Social and physical environments early in development predict DNA methylation of inflammatory genes in young adulthood

Edited by Bruce S. McEwen, The Rockefeller University, New York, NY, and approved May 25, 2017 (received for review December 16, 2016)
July 3, 2017
114 (29) 7611-7616

Significance

Environments in infancy and childhood influence levels of inflammation in adulthood—an important risk factor for multiple diseases of aging—but the underlying biological mechanisms remain uncertain. Using data from a unique cohort study in the Philippines with a lifetime of information on each participant, we provide evidence that nutritional, microbial, and psychosocial exposures in infancy and childhood predict adult levels of DNA methylation—biochemical marks on the genome that affect gene expression—in genes that regulate inflammation. We also show that DNA methylation in these genes relates to levels of inflammatory biomarkers implicated in cardiovascular and other diseases. These results suggest that epigenetic mechanisms may partially explain how early environments have enduring effects on inflammation and inflammation-related diseases.

Abstract

Chronic inflammation contributes to a wide range of human diseases, and environments in infancy and childhood are important determinants of inflammatory phenotypes. The underlying biological mechanisms connecting early environments with the regulation of inflammation in adulthood are not known, but epigenetic processes are plausible candidates. We tested the hypothesis that patterns of DNA methylation (DNAm) in inflammatory genes in young adulthood would be predicted by early life nutritional, microbial, and psychosocial exposures previously associated with levels of inflammation. Data come from a population-based longitudinal birth cohort study in metropolitan Cebu, the Philippines, and DNAm was characterized in whole blood samples from 494 participants (age 20–22 y). Analyses focused on probes in 114 target genes involved in the regulation of inflammation, and we identified 10 sites across nine genes where the level of DNAm was significantly predicted by the following variables: household socioeconomic status in childhood, extended absence of a parent in childhood, exposure to animal feces in infancy, birth in the dry season, or duration of exclusive breastfeeding. To evaluate the biological significance of these sites, we tested for associations with a panel of inflammatory biomarkers measured in plasma obtained at the same age as DNAm assessment. Three sites predicted elevated inflammation, and one site predicted lower inflammation, consistent with the interpretation that levels of DNAm at these sites are functionally relevant. This pattern of results points toward DNAm as a potentially important biological mechanism through which developmental environments shape inflammatory phenotypes across the life course.

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Acknowledgments

Research reported in this manuscript was supported by National Institutes of Health Grants RO1 HL085144 and RO1 TW05596 and Biological Anthropology Program at the National Science Foundation Grants BCS-0746320 and BCS-1440564. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health or the National Science Foundation.

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Dataset_S02 (CSV)

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Information & Authors

Information

Published in

Go to Proceedings of the National Academy of Sciences
Proceedings of the National Academy of Sciences
Vol. 114 | No. 29
July 18, 2017
PubMed: 28673994

Classifications

Submission history

Published online: July 3, 2017
Published in issue: July 18, 2017

Keywords

  1. epigenetics
  2. inflammation
  3. ecological immunology
  4. developmental origins of health
  5. developmental origins of disease

Acknowledgments

Research reported in this manuscript was supported by National Institutes of Health Grants RO1 HL085144 and RO1 TW05596 and Biological Anthropology Program at the National Science Foundation Grants BCS-0746320 and BCS-1440564. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health or the National Science Foundation.

Notes

This article is a PNAS Direct Submission.

Authors

Affiliations

Thomas W. McDade1 [email protected]
Department of Anthropology, Northwestern University, Evanston, IL 60208;
Institute for Policy Research, Northwestern University, Evanston, IL 60208;
Child and Brain Development Program, Canadian Institute for Advanced Research, Toronto, Ontario M5G 1Z8, Canada;
Calen Ryan
Department of Anthropology, Northwestern University, Evanston, IL 60208;
BC Children’s Hospital Research Institute, University of British Columbia, Vancouver, BC V5Z 4H4, Canada;
Julia L. MacIsaac
BC Children’s Hospital Research Institute, University of British Columbia, Vancouver, BC V5Z 4H4, Canada;
Alexander M. Morin
BC Children’s Hospital Research Institute, University of British Columbia, Vancouver, BC V5Z 4H4, Canada;
Department of Sociology, Northwestern University, Evanston, IL 60208;
Judith B. Borja
USC–Office of Population Studies Foundation, Inc., University of San Carlos, Cebu City, Philippines;
Department of Nutrition and Dietetics, University of San Carlos, Cebu City, Philippines;
Gregory E. Miller
Institute for Policy Research, Northwestern University, Evanston, IL 60208;
Department of Psychology, Northwestern University, Evanston, IL 60208
Michael S. Kobor
Child and Brain Development Program, Canadian Institute for Advanced Research, Toronto, Ontario M5G 1Z8, Canada;
BC Children’s Hospital Research Institute, University of British Columbia, Vancouver, BC V5Z 4H4, Canada;
Christopher W. Kuzawa
Department of Anthropology, Northwestern University, Evanston, IL 60208;
Institute for Policy Research, Northwestern University, Evanston, IL 60208;

Notes

1
To whom correspondence should be addressed. Email: [email protected].
Author contributions: T.W.M., J.M.M., J.B.B., G.E.M., M.S.K., and C.W.K. designed research; T.W.M., M.J.J., J.L.M., A.M.M., J.M.M., J.B.B., G.E.M., M.S.K., and C.W.K. performed research; T.W.M., C.R., M.J.J., and G.E.M. analyzed data; and T.W.M. wrote the paper.

Competing Interests

The authors declare no conflict of interest.

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    Social and physical environments early in development predict DNA methylation of inflammatory genes in young adulthood
    Proceedings of the National Academy of Sciences
    • Vol. 114
    • No. 29
    • pp. 7469-E6026

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