Thousands of genes and their interactions across tissues mediating cardiometabolic diseases have been identified. The research, published in Science , is a result of a joint collaboration between the Icahn School of Medicine at Mount Sinai, Tartu University Hospital in Estonia, Karolinska Institutet and Science for Life Laboratory (SciLifeLab) in Sweden, and AstraZeneca.
The identified level of complexity and interaction among these genes also includes processes that lead to heart attack and stroke.
“By analyzing gene-expression data from multiple tissues in hundreds of patients with coronary artery disease, we were able to identify disease-causing genes that either were specific to single tissues or acted across multiple tissues in networks to cause cardiometabolic diseases,” said Johan Björkegren, MD, PhD, principal investigator of the study, Professor of Genetics and Genomic Sciences at the Icahn School of Medicine at Mount Sinai, visiting professor at University of Tartu and senior investigator at the Karolinska Institutet.
The research was done as part of the STARNET study – the first systematic analysis of RNA sequence data from blood, vascular, and metabolic tissues from patients with coronary artery disease (CAD). RNA sequences are copies of the DNA in each cell that serve as templates for protein synthesis and determine whether a tissue remains healthy or becomes diseased.
“Genome-wide association studies (GWAS) have identified thousands of DNA variants increasing risk for common diseases like CAD,” said Dr. Björkegren. “However, while GWAS was an important first line of investigations of the inheritance of CAD, in order to translate these risk markers into opportunities for new diagnostics and therapies, we must now move into a new phase of discovery and identify the genes perturbed by these DNA variants responsible for driving disease development. Unraveling disease-driving genes with their tissue-belonging, as we have started to achieve using STARNET, will also be a prerequisite for developing precision medicine with individualized diagnostics and therapies.”
Improve drug target development
In collaboration with AstraZeneca and SciLifeLab team, Dr. Björkegren’s team has also used STARNET to try to improve drug target development.
“We are excited about our joint project with Dr. Björkegren’s team at Karolinska Institutet and AstraZeneca, which now with the Science report has delivered the first wave of ground-breaking data that we have supported for the past three years,” said Li-Ming Gan MD, PhD, a co-author of the study, Senior Medical Director and collaboration lead at AstraZeneca. “During the course of our project we have found that Dr. Björkegren’s datasets including STARNET provide essential translation information to help us identify new drug targets, as well as informing on existing targets in cardiovascular and metabolic diseases, a main therapy area for AstraZeneca.”
STARNET was launched in 2007 by Dr. Björkegren, and Arno Ruusalepp MD, PhD, Chief Cardiac Surgeon at Tartu University Hospital in Estonia, and senior co-author on the study. Unlike similar studies, it obtained samples of several key tissues from 600 clinically well-characterized patients with CAD during coronary artery bypass surgery. By using sophisticated data analysis techniques, the researchers found that the gene expression data were highly informative in identifying causal disease genes and their activity in networks for CAD, related cardiometabolic diseases as well as Alzheimer’s disease.
“One unexpected and thus potentially important finding of the study was that besides the liver, abdominal fat emerged as a key site for regulation of blood lipid levels” said Dr. Franzén, first author and computational biologist in Dr. Björkegren’s laboratory. “For example, a gene called PCSK9, which is implicated in controlling plasma levels of low-density lipoprotein (LDL) – the so-called bad cholesterol – was found to do so by acting in abdominal fat, not in the liver where blood levels of LDL are mainly regulated”.
The gene PCSK9 has lately gained substantial attention as the latest target for lipid-lowering drugs now reaching the market .