To what extent is our risk of heart disease determined by our genes? We’re stuck with the genes we’ve got, but can lifestyle modify genetically conferred risk?
Despite marked reductions in recent years, coronary artery disease remains a major cause of morbidity and mortality. Although a genetic component to coronary disease is well recognised, it is not an inherited condition in the way that a disease like, say, cystic fibrosis is directly due to genetic abnormalities. In cystic fibrosis, individuals who inherit defective copies of a single gene from both mother and father will display characteristics of the condition. In coronary disease, the influence of genetic variants is more subtle — and reflects the integration of many potential variants, each exerting a relatively small effect.
The genome has often been considered as a blueprint, in which the genes code for specific protein components that make up the organism. Not surprisingly, in addition to the component parts, it turns out that a large amount of the genome also carries information and control mechanisms for regulating the timing, location and rate of production of these components.
Contemporary techniques allow an individual’s entire genetic code (coding for both components and the directions for construction) to be described ‘letter by letter’. One benefit of this is the ability to define points in the genetic blueprint where minor modifications can translate into small changes in susceptibility to a given disease.
Genome-wide association studies (GWAS) have defined the extent to which minor variations in the genetic code can lead to (usually marginal) increases in cardiovascular risk. Unlike diseases that are directly caused by single gene defects (which lead directly to functionally defective protein components), these minor variations are much more low key in their manifestations. Indeed the demonstration of any association with increased risk of a given condition or clinical event often requires thousands of patients to establish a statistically robust connection.
For coronary artery disease about 50 minor genetic variations that confer risk have been identified. One important question is whether the cumulative risk of these variations can be approximated in an individual. A second critical question is the extent to which variations in lifestyle might be able to alter or attenuate the genetic risks. In other words, is the influence of our genes fixed in respect of coronary disease risk?
Both of these questions are addressed in a study by Khera et al reported in the New England Journal of Medicine last week. To estimate an individual’s genetic risk, the study counted how many of the possible 50-ish cardiovascular disease-related variants a person had and then weighted that score according to the known risk conferred by each genetic variant.
The authors then examined the extent to which their genetic risk score mirrored actual events measured prospectively in more than 50,000 patients who were part of three separate studies with follow-up data over several years. By integrating the predicted influence of more than 50 variant genes, they were able to estimate the combined risk.
Individuals in the highest quintile of risk showed a 1.91-fold increase compared with those in the lowest quintile of risk. In other words, the risk of a serious cardiovascular event in the highest genetic risk group was about twice as high as in the lowest risk group. In real terms the very highest risk group had about a 10 per cent chance of suffering an event over 10 years of follow up.
Of course our genes are with us for life and the basic gene set is defined at conception. So can the effects of those genes on cardiovascular risk be modified by lifestyle? Using the same three cohorts of patients, the study showed that adopting at least three out of four healthy lifestyle characteristics (non-obese, physical exercise, not smoking, ‘healthy’ diet) was associated with risk reduction of about 50 per cent.
This is an important study. Not only does it give a good insight into risk stratification according to variations across the whole genome, but it also highlights opportunities to modify dramatically the risks that we are born with.