Both genetic and lifestyle factors are key drivers of coronary artery disease, a complex disorder that is the leading cause of death worldwide. Long recognized to be heritable, genomewide association analyses have identified more than 50 independent variants robustly associated with risk of coronary disease. These risk alleles, when aggregated into a polygenic risk score, are predictive of incident coronary events and provide a continuous and quantitative measure of genetic susceptibility. Here, we determined the extent to which increased genetic risk can be offset by a healthy lifestyle.

The relationship between genetic and lifestyle factors and incident coronary events was explored in more than 50,000 individuals of prospective cohort studies (Khera AV et al; N Eng J Med; 2016). The relative risk of incident coronary events was 91% higher among participants at high genetic risk (top quintile of polygenic scores) than among those at low genetic risk (bottom quintile of polygenic scores). A favorable lifestyle (defined as at least three of the four healthy lifestyle factors – no current smoking, no obesity, regular physical activity, and a healthy diet) was associated with a substantially lower risk of coronary events than an unfavorable lifestyle (defined as no or only one healthy lifestyle factor), regardless of the genetic risk category. Among participants at high genetic risk, a favorable lifestyle was associated with ≈ 50% reduction in coronary risk as compared to an unfavorable lifestyle.

Patients may equate DNA-based risk estimates with determinism, a perceived lack of control over the ability to improve outcomes.32 However, our results provide evidence that life- style factors may powerfully modify risk regardless of the patient’s genetic risk profile.

Ongoing work seeks to refine the polygenic score to improve its ability to discriminate genetic risk in multiethnic populations. Moving forward, genomic medicine may facilitate identification of a small subset of individuals with significantly increased risk of coronary disease and application of a targeted intervention to mitigate this predisposition.

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