A longitudinal study of DNA methylation as a potential mediator of age-related diabetes risk

Crystal D. Grant*, Nadereh Jafari, Lifang Hou, Yun Li, James D. Stewart, Guosheng Zhang, Archana Lamichhane, Jo Ann E. Manson, Andrea A. Baccarelli, Eric A. Whitsel, Karen N. Conneely

*Corresponding author for this work

Research output: Contribution to journalArticle

13 Citations (Scopus)

Abstract

DNA methylation (DNAm) has been found to show robust and widespread age-related changes across the genome. DNAm profiles from whole blood can be used to predict human aging rates with great accuracy. We sought to test whether DNAm-based predictions of age are related to phenotypes associated with type 2 diabetes (T2D), with the goal of identifying risk factors potentially mediated by DNAm. Our participants were 43 women enrolled in the Women’s Health Initiative. We obtained methylation data via the Illumina 450K Methylation array on whole blood samples from participants at three timepoints, covering on average 16 years per participant. We employed the method and software of Horvath, which uses DNAm at 353 CpGs to form a DNAm-based estimate of chronological age. We then calculated the epigenetic age acceleration, or Δage, at each timepoint. We fit linear mixed models to characterize how Δage contributed to a longitudinal model of aging and diabetes-related phenotypes and risk factors. For most participants, Δage remained constant, indicating that age acceleration is generally stable over time. We found that Δage associated with body mass index (p = 0.0012), waist circumference (p = 0.033), and fasting glucose (p = 0.0073), with the relationship with BMI maintaining significance after correction for multiple testing. Replication in a larger cohort of 157 WHI participants spanning 3 years was unsuccessful, possibly due to the shorter time frame covered. Our results suggest that DNAm has the potential to act as a mediator between aging and diabetes-related phenotypes, or alternatively, may serve as a biomarker of these phenotypes.

Original languageEnglish (US)
Pages (from-to)475-489
Number of pages15
JournalGeroScience
Volume39
Issue number5-6
DOIs
StatePublished - Dec 1 2017

Fingerprint

DNA Methylation
Longitudinal Studies
Phenotype
Methylation
Waist Circumference
Women's Health
Epigenomics
Type 2 Diabetes Mellitus
Linear Models
Fasting
Body Mass Index
Software
Biomarkers
Genome
Glucose

Keywords

  • Aging
  • BMI
  • DNA methylation
  • biological age
  • biomarker
  • diabetes

ASJC Scopus subject areas

  • Aging
  • Geriatrics and Gerontology

Cite this

Grant, C. D., Jafari, N., Hou, L., Li, Y., Stewart, J. D., Zhang, G., ... Conneely, K. N. (2017). A longitudinal study of DNA methylation as a potential mediator of age-related diabetes risk. GeroScience, 39(5-6), 475-489. https://doi.org/10.1007/s11357-017-0001-z
Grant, Crystal D. ; Jafari, Nadereh ; Hou, Lifang ; Li, Yun ; Stewart, James D. ; Zhang, Guosheng ; Lamichhane, Archana ; Manson, Jo Ann E. ; Baccarelli, Andrea A. ; Whitsel, Eric A. ; Conneely, Karen N. / A longitudinal study of DNA methylation as a potential mediator of age-related diabetes risk. In: GeroScience. 2017 ; Vol. 39, No. 5-6. pp. 475-489.
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Grant, CD, Jafari, N, Hou, L, Li, Y, Stewart, JD, Zhang, G, Lamichhane, A, Manson, JAE, Baccarelli, AA, Whitsel, EA & Conneely, KN 2017, 'A longitudinal study of DNA methylation as a potential mediator of age-related diabetes risk', GeroScience, vol. 39, no. 5-6, pp. 475-489. https://doi.org/10.1007/s11357-017-0001-z

A longitudinal study of DNA methylation as a potential mediator of age-related diabetes risk. / Grant, Crystal D.; Jafari, Nadereh; Hou, Lifang; Li, Yun; Stewart, James D.; Zhang, Guosheng; Lamichhane, Archana; Manson, Jo Ann E.; Baccarelli, Andrea A.; Whitsel, Eric A.; Conneely, Karen N.

In: GeroScience, Vol. 39, No. 5-6, 01.12.2017, p. 475-489.

Research output: Contribution to journalArticle

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T1 - A longitudinal study of DNA methylation as a potential mediator of age-related diabetes risk

AU - Grant, Crystal D.

AU - Jafari, Nadereh

AU - Hou, Lifang

AU - Li, Yun

AU - Stewart, James D.

AU - Zhang, Guosheng

AU - Lamichhane, Archana

AU - Manson, Jo Ann E.

AU - Baccarelli, Andrea A.

AU - Whitsel, Eric A.

AU - Conneely, Karen N.

PY - 2017/12/1

Y1 - 2017/12/1

N2 - DNA methylation (DNAm) has been found to show robust and widespread age-related changes across the genome. DNAm profiles from whole blood can be used to predict human aging rates with great accuracy. We sought to test whether DNAm-based predictions of age are related to phenotypes associated with type 2 diabetes (T2D), with the goal of identifying risk factors potentially mediated by DNAm. Our participants were 43 women enrolled in the Women’s Health Initiative. We obtained methylation data via the Illumina 450K Methylation array on whole blood samples from participants at three timepoints, covering on average 16 years per participant. We employed the method and software of Horvath, which uses DNAm at 353 CpGs to form a DNAm-based estimate of chronological age. We then calculated the epigenetic age acceleration, or Δage, at each timepoint. We fit linear mixed models to characterize how Δage contributed to a longitudinal model of aging and diabetes-related phenotypes and risk factors. For most participants, Δage remained constant, indicating that age acceleration is generally stable over time. We found that Δage associated with body mass index (p = 0.0012), waist circumference (p = 0.033), and fasting glucose (p = 0.0073), with the relationship with BMI maintaining significance after correction for multiple testing. Replication in a larger cohort of 157 WHI participants spanning 3 years was unsuccessful, possibly due to the shorter time frame covered. Our results suggest that DNAm has the potential to act as a mediator between aging and diabetes-related phenotypes, or alternatively, may serve as a biomarker of these phenotypes.

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