Genes responsible for risk of heart attack, stroke and related cardiometabolic diseases identified

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 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.

Systematic analysis

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.”

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.

Highly informative

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.

The STARNET study was supported by the University of Tartu; the Estonian Research Council; Karolinska Institutet - AstraZeneca Joint Research Program in Translational Science; Clinical Gene Networks AB (an SME of the EU-funded integrated project CVgenes@target); the Leducq transatlantic networks; CAD Genomics and Sphingonet; Torsten and Ragnar Söderberg Foundation; Knut and Alice Wallenberg Foundation; the American Heart Association; the National Institutes of Health and the Veterans Affairs.

The DNA genotyping and RNA sequencing were in part performed by the SNP&SEQ technology platform at SciLifeLab National Genomics Infrastructure in Uppsala and Stockholm supported by Swedish Research Council, Knut and Alice Wallenberg Foundation and UPPMAX. Björkegren is the founder and chairman of the company Clinical Gene Networks AB, CGN. CGN has financially contributed to the STARNET study. Schadt and Ruusalepp are members of CGN board of directors.

Björkegren, Michoel and Ruusalepp own equity in CGN and receive financial compensation from CGN.

Publication

Cardiometabolic risk loci share downstream cis- and trans-gene regulation across tissues and diseases
Oscar Franzén, Raili Ermel, Ariella Cohain, Nicholas K. Akers, Antonio Di Narzo, Husain A. Talukdar, Hassan Foroughi-Asl, Claudia Giambartolomei, John F. Fullard, Katyayani Sukhavasi, Sulev Köks, Li-Ming Gan, Chiara Giannarelli, Jason C. Kovacic, Christer Betsholtz, Bojan Losic, Tom Michoel, Ke Hao, Panos Roussos, Josefin Skogsberg, Arno Ruusalepp, Eric E. Schadt, Johan L. M. Björkegren.
Science, published online 18th August 2016, doi: 10.1126/science.aad6970