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

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

doi:10.1186/s13148-021-01194-3

Abstract

BackgroundBody 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.ResultsThe 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.ConclusionsDifferential 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.

Highlights

Body mass index (BMI), a well-known risk factor for poor cardiovascular outcomes, is associated with differential DNA methylation (DNAm)
Examining the molecular underpinnings of this phenotype may guide our understanding of this epidemiological phenomenon by identifying the biological mechanisms which may be leading to a reduction in risk of health outcomes associated with obesity
When metabolic health status was examined continuously (MHZ), 22 CpG sites were associated with BMIxMHZ

Summary

Introduction

Body mass index (BMI), a well-known risk factor for poor cardiovascular outcomes, is associated with differential DNA methylation (DNAm). While obesity is most typically defined as body mass index (BMI) > 30 kg/m2, limitations in the use of BMI have been noted, including variation in associations with health outcomes by race/ancestry, physical activity, and age [2, 3], as well as some reports finding no association between higher-risk categories (overweight and middle obesity) with mortality [4, 5] These conflicting reports have motivated several studies to examine whether differential phenotypes of obesity exist and whether examining BMI in isolation of additional metabolic health parameters is a sufficient metric of overall health. Identifying biomarkers of MHO, if they can identify individuals more likely to remain in MHO, would be advantageous for more targeted interventions

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