Combination of Genetic and Metabolic Analysis Links Endoplasmic Reticulum Stress to Cardiovascular Disease Risk

A novel investigative approach utilizing a combination of genetics, transcriptomics, epigenetics, and metabolomics has enabled researchers to link endoplasmic reticulum (ER) stress to heritable cardiovascular disease (CVD) risk.

It is known that CVD is a strongly heritable trait. However, despite application of the latest genomic technologies, the genetic architecture underlying CVD risk has remained poorly defined, and mechanisms underlying this susceptibility are incompletely understood.

In a dynamic new approach, investigators at Duke University (Durham, NC, USA) combined genetics, epigenetics, and transcriptomics with metabolomics to analyze samples from a large CVD cohort to identify novel genetic markers for CVD and to better understand the role of metabolites in CVD pathogenesis. Metabolomics is the study of chemical processes involving metabolites, while the metabolome represents the collection of all metabolites in a biological cell, tissue, organ, or organism that are the end products of cellular processes.

In this study, the investigators performed genome-wide mapping of heart disease-related metabolites measured in the blood as the genetic traits of interest (instead of the disease itself), in a large cohort of 3,512 patients at risk of heart disease from the CATHGEN study.

The CATHGEN Research Project is a resource for the investigation of genes associated with coronary heart disease and related disorders. The project collected peripheral blood samples from consenting research subjects undergoing cardiac catheterization at Duke University Medical Center from 2001 through 2011. CATHGEN offers DNA, RNA, and plasma samples and a database of genetic information, blood biochemical markers, clinical information, and clinical follow-up to investigate the relationships between genes, cardiovascular disease, and outcomes.

Results published in the November 5, 2015, online edition of the journal PLOS Genetics, linked ER stress to the risk of future heart events. Among its many activities, the endoplasmic reticulum folds and modifies newly formed proteins so they have the correct three-dimensional shape to function properly. The ER also helps transport proteins, fats, and other materials to specific sites within the cell or to the cell surface. When placed under certain types of stress, the ER can leak molecules into other parts of the cell, which can trigger the apoptotic pathway that leads to cell death and eventually to organ dysfunction.

"ER stress has long been linked to Type I diabetes and Parkinson's disease, among others, but this is the first indication that it is also playing a role in common heart attacks and death from heart disease," said senior author Dr. Svati H. Shah, associate professor of medicine at Duke University. "It is also exciting that we are able to measure this ER stress in a small drop of blood, providing a potential way to intercede and lower the risk of a major cardiovascular event."

"Using this multiplatform "omics" approach, we identified these novel genetic variants associated with metabolite levels and with cardiovascular disease itself," said Dr. Shah. "We do not believe that the metabolites themselves are causing heart attacks—they might just be byproducts of a dysregulated process that people are genetically susceptible to—but that is something we need to study further."

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