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Differential SLC6A4 methylation: a predictive epigenetic marker of adiposity from birth to adulthood

Differential SLC6A4 methylation: a predictive epigenetic marker of adiposity from birth to adulthood
Differential SLC6A4 methylation: a predictive epigenetic marker of adiposity from birth to adulthood

Background: The early life environment may influence susceptibility to obesity and metabolic disease in later life through epigenetic processes. SLC6A4 is an important mediator of serotonin bioavailability, and has a key role in energy balance. We tested the hypothesis that methylation of the SLC6A4 gene predicts adiposity across the life course. Methods: DNA methylation at 5 CpGs within the SLC6A4 gene identified from a previous methyl binding domain array was measured by pyrosequencing. We measured DNA methylation in umbilical cord (UC) from children in the Southampton Women’s Survey cohort (n = 680), in peripheral blood from adolescents in the Western Australian Pregnancy Cohort Study (n = 812), and in adipose tissue from lean and obese adults from the UK BIOCLAIMS cohort (n = 81). Real-time PCR was performed to assess whether there were corresponding alterations in gene expression in the adipose tissue. Results: Lower UC methylation of CpG5 was associated with higher total fat mass at 4 years (p = 0.031), total fat mass at 6–7 years (p = 0.0001) and % fat mass at 6–7 years (p = 0.004). Lower UC methylation of CpG5 was also associated with higher triceps skinfold thickness at birth (p = 0.013), 6 months (p = 0.038), 12 months (p = 0.062), 2 years (p = 0.0003), 3 years (p = 0.00004) and 6–7 years (p = 0.013). Higher maternal pregnancy weight gain (p = 0.046) and lower parity (p = 0.029) were both associated with lower SLC6A4 CpG5 methylation. In adolescents, lower methylation of CpG5 in peripheral blood was associated with greater concurrent measures of adiposity including BMI (p ≤ 0.001), waist circumference (p = 0.011), subcutaneous fat (p ≤ 0.001) and subscapular, abdominal and suprailiac skinfold thicknesses (p = 0.002, p = 0.008, p = 0.004, respectively). In adipose tissue, methylation of both SLC6A4 CpG5 (p = 0.019) and expression of SLC6A4 (p = 0.008) was lower in obese compared with lean adults. Conclusions: These data suggest that altered methylation of CpG loci within SLC6A4 may provide a robust marker of adiposity across the life course.

0307-0565
Lillycrop, Karen A.
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Garratt, Emma S.
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Titcombe, Philip
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Melton, Phillip E.
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Murray, Robert J.S.
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Barton, Sheila J.
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Clarke-Harris, Rebecca
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Costello, Paula M.
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Holbrook, Joanna D.
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Hopkins, James C.
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Childs, Caroline E.
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Paras-Chavez, Carolina
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Calder, Philip C.
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Mori, Trevor A.
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Beilin, Lawrie
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Burdge, Graham C.
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Gluckman, Peter D.
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Inskip, Hazel M.
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Harvey, Nicholas C.
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Hanson, Mark A.
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Huang, Rae Chi
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Cooper, Cyrus
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Godfrey, Keith M.
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EpiGen Consortium
Lillycrop, Karen A.
eeaaa78d-0c4d-4033-a178-60ce7345a2cc
Garratt, Emma S.
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Titcombe, Philip
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Melton, Phillip E.
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Murray, Robert J.S.
c3e973b5-525c-49b3-96ee-af60a666a0f4
Barton, Sheila J.
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Clarke-Harris, Rebecca
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Costello, Paula M.
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Holbrook, Joanna D.
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Hopkins, James C.
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Childs, Caroline E.
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Paras-Chavez, Carolina
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Calder, Philip C.
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Mori, Trevor A.
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Beilin, Lawrie
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Burdge, Graham C.
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Gluckman, Peter D.
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Inskip, Hazel M.
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Harvey, Nicholas C.
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Hanson, Mark A.
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Huang, Rae Chi
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Cooper, Cyrus
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Godfrey, Keith M.
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Lillycrop, Karen A., Garratt, Emma S., Titcombe, Philip, Melton, Phillip E., Murray, Robert J.S., Barton, Sheila J., Clarke-Harris, Rebecca, Costello, Paula M., Holbrook, Joanna D., Hopkins, James C., Childs, Caroline E., Paras-Chavez, Carolina, Calder, Philip C., Mori, Trevor A., Beilin, Lawrie, Burdge, Graham C., Gluckman, Peter D., Inskip, Hazel M., Harvey, Nicholas C., Hanson, Mark A., Huang, Rae Chi, Cooper, Cyrus and Godfrey, Keith M. , EpiGen Consortium (2019) Differential SLC6A4 methylation: a predictive epigenetic marker of adiposity from birth to adulthood. International Journal of Obesity. (doi:10.1038/s41366-018-0254-3).

Record type: Article

Abstract

Background: The early life environment may influence susceptibility to obesity and metabolic disease in later life through epigenetic processes. SLC6A4 is an important mediator of serotonin bioavailability, and has a key role in energy balance. We tested the hypothesis that methylation of the SLC6A4 gene predicts adiposity across the life course. Methods: DNA methylation at 5 CpGs within the SLC6A4 gene identified from a previous methyl binding domain array was measured by pyrosequencing. We measured DNA methylation in umbilical cord (UC) from children in the Southampton Women’s Survey cohort (n = 680), in peripheral blood from adolescents in the Western Australian Pregnancy Cohort Study (n = 812), and in adipose tissue from lean and obese adults from the UK BIOCLAIMS cohort (n = 81). Real-time PCR was performed to assess whether there were corresponding alterations in gene expression in the adipose tissue. Results: Lower UC methylation of CpG5 was associated with higher total fat mass at 4 years (p = 0.031), total fat mass at 6–7 years (p = 0.0001) and % fat mass at 6–7 years (p = 0.004). Lower UC methylation of CpG5 was also associated with higher triceps skinfold thickness at birth (p = 0.013), 6 months (p = 0.038), 12 months (p = 0.062), 2 years (p = 0.0003), 3 years (p = 0.00004) and 6–7 years (p = 0.013). Higher maternal pregnancy weight gain (p = 0.046) and lower parity (p = 0.029) were both associated with lower SLC6A4 CpG5 methylation. In adolescents, lower methylation of CpG5 in peripheral blood was associated with greater concurrent measures of adiposity including BMI (p ≤ 0.001), waist circumference (p = 0.011), subcutaneous fat (p ≤ 0.001) and subscapular, abdominal and suprailiac skinfold thicknesses (p = 0.002, p = 0.008, p = 0.004, respectively). In adipose tissue, methylation of both SLC6A4 CpG5 (p = 0.019) and expression of SLC6A4 (p = 0.008) was lower in obese compared with lean adults. Conclusions: These data suggest that altered methylation of CpG loci within SLC6A4 may provide a robust marker of adiposity across the life course.

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Accepted/In Press date: 27 August 2018
e-pub ahead of print date: 8 January 2019

Identifiers

Local EPrints ID: 427537
URI: https://eprints.soton.ac.uk/id/eprint/427537
ISSN: 0307-0565
PURE UUID: 35d11b3f-a069-4246-897c-4d5b1489f968
ORCID for Karen A. Lillycrop: ORCID iD orcid.org/0000-0001-7350-5489
ORCID for Emma S. Garratt: ORCID iD orcid.org/0000-0001-5268-4203
ORCID for Philip Titcombe: ORCID iD orcid.org/0000-0002-7797-8571
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 Caroline E. Childs: ORCID iD orcid.org/0000-0001-6832-224X
ORCID for Graham C. Burdge: ORCID iD orcid.org/0000-0002-7665-2967
ORCID for Hazel M. Inskip: ORCID iD orcid.org/0000-0001-8897-1749
ORCID for Nicholas C. Harvey: ORCID iD orcid.org/0000-0002-8194-2512
ORCID for Mark A. Hanson: ORCID iD orcid.org/0000-0002-6907-613X
ORCID for Cyrus Cooper: ORCID iD orcid.org/0000-0003-3510-0709
ORCID for Keith M. Godfrey: ORCID iD orcid.org/0000-0002-4643-0618

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Date deposited: 22 Jan 2019 17:30
Last modified: 11 Apr 2019 00:38

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Contributors

Author: Emma S. Garratt ORCID iD
Author: Philip Titcombe ORCID iD
Author: Phillip E. Melton
Author: Robert J.S. Murray
Author: Rebecca Clarke-Harris
Author: Paula M. Costello
Author: James C. Hopkins
Author: Carolina Paras-Chavez
Author: Trevor A. Mori
Author: Lawrie Beilin
Author: Peter D. Gluckman
Author: Hazel M. Inskip ORCID iD
Author: Mark A. Hanson ORCID iD
Author: Rae Chi Huang
Author: Cyrus Cooper ORCID iD

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