Genetic 'off switch' may raise risk for heart disease

Issue: September 2013

People with a certain gene that has been naturally “switched off” appear to be at increased CV risk, researchers reported at an American Heart Association Emerging Science Series webinar.

Perspective from Christopher J. O’Donnell, MD, MPH

Working with 888 patients from the Genetics of Lipid Lowering Drugs and Diet Network (GOLDN) study, researchers examined three biomarkers (LDL, elevated triglycerides, adiponectin) in relation to the gene encoding carnitine palmitoyltransferase 1A (CPT1A), a key enzyme in lipid metabolism.

Patients were randomly assigned to a discovery (n=593) or replication (n=295) data subset. In the discovery stage, researchers modeled percent methylation at each CpG site as a function of fasting plasma lipids and adiponectin using adjusted mixed linear regression models. They then evaluated all markers for association with the trait of interest in the replication cohort, according to the study abstract.

“Our results showed that two markers in CPT1A reached and surpassed statistical significance and were consequently successfully replicated in our data set. Perhaps, unsurprisingly, a very similar pattern emerged for VLDL, where the same two CPT1A markers reached statistical significance. One of those markers even reached statistical significance for models of adiponectin,” Stella Aslibekyan, PhD, assistant professor of epidemiology at the University of Alabama at Birmingham, said during the webinar.

Patients who had methyl groups bound to CPT1A (cg00574958 and cg17058475) had significantly higher triglycerides and LDL levels, and lower adiponectin. The associations were successfully replicated with triglycerides and adiponectin.

“We have identified differential DNA methylation in CPT1A as a novel contributor to inter-individual variability in plasma triglycerides, VLDL cholesterol and adiponectin,” the researchers concluded in the study abstract. “Our findings lay the groundwork for incorporating epigenetic data in cardiovascular risk stratification, disease prevention and treatment strategies.”

For more information:

Aslibekyan S. AHA Emerging Science Series. Cardiovascular Risk: From Epigenetics to Pharmacotherapy; June 19, 2013.

Aslibekyan S. Circulation. 2013;doi:10.1161/CIR.0b013e31829ecc16.

Disclosure: This study was funded by the NIH. Aslibekyan reports no relevant financial disclosures.

Perspective

Christopher J. O’Donnell, MD, MPH

This is a very exciting time in genetic and medical research. With the completion of the human genome sequencing about a decade ago, there came a wave of genome-wide association studies and genome-wide sequencing studies to examine for associations of variation in the DNA sequence with many CV phenotypes, including lipids. As part of that whole series of studies, there came a seminal study that identified around 95 single nucleotide polymorphism variants associated with the various lipids. We have a remarkable portfolio of genetic associations that we are now perusing for their function. Now, we are in the second wave of studies looking at the structure of DNA and how that structure is related to disease and health.

The research presented at the webinar gets to exactly the epigenetic structure of the DNA and potentially the resulting gene expression. I think that this is one of the initial studies in the next wave of studies.

[In] the Framingham Heart Study, [we embrace] two phrases [to] describe where [such research] is going: system[s] approaches and collaboration. In the Framingham study, there has been much gene sequencing and genotyping conducted. Now, we are just getting into methylation studies, gene expression studies and many omic studies, including metabolomics, and also induced pluripotent stem cell research that is adding on multiple layers of the DNA sequence and structure of the DNA. With many companion studies across the portfolio of population based studies, we are working together and it is a very exciting time.

Christopher J. O’Donnell, MD, MPH

Clinical Associate Professor of Medicine, Harvard Medical School

Senior Investigator of the NHLBI Division of Intramural Research

Disclosures: