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Mr. Locke, a 48-year-old man with prehypertension, comes to your office for a routine visit. He has a strong family history of coronary artery disease (CAD); his father and two brothers had myocardial infarctions in their 50s. His BMI is 31 kg/m2, he is a nonsmoker, but he does not exercise routinely. You suggest that exercising and focusing on a healthy diet might reduce his risk for CAD, but he wants to know by how much? Is his fate sealed by his family history or could a healthier lifestyle help him reduce the risk of CAD?
Previous observational studies have identified lifestyle factors associated with increased risk of CAD, including family history, smoking, obesity, unhealthy diet, and lack of physical activity. But how much of family history is genetic versus behavioral? How much can lifestyle choices modulate genetic risk? These gene-environment interactions have previously been difficult to quantify, but increasingly the collection and study of genetic data have contributed new insights.
In a study entitled “Genetic Risk, Adherence to a Healthy Lifestyle, and Coronary Disease” published in this week’s issue of NEJM, investigators examined gene-environment interactions in three large prospective cohorts — the Atherosclerosis Risk in Communities (ARIC) study, the Women’s Genome Health Study (WGHS), and the Malmö Diet and Cancer Study (MDCS) — as well as the Bio-Image cross-sectional study. To determine genetic risk, the authors derived a polygenic risk score using single-nucleotide polymorphisms (SNPs) previously associated with CAD in genome-wide association studies, and divided the patients into quintiles from lowest to highest risk. They also collected data on four healthy lifestyle factors (no current smoking, no obesity, physical activity at least once weekly, and a healthy diet pattern) and divided patients into three lifestyle risk categories: favorable (3-4 factors), intermediate (2 factors), and unfavorable (0 or 1 factor).
As expected, in more than 50,000 patients from the three prospective cohorts, the risk of CAD increased from the lowest to the highest quintiles (hazard ratio, 1.91 among participants with high vs. low genetic risk). A family history of CAD was a surrogate, although imperfect, for genetic risk. Likewise, the risk of coronary events was higher in those with unfavorable versus favorable lifestyle.
In this study, the investigators set out to understand not only the role of genes and environment on CAD risk, but also the interaction between genetic and lifestyle risk. To this end, they assessed the effect of lifestyle on the risk of CAD within each category of genetic risk and found that adherence to a favorable lifestyle was beneficial across all genetic risk groups: The relative risk associated with a favorable lifestyle (versus an unfavorable lifestyle) was 45% lower in patients with low genetic risk, 47% lower in those at intermediate genetic risk, and 46% lower in those at high genetic risk. Similarly, they found that the benefit of having a low genetic risk of CAD was offset by an unfavorable lifestyle. The full results are represented visually in the paper, as in the bar graph above. Similar results were found in the cross-sectional Bio-Image study using coronary artery calcification, rather than clinical outcomes, as a marker of subclinical coronary burden.
This study represents the most precise estimates to date of the relative contribution of genetics and lifestyle on risk of CAD. In a large cohort and using robust genetic data, genetic risk and lifestyle behaviors were each independently associated with CAD risk, but favorable or unfavorable lifestyle appeared to modulate genetic risk positively or negatively.
We do not routinely perform genetic testing on patients to calculate genetic risk scores. Therefore, our ability to use these specific risk assessments for counseling is limited. However, this study reinforces the beneficial effect of lifestyle modification on CAD risk, regardless of one’s genetic load. Public health efforts and individual patient counseling should continue to stress the importance of a healthy lifestyle, including smoking cessation, weight reduction, physical activity, and healthy diet, on reducing the risk of CAD.
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Rebecca is a 2016-2017 NEJM Editorial Fellow and a hospitalist at Massachusetts General Hospital. She graduated from Columbia University College of Physicians and Surgeons in 2013 and completed internal medicine residency at Massachusetts General Hospital in 2016. Her interests include medical education, quality improvement, patient safety, health care delivery innovation, and teaching value in health care.