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

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.

Epigenomic and Other Evidence for Cannabis-Induced Aging Contextualized in a Synthetic Epidemiologic Overview of Cannabinoid-Related Teratogenesis and Cannabinoid-Related Carcinogenesis

“…Evidence from many studies indicates extensive perturbation of the human epigenome by exposure to many cannabinoids. Since the epigenome has emerged as the key and central mediator of the panorganismal aging process [ 13 , 14 , 15 , 16 , 202 , 382 ], it becomes of primary importance to investigate its likely implication in aging processes directly by the application of late-generation epigenomic clocks [ 383 , 384 , 385 , 386 , 387 , 388 , 389 ]. The likely involvement of spermatogonia, oocyte and fertilized zygote in this accelerated aging process increases the importance of this enquiry for the health of subsequent generations, an enquiry which is heightened and intensified by the transgenerational transmission of cannabinoid-related epigenotoxicity in human sperm [ 26 , 27 ], to subsequent rodent generations [ 28 , 29 , 30 , 31 , 32 , 390 ], for pediatric brain function and development including autistic-like disorders [ 117 , 174 , 288 , 290 , 292 , 295 , 296 , 297 , 298 , 299 , 391 ] and through the heritable passage of many birth defects [ 103 , 108 , 109 , 110 , 111 , 115 , 118 , 120 ] including several pediatric cancers [ 63 , 64 , 65 , 66 , 105 ,…”

Identification of DNA methylation-regulated genes as potential biomarkers for coronary heart disease via machine learning in the Framingham Heart Study

“…It has been extensively documented that DNA methylation is involved in the etiopathogenesis of CHD as a dominant epigenetic factor [ 11 – 13 ]. In addition to the previously reported enrichment of DMGs in TSS regions, CpG islands and adjacent intragenic regions [ 14 , 15 ], we noticed differences in the distribution of DMGs between TSS1500 and TSS200.…”

Epigenome-wide meta-analysis of BMI in nine cohorts: examining the utility of epigenetic BMI in predicting metabolic health

“…Low-grade inflammation in obesity is a hallmark of the disease, which leads to significant metabolic dysregulation [38]. Several studies have found BMI-associated CpG sites are enriched for immune pathways [13, 39]. Mechanistic studies have identified DNA methylation as playing a key role in promoting macrophage polarization in response to obesity, with more M1 macrophages associated with obesity [40].…”