School of Medicine researchers have linked 13 new gene regions to the risk of heart disease in an unprecedented collaborative study that examined the genomes of more than 80,000 individuals. The results were published in this week’s issue of Nature Genetics.
The study analyzed the genomes of 22,000 people with a history of heart disease and 60,000 healthy individuals. This investigation, which drew data from 14 previous studies, is almost 10 times larger than the next-largest whole-genome study to date.
Stanford researchers identified 23 gene regions that predispose individuals to heart disease. They subsequently examined these regions in 25,000 afflicted and 25,000 healthy patients.
“These chips generate 500,000 data points, but we only took 23 to the next level,” said Themistocles Assimes, assistant professor of cardiovascular medicine.
Of these 23 gene regions, only 13 passed statistical tests for validation.
The study replicated and confirmed evidence from previous investigations in a meta-analysis, doubling the number of identified gene regions related to heart disease. The results are essential in understanding heart disease because, unlike other major illnesses, it is a product of multiple gene interactions.
“It’s not one gene region or one gene; it’s a bunch that all have subtle effects,” Assimes said. “You inherit a profile of those mutations and depending on the number of mutations you have, that dictates the lifetime risk of having heart disease.”
Interestingly, only three of these 13 regions are related to traditional risk factors for heart disease — for example, diabetes, high cholesterol, high blood pressure or smoking.
Heart disease is caused by the buildup of cholesterol crystals in blood vessels, a process known as coronary atherosclerosis. The remaining 10 genes may influence the degree to which individuals’ vessels are susceptible to this buildup.
“Essentially all of these traditional risk factors are irritating the blood vessel wall and are promoting plaque formation in the wall,” Assimes said. “And then there are players inside the wall. The signals that are not coming from the traditional risk factors are probably something in the vessel wall [but] we don’t know exactly what.”
The study is also groundbreaking because of its scope: it examined a large number of patients in order to “overcome statistical noise,” Assimes said.
According to principal investigator Thomas Quertermous, who is a professor of cardiovascular medicine, a collaborative effort of this magnitude is “unprecedented.”
“Five or 10 years ago we would never thought we would have been able to come together,” he said. “I’ve never met most of the people that I’m working with, but we’ve come together through e-mail and through telephone because we’ve needed to.”
While unprecedented, the study had its limitations. Researchers only examined individuals of European descent, mostly due to the availability of data.
“The individuals in the study have been collected over the course of years, through recruitment of individuals who’ve had a heart attack,” Quertermous said. “It just turns out that those kinds of studies were done in countries where the vast majority of the population is Caucasian — Italy, Sweden, United States, Germany.”
According to Quertermous, there are ongoing studies that look at individuals of African, South Asian and Hispanic descent.
At present, the Stanford study has two preponderant implications: it paves the way for future research on new therapies that could reduce the risk of heart disease and simultaneously helps identify individuals who may be at higher risk of heart disease.
“We’ve identified single base pair differences and said that these signal differences, out of three billion, change your risk of having heart disease,” Quertermous said.
But there’s still more to be done. Quertermous hopes to continue to investigate the relationship between single base pair differences and changes in the function of a particular gene or set of genes.
“If I change that gene, either in terms of structure or level of activity, how does that change the biology and the risk of heart disease?” he asked.
“We shouldn’t stop until we figure out what’s going on,” Assimes said. “And when we do figure it out, obviously there’s the potential to develop a therapeutic [solution] to block that pathway that’s involved.”
Still, doctors must be cautious when genetically-profiling individuals and assessing their risk.
“The reality is that we still need to find a few more gene regions before we’ll get to a point where profiling will be useful,” Assimes said.