The first systematic analysis of RNA sequence data from blood, vascular and metabolic tissues from patients with CAD has uncovered a new level of complexity and interaction among genes responsible for the inherited risk for MI, stroke and related cardiometabolic diseases.
“This is the first study to have an unbiased data-driven approach to understand the underlying molecular processes in tissues leading to [CAD],” Johan Björkegren, MD, PhD, professor of genetics and genomic sciences at the Icahn School of Medicine at Mount Sinai, visiting professor at the University of Tartu, Estonia, and senior investigator at Karolinska Institutet, Stockholm, Sweden, told Cardiology Today.
Björkegren and colleagues genotyped and RNA-sequenced vascular and metabolic tissues from 600 patients with CAD from the STARNET study.
According to the researchers, substantially more gene expression traits for single-nucleotide polymorphisms associated with cardiometabolic disease risk were found in STARNET than in earlier similar studies that have been tissue- and disease- unspecific, leading to the discovery of extensive sharing of downstream cis-/trans-gene regulation across tissues and cardiometabolic diseases. The regulatory effects of other genome-wide association studies, risk single-nucleotide polymorphisms, however, were tissue-specific.
Björkegren said that one unexpected finding was that the gene PCSK9 was found to be controlling risk of increased plasma levels of LDL in abdominal fat not in the liver, where LDL levels are mainly regulated. “This suggests a mechanistic possibility for the independent association between belly fat and CAD,” he said.
Björkegren told Cardiology Today his team has also collaborated with industry on drug target development. “With the data from STARNET, you can find how target genes are specifically affecting disease in specific tissue. We have worked with AstraZeneca on identifying a mechanism of action for their novel drug targets as well as validating known mechanisms of action for their existing ones.”
This line of research could lead to better understanding of the underlying molecular pathologies of individual patients, Björkegren said in an interview.
“We are slowly moving towards unraveling the molecular landscape underlying complex diseases. So instead of talking about treating BP or lipid levels, at a less granular level we are going to classify and treat diseases based on their molecular appearances,” he said. – by Tracey Romero
For more information:
Johan Björkegren, MD, PhD, can be reached at Department of Genetics and Genomic Sciences, Institute of Genomics and Multiscale Biology, Icahn School of Medicine at Mount Sinai, 1 Gustave L. Levy Place, New York, NY, 10029; email: firstname.lastname@example.org.
Disclosure: Björkegren reports being the founder and chairman of, holding equity in and receiving compensation from Clinical Gene Networks AB. Please see the full study for a list of the other researchers’ relevant financial disclosures.