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

Whitney L. Do, Steve Nguyen, Jie Yao, Xiuqing Guo, Eric A. Whitsel, Ellen Demerath, Jerome I. Rotter, Stephen S. Rich, Leslie Lange, Jingzhong Ding, David Van Den Berg, Yongmei Liu, Anne E. Justice, Weihua Guan, Steve Horvath, Themistocles L. Assimes, Parveen Bhatti, Kristina Jordahl, Aladdin Shadyab, Celina I. ValenciaAryeh D. Stein, Alicia Smith, Lisa R. Staimez, Karen Conneely, K. M.Venkat Narayan

Research output: Contribution to journalArticlepeer-review

6 Scopus citations


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.

Original languageEnglish (US)
Article number230
JournalClinical epigenetics
Issue number1
StatePublished - Dec 2021

Bibliographical note

Funding Information:
The authors would like to acknowledge and thank all participants from the WHI, ARIC, and MESA.

Funding Information:
The WHI program is funded by the National Heart, Lung, and Blood Institute, National Institutes of Health, US Department of Health and Human Services through contracts HHSN268201600018C, HHSN268201600001C, HHSN268201600002C, HHSN268201600003C, and HHSN268201600004C. The Atherosclerosis Risk in Communities study has been funded in whole or in part with Federal funds from the National Heart, Lung, and Blood Institute (NHLBI), National Institutes of Health, Department of Health and Human Services (contract numbers HHSN268201700001I, HHSN268201700002I, HHSN268201700003I, HHSN268201700004I, and HHSN268201700005I). The authors thank the staff and participants of the ARIC study for their important contributions. Funding was also supported by 5RC2HL102419 and R01NS087541. MESA TOPMed Methylation data for the Trans-Omics in Precision Medicine (TOPMed) program was supported by the NHLBI. MESA TOPMed Methylation data for “Genome-wide methylation for NHLBI TOPMed: Multi-Ethnic Study of Atherosclerosis (MESA)” (phs001416.v1.p1) were performed at Keck Molecular Genomics Core Facility (HHSN268201600034I). Centralized read mapping and genotype calling, along with variant quality metrics and filtering were provided by the TOPMed Informatics Research Center (3R01HL-117626-02S1, contract HHSN268201800002I). Phenotype harmonization, data management, sample-identity QC, and general study coordination were provided by the TOPMed Data Coordinating Center (R01HL-120393; U01HL-120393; contract HHSN268201800001I). We gratefully acknowledge the studies and participants who provided biological samples and data for TOPMed. WLD was supported in part by the Nalini and Ravi Saligram Scholarship.

Publisher Copyright:
© 2021, The Author(s).


  • DNA methylation
  • Epigenetics
  • Metabolically healthy
  • Obesity


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