In a study that brings together genetics, gene expression and blood biomarkers, investigators have built a framework for exploring multiorgan cross talk in human health and disease.
The research, led by scientists at Vanderbilt University Medical Center and Mass General Brigham, characterizes the molecular “cargo” of circulating extracellular vesicles (EVs) in obesity and links the findings to human genetic approaches to identify potential therapeutic targets for metabolic disease. The study was published July 15 in the journal Cell Genomics.
“The paper, in our view, develops concepts and tools for a new genomics of interorgan communication,” said Eric Gamazon, PhD, associate professor of Medicine in the Division of Genetic Medicine and Clinical Pharmacology at VUMC and co-senior author with Ravi Shah, MD, of VUMC and Saumya Das, MD, PhD, of Mass General Brigham and Harvard Medical School.
Genome-wide association studies (GWAS) have been valuable for identifying genomic regions associated with diseases including obesity, Gamazon noted.
“GWAS to date, however, have been primarily focused on ‘static’ phenotypes, and current genomic tools lack resolution on how genetic variation regulates cross-organ diseases,” he said.
EVs are membrane-bound “packages” of molecular cargo such as RNA and protein that are released from cells and are involved in cross-organ communication.
“EVs may reflect dynamic, tissue-dependent disease states,” said Shah, professor of Medicine at VUMC and holder of the Gottlieb C. Friesinger II Chair in Cardiovascular Medicine.
The researchers characterized EVs circulating in the blood from obese and lean volunteers and identified transcriptional cargo (RNA molecules) that were differentially expressed in obesity. This “obesity EV transcriptome” includes 277 unique genes.
Since circulating EVs could come from anywhere in the body, the researchers wanted to understand how circulating EV cargo was related to cargo in EVs released from visceral adipose tissue (fat inside the abdominal cavity). They collected and cultured visceral adipose tissue from the same obese volunteers and compared adipose-derived EVs to circulating EVs. They observed high similarity between the two.
Then, using genomic tools, they showed that the RNA molecules enriched in circulating and adipose EVs reflected the same transcripts regulated in visceral adipose tissue by genetic variations identified in a GWAS of body mass index (BMI, a measure that relates body weight to height).
Using a phenome-wide association study of the regulatory variants for the EV transcripts in the UK Biobank, the researchers identified enrichment for inflammatory phenotypes, including type 2 diabetes.
“Our findings show that circulating EVs isolated from plasma can differentiate states in obesity and transfer phenotypes across organs,” Shah said.
“The EV molecular cargo may be very useful in helping us interpret the many discoveries from GWAS, which has been one of the major challenges in the GWAS field,” Gamazon said.
The authors noted that the study “represents a convergence of the GWAS (genetics), epigenomics (transcript regulation), and EV (liquid biopsy) fields, with important methodological implications for future genomic studies of complex diseases.”
Co-first authors of the Cell Genomics paper are Emeli Chatterjee, PhD, instructor in Medicine at Harvard Medical School; Michael Betti, graduate student in Human Genetics at Vanderbilt University; and Quanhu Sheng, PhD, associate professor of Biostatistics at VUMC. Co-senior author and lead contact Das is professor of Medicine at Harvard Medical School and co-director of the Inherited Arrhythmia Clinic at Massachusetts General Hospital.
The research was supported by the American Heart Association Strategically Focused Research Network and the National Institutes of Health (grants R35HL150807, UH3TR002878, R35HG010718, R01HG011138, R01GM140287, U01DK140952 and RC2DK116691).
