and GDM diagnosis was based on diagnostic criteria recommended by the International Association of Diabetes and Pregnancy Study Groups (IADPSG), with 159 women having a diagnosis of GDM. Cord blood DNA samples from the infants were interrogated for genome-wide DNA methylation levels using the Infinium Human MethylationEPIC BeadChip array. Robust regression was carried out, adjusting for maternal age, smoking, parity, ethnicity, neonate sex, and predicted cell-type composition. Maternal GDM, fasting glucose, 1-h, and 2-h glucose concentrations following an OGTT were associated with 242, 1, 592, and 17 differentially methylated cytosine-phosphate-guanine (dmCpG) sites (false discovery rate (FDR) ≤ 0.05), respectively, in the infant's cord blood DNA. The most significantly GDM-associated CpG was cg03566881 located within the leucine-rich repeat-containing G-protein coupled receptor 6 (LGR6) (FDR = 0.0002). Moreover, we show that the GDM and 1-h glucose-associated methylation signatures in the cord blood of the infant appeared to be attenuated by the dietary and physical activity intervention during pregnancy; in the intervention arm, there were no GDM and two 1-h glucose-associated dmCpGs, whereas in the standard care arm, there were 41 GDM and 160 1-h glucose-associated dmCpGs. A total of 87% of the GDM and 77% of the 1-h glucose-associated dmCpGs had smaller effect sizes in the intervention compared to the standard care arm; the adjusted r2 for the association of LGR6 cg03566881 with GDM was 0.317 (95% confidence interval (CI) 0.012, 0.022) in the standard care and 0.240 (95% CI 0.001, 0.015) in the intervention arm. Limitations included measurement of DNA methylation in cord blood, where the functional significance of such changes are unclear, and because of the strong collinearity between treatment modality and severity of hyperglycaemia, we cannot exclude that treatment-related differences are potential confounders.

CONCLUSIONS: Maternal dysglycaemia was associated with significant changes in the epigenome of the infants. Moreover, we found that the epigenetic impact of a dysglycaemic prenatal maternal environment appeared to be modified by a lifestyle intervention in pregnancy. Further research will be needed to investigate possible medical implications of the findings.

TRIAL REGISTRATION: ISRCTN89971375.

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More information

Accepted/In Press date: 6 October 2020
Published date: 5 November 2020

Identifiers

Local EPrints ID: 445508
URI: http://eprints.soton.ac.uk/id/eprint/445508
ISSN: 1549-1277
PURE UUID: 54fd8342-4567-4392-9435-cc91f88f87b2
ORCID for Negusse T. Kitaba: ORCID iD orcid.org/0000-0001-7518-9096
ORCID for Philip Titcombe: ORCID iD orcid.org/0000-0002-7797-8571
ORCID for Emma S. Garratt: ORCID iD orcid.org/0000-0001-5268-4203
ORCID for Sheila J. Barton: ORCID iD orcid.org/0000-0003-4963-4242
ORCID for Joanna D. Holbrook: ORCID iD orcid.org/0000-0003-1791-6894
ORCID for Graham C. Burdge: ORCID iD orcid.org/0000-0002-7665-2967
ORCID for Keith M. Godfrey: ORCID iD orcid.org/0000-0002-4643-0618
ORCID for Karen A. Lillycrop: ORCID iD orcid.org/0000-0001-7350-5489

Catalogue record

Date deposited: 14 Dec 2020 17:30
Last modified: 26 Nov 2021 03:10

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Contributors

Author: Elie Antoun
Author: Philip Titcombe ORCID iD
Author: Kathryn V. Dalrymple
Author: Emma S. Garratt ORCID iD
Author: Robert Murray
Author: Paul T. Seed
Author: Joanna D. Holbrook ORCID iD
Author: Michael S. Kobor
Author: David Ts Lin
Author: Julia L. Macisaac
Author: Sara L. White
Author: Lucilla Poston

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