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Associations between DNA methylation and BMI vary by metabolic health status: a potential link to disparate cardiovascular outcomes.

TitleAssociations between DNA methylation and BMI vary by metabolic health status: a potential link to disparate cardiovascular outcomes.
Publication TypeJournal Article
Year of Publication2021
AuthorsDo WL, Nguyen S, Yao J, Guo X, Whitsel EA, Demerath E, Rotter JI, Rich SS, Lange L, Ding J, Van Den Berg D, Liu Y, Justice AE, Guan W, Horvath S, Assimes TL, Bhatti P, Jordahl K, Shadyab A, Valencia CI, Stein AD, Smith A, Staimez LR, Conneely K, Narayan KMVenkat
JournalClin Epigenetics
Volume13
Issue1
Pagination230
Date Published2021 12 22
ISSN1868-7083
KeywordsAged, Body Mass Index, Cardiovascular Diseases, Cohort Studies, DNA Methylation, Female, Humans, Male, Metabolic Diseases, Middle Aged
Abstract

BACKGROUND: Body mass index (BMI), a well-known risk factor for poor cardiovascular outcomes, is associated with differential DNA methylation (DNAm). Similarly, metabolic health has also been associated with changes in DNAm. It is unclear how overall metabolic health outside of BMI may modify the relationship between BMI and methylation profiles, and what consequences this may have on downstream cardiovascular disease. The purpose of this study was to identify cytosine-phosphate-guanine (CpG) sites at which the association between BMI and DNAm could be modified by overall metabolic health.

RESULTS: The discovery study population was derived from three Women's Health Initiative (WHI) ancillary studies (n = 3977) and two Atherosclerosis Risk in Communities (ARIC) ancillary studies (n = 3520). Findings were validated in the Multi-Ethnic Study of Atherosclerosis (MESA) cohort (n = 1200). Generalized linear models regressed methylation β values on the interaction between BMI and metabolic health Z score (BMI × MHZ) adjusted for BMI, MHZ, cell composition, chip number and location, study characteristics, top three ancestry principal components, smoking, age, ethnicity (WHI), and sex (ARIC). Among the 429,566 sites examined, differential associations between BMI × MHZ and DNAm were identified at 22 CpG sites (FDR q < 0.05), with one site replicated in MESA (cg18989722, in the TRAPPC9 gene). Three of the 22 sites were associated with incident coronary heart disease (CHD) in WHI. For each 0.01 unit increase in DNAm β value, the risk of incident CHD increased by 9% in one site and decreased by 6-10% in two sites over 25 years.

CONCLUSIONS: Differential associations between DNAm and BMI by MHZ were identified at 22 sites, one of which was validated (cg18989722) and three of which were predictive of incident CHD. These sites are located in several genes related to NF-kappa-B signaling, suggesting a potential role for inflammation between DNA methylation and BMI-associated metabolic health.

DOI10.1186/s13148-021-01194-3
Alternate JournalClin Epigenetics
PubMed ID34937574
PubMed Central IDPMC8697469
Grant ListHHSN268201600002C / HL / NHLBI NIH HHS / United States
HHSN268201800001I / HL / NHLBI NIH HHS / United States
HHSN268201800002I / HL / NHLBI NIH HHS / United States
HHSN268201600004C / HL / NHLBI NIH HHS / United States
HHSN268201700004I / HL / NHLBI NIH HHS / United States
HHSN268201800001C / HL / NHLBI NIH HHS / United States
HHSN268201700003I / HL / NHLBI NIH HHS / United States
HHSN268201700001I / HL / NHLBI NIH HHS / United States
HHSN268201600018C / HL / NHLBI NIH HHS / United States
R01 CA253302 / CA / NCI NIH HHS / United States
HHSN268201700002I / HL / NHLBI NIH HHS / United States
HHSN268201600001C / HL / NHLBI NIH HHS / United States
T32 CA078447 / CA / NCI NIH HHS / United States
T32 AG058529 / AG / NIA NIH HHS / United States
HHSN268201700005I / HL / NHLBI NIH HHS / United States
HHSN268201600034I / HL / NHLBI NIH HHS / United States
HHSN268201600003C / HL / NHLBI NIH HHS / United States