Epigenetics meets metabolomics: an epigenome-wide association study with blood serum metabolic traits

Abstract

Previously, we reported strong influences of genetic variants on metabolic phenotypes, some of them with clinical relevance. Here, we hypothesize that DNA methylation may have an important and potentially independent effect on human metabolism. To test this hypothesis, we conducted what is to the best of our knowledge the first epigenome-wide association study (EWAS) between DNA methylation and metabolic traits (metabotypes) in human blood. We assess 649 blood metabolic traits from 1814 participants of the Kooperative Gesundheitsforschung in der Region Augsburg (KORA) population study for association with methylation of 457 004 CpG sites, determined on the Infinium HumanMethylation450 BeadChip platform. Using the EWAS approach, we identified two types of methylome–metabotype associations. One type is driven by an underlying genetic effect; the other type is independent of genetic variation and potentially driven by common environmental and life-style-dependent factors. We report eight CpG loci at genome-wide significance that have a genetic variant as confounder (P = 3.9 × 10−20 to 2.0 × 10−108, r2 = 0.036 to 0.221). Seven loci display CpG site-specific associations to metabotypes, but do not exhibit any underlying genetic signals (P = 9.2 × 10−14 to 2.7 × 10−27, r2 = 0.008 to 0.107). We further identify several groups of CpG loci that associate with a same metabotype, such as 4-vinylphenol sulfate and 4-androsten-3-beta,17-beta-diol disulfate. In these cases, the association between CpG-methylation and metabotype is likely the result of a common external environmental factor, including smoking. Our study shows that analysis of EWAS with large numbers of metabolic traits in large population cohorts are, in principle, feasible. Taken together, our data suggest that DNA methylation plays an important role in regulating human metabolism.

Epigenomic profiling reveals an association between persistence of DNA methylation and metabolic memory in the DCCT/EDIC type 1 diabetes cohort

“…This finding was further validated in WB by pyrosequencing and ampliconseq. Interestingly, association of TXNIP hypo-me at the same CpG3 with type 2 diabetes and related traits (including fasting glucose, HbA1C, and insulin resistance) (57-60), serum metabolites related to diabetes (61), and high blood triglycerides (62) in WB DNA from various cohorts was recently reported. Because Txnip was associated with lipids in a mouse model (63), we reanalyzed methylation differences in cases vs. controls at CpG3 after adding triglycerides at the EDIC Study baseline as a covariate.…”

Metabolic profiling in diabetes

“…A recent epigenome-wide association study (EWAS) of DNA methylation with metabolomics has shown that DNA methylation also plays an important role in human metabolism (Petersen et al 2014). In this study, we briefly highlight one diabetes-relevant example from that study: the thioredoxin-interacting protein (TXNIP) plays a functional role in glucose regulation.…”

Integration of ‘omics’ data in aging research: from biomarkers to systems biology

“…Following the central dogma of molecular biology, genomics, transcriptomics and proteomics are correlated ‘by definition’. Furthermore, metabolite concentrations are influenced by genetic variants (Shin et al ., 2014) and epigenetic factors (Petersen et al ., 2014) mediated through changes in gene expression or enzyme activity. Methylation levels do not only influence the gene expression (Jaenisch & Bird, 2003), but are also correlated with gene variants (Bell et al ., 2012) and environmental factors (Breitling et al ., 2011).…”