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 Valencia; Aryeh D Stein; Alicia Smith; Lisa R Staimez; Karen Conneely; K M Venkat Narayan

doi:10.1186/s13148-021-01194-3

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

Clin Epigenetics. 2021 Dec 22;13(1):230. doi: 10.1186/s13148-021-01194-3.

Authors

Whitney L Do¹, Steve Nguyen², Jie Yao³, Xiuqing Guo³, Eric A Whitsel⁴, Ellen Demerath⁵, Jerome I Rotter³, Stephen S Rich⁶, Leslie Lange⁷, Jingzhong Ding⁸, David Van Den Berg⁹, Yongmei Liu¹⁰, Anne E Justice¹¹, Weihua Guan¹², Steve Horvath¹³, Themistocles L Assimes¹⁴, Parveen Bhatti¹⁵, Kristina Jordahl¹⁶, Aladdin Shadyab², Celina I Valencia¹⁷, Aryeh D Stein¹⁸, Alicia Smith¹⁹, Lisa R Staimez¹⁸, Karen Conneely²⁰, K M Venkat Narayan¹⁸

Affiliations

¹ Nutrition and Health Sciences Program, Laney Graduate School, Emory University, 1518 Clifton Rd, Atlanta, GA, 30322, USA. lwhitney16@gmail.com.
² Herbert Wertheim School of Public Health and Human Longevity Science, University of California, San Diego, CA, USA.
³ Department of Pediatrics, The Institute for Translational Genomics and Population Sciences, The Lundquist Institute for Biomedical Innovation at Harbor-UCLA Medical Center, Torrance, CA, USA.
⁴ Departments of Epidemiology and Medicine, University of North Carolina, Chapel Hill, NC, USA.
⁵ Division of Epidemiology and Community Health, School of Public Health, University of Minnesota, Minneapolis, MN, USA.
⁶ Center for Public Health Genomics, University of Virginia, Charlottesville, VA, USA.
⁷ Division of Biomedical Informatics & Personalized Medicine, School of Medicine, Colorado University Anschutz Medical Campus, Aurora, CO, USA.
⁸ Gerontology and Geriatric Medicine, School of Medicine, Wake Forest, Winston-Salem, NC, USA.
⁹ Department of Population and Public Health Sciences, University of Southern California, Los Angeles, CA, USA.
¹⁰ Duke Molecular Physiology Institute, Duke University, Durham, NC, USA.
¹¹ Center for Biomedical and Translational Informatics, Geisinger, Wilkes-Barre, PA, USA.
¹² Division of Biostatistics, School of Public Health, University of Minnesota, Minneapolis, MN, USA.
¹³ Department of Human Genetics, University of California, Los Angeles, Los Angeles, CA, USA.
¹⁴ Department of Medicine, Stanford University, Stanford, CA, USA.
¹⁵ Cancer Control Research, BC Cancer, Vancouver, BC, Canada.
¹⁶ Department of Epidemiology, University of Washington, Seattle, WA, USA.
¹⁷ College of Medicine, University of Arizona Cancer Center, Tucson, AZ, USA.
¹⁸ Hubert Department of Global Health, Rollins School of Public Health, Emory University, Atlanta, GA, USA.
¹⁹ Department of Gynecology and Obstetrics, School of Medicine, Emory University, Atlanta, GA, USA.
²⁰ Department of Human Genetics, Emory University, Atlanta, GA, USA.

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.

Keywords: DNA methylation; Epigenetics; Metabolically healthy; Obesity.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Aged
Body Mass Index*
Cardiovascular Diseases / etiology
Cardiovascular Diseases / genetics*
Cohort Studies
DNA Methylation / genetics
DNA Methylation / physiology
Female
Humans
Male
Metabolic Diseases / complications*
Metabolic Diseases / genetics
Middle Aged

Abstract

Publication types

MeSH terms

Grants and funding