Roughly half of our risk of getting heart disease is due to our genetics. The other half is due to age, lifestyle and other environmental factors. Of the genetic half, some of the risk comes from rare genetic variants that have a big impact on a person’s individual risk. Some comes from the additive and possibly synergistic effect of many common genetic variants that, on their own, have only a relatively small impact. All of us carry some combination of variants that affect our likelihood of developing heart disease.
For some time, it has been a point of debate in the scientific community whether the high-impact rare variants or the low-impact common variants are more responsible for the genetic basis of heart disease.
Now, researchers from the University of Ottawa Heart Institute, together with the teams at Oxford University and the Broad Institute in Cambridge, Massachusetts, have an answer. Ruth McPherson, MD, PhD, Director of the Heart Institute’s Ruddy Canadian Cardiovascular Genetics Centre, and post-doctoral fellow Majid Nikpay, PhD, report that the cumulative effect of multiple common genetic variants is most responsible for the genetic basis of heart disease.
The study, published in September in the leading journal Nature Genetics, used the data from the 1000 Genomes Project in order to obtain information on close to 10 million genetic variants (called single nucleotide polymorphisms (SNPs)). The analysis involved 60,000 heart disease patients and 120,000 healthy individuals from a total of 48 studies around the world. Not only is the number of genetic variants much greater than the approximately 1 million previously studied, this is the first time that researchers have been able to study the link of rare genetic variants present in as few as one in 1,000 people at risk of heart disease.
“Our analysis provides a comprehensive survey of the fine genetic architecture of coronary artery disease [CAD], showing that genetic susceptibility to this common disease is largely determined by common SNPs of small effect size,” said the authors.
Dr. Nikpay, post-doctoral fellow at the Heart Institute, also used an alternative statistical method of analysis to find two new risk markers that have an effect only if an individual has inherited two copies of the “bad gene”; that is, one from each parent. In addition to discovering a total of 10 new risk markers by using other statistical approaches, the research team produced a list of 202 genetic variants in 129 gene regions that together explain approximately 23 per cent of the heritability of coronary heart disease as compared to only 11 per cent reported in previous studies.
“Many of these genetic variants are likely to exert their effects on the walls of arteries, making the vessels more susceptible to the common heart disease risk factors such as cigarette smoking, diabetes and high cholesterol,” added Dr. McPherson.
A number of preventative strategies target the vessel wall (for example, controlling high blood pressure and quitting smoking), but the large majority of existing drug treatments for lowering CAD risk operate through manipulation of circulating cholesterol levels. Few directly target vessel wall processes. Further research into new aspects of vessel wall biology that have a genetic link but have not previously been explored in atherosclerosis may provide a new understanding of the complex basis of coronary artery disease and identify new targets for treatment.