AstraZeneca has supported a joint collaboration with leading geneticist Professor Johan Björkegren, to further our understanding of the molecular drivers of cardiometabolic diseases
Although genome-wide association studies (GWAS) have identified hundreds of DNA variants associated with risk for coronary artery disease, identifying susceptibility genes responsible for these loci has proven difficult. Moreover, a better understanding of gene regulation around these variants may reveal why these loci explain only a fraction (around 10%) of expected heritable variance in cardiometabolic disease.
Now, research supported by AstraZeneca and published in the prestigious journal Science identifies not only new genes that are responsible for inherited risk of cardiometabolic diseases, but importantly, in which tissues these genes are exaggerated in disease development.
“By analysing 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 tissue or acted across multiple tissues in networks to cause cardiometabolic diseases,” says Johan Björkegren, senior author 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 Insitutet.
The research was done in collaboration with scientists at Tartu University Hospital in Estonia and the Karolinska Institutet together with Science for Life laboratories in Sweden and AstraZeneca as part of the STARNET study. This is the first systematic analysis of RNA sequence data from seven tissues isolated from 600 patients with coronary artery disease (CAD). It was a huge task, and approximately eight million pieces of genetic information were processed together with the RNA sequence data at 30 million read depth in each of the seven tissues. This multi-dimensional dataset identified an unprecedented number of causal disease genes for cardiometabolic diseases.
AstraZeneca has a long-standing relationship with Prof Björkegren since the first and largest genome-wide association study (GWAS) in coronary heart disease called PROCARDIS in the late ‘90’s, to which AstraZeneca was one of the ten pioneering partners.
“The STARNET study goes beyond classical GWAS studies thanks to exciting new sequencing technology and novel bioinformatics modelling from the group at Mount Sinai,” comments Prof Björkegren. STARTNET was launched in 2007 by Professor Björkegren, then at the Karolinska Institutet, and Dr. Arno Ruusalepp, chief cardiac surgeon at Tartu University Hospital in Estonia.
“The STARNET study goes beyond the classical design of GWAS thanks to exciting new high-throughput sequencing technologies and state of the art bioinformatics modelling skills from the group at Mount Sinai,” commented Prof Björkegren. The STARTNET study was first launched in 2007 by Professor Björkegren, then at the Karolinska Institutet, and Dr. Arno Ruusalepp, chief cardiac surgeon at Tartu University Hospital in Estonia.
A particularly interesting discovery in the study was that the regulatory mechanisms for expression of PCSK9, a gene involved in controlling plasma levels of low-density lipoprotein (LDL) – the so-called ‘bad cholesterol’ – are occurring in abdominal fat and not in the liver where both synthesis and uptake of LDL is believed to be controled. Indeed, two thirds of the genes affecting cardiovascular risk related to blood lipid levels were found to be regulated in visceral abdominal or subcutaneous fat. Furthermore, the STARNET patients with the most excessive abdominal fat (greatest waist-to-hip ratio) also had the highest levels of circulating PCSK9 protein and ratio of bad LDL to ‘good HDL cholesterol (high-density lipoprotein, HDL). This new information about the regulation of PCSK9 production in abdominal fat may start to explain the ‘missing link’ between obesity and heart disease.
This is just one example of how the joint research team is gradually recognising how functional genomic data like that generated in STARNET is increasingly important to take the initial findings made by GWAS and find novel drug targets for cardiometabolic diseases.
“We are excited about our joint project with Prof Björkegren´s team at the 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 3 years,” said Prof Li-Ming Gan, AstraZeneca co-author of the study, Senior Medical Director, Early Clinical Development. “During the course of our project we have found that Prof 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.”