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Cardiometabolic Risk Epigenetic Variants Emerge From Obesity Study

NEW YORK (GenomeWeb) – Using an epigenome-wide association study, an international team has uncovered adipose tissue methylation marks that appear to coincide with obesity or blood plasma lipid levels.

In a study published today in Nature Communications, researchers from Canada, Sweden, and the UK shared details from the EWAS, which relied on methylC-capture (MCC) sequencing-based methylation profiles for visceral adipose tissue and matched blood samples from 199 severely obese individuals receiving bariatric surgery in Quebec. Their search led to CpG sites with apparent ties to blood plasma lipid profiles, while a series of follow-up fine-mapping steps and functional analysis refined this set and revealed apparent regulatory elements involved in obesity, lipid traits, or metabolic disease.

"Overall, the comprehensive sequencing of regulatory element methylomes reveals a rich landscape of functional variants linked genetically as well as epigenetically to plasma lipid traits," senior and corresponding author Elin Grundberg, and her colleagues wrote.

Grundberg was a researcher with McGill University and the McGill University and Genome Quebec Innovation Centre when the research was performed. She is currently based at the Children's Mercy Hospitals and Clinics in Kansas.

The researchers used MCC-seq to profile methylation patterns at as many as 3.3 million CpG sites in visceral adipose tissue and matched blood samples from 79 men and 120 women undergoing bariatric surgery for severe obesity. In these cases, they saw 1.3 million sites with dramatically reduced or enhanced adipose tissue methylation levels that appeared to coincide with circulating blood plasma triglycerides, high-density lipoprotein cholesterol, low-density lipoprotein cholesterol, or total cholesterol levels.

By digging into these potential associations, the team identified 1,230 CpG sites with methylation levels that were particularly prone to variation that coincided with one or more of these blood lipid traits. Together with human adipocyte histone maps pointing to active enhancer or promoter regions in the genome, and other available data from past studies, the lipid CpG set was subsequently used to focus in on 567 blood lipid-associated regulatory elements.

Using array-based adipose tissue methylation profiles and lipid traits for another 650 individuals enrolled for the Wellcome Trust Multiple Tissue Human Expression Resource (MuTHER), the researchers validated 21 of those blood lipid-associated regulatory sites in adipose samples.

From there, the team not only fine-mapped a subset of the lipid-associated CpGs in adipose tissue with data from MuTHER and other cohorts but also delved into the functions, expression profiles, and genetic variants related to these regulatory regions in adipose tissue and in other tissue types.

The researchers noted that adipogenesis pathway genes and genes involved in cardiometabolic features tended to turn up at sites with lipid-related regulatory regions active across multiple tissue types. Their results hinted that at least some lipid-associated regulatory sites overlap with genetic variants identified in prior genome-wide association studies of lipid traits, obesity, or metabolic disease.

"We showed that targeted sequencing approaches enables us to refine methylome landscape features and to further disentangle the genetic versus environmental contributions to complex traits," the authors wrote, calling their results "an expanded dataset of cardiometabolic risk-linked epigenetic regulatory regions in the disease-relevant adipose tissue."