Genetic Risk, Adherence to a Healthy Lifestyle, and Coronary Disease

Abstract

Background: Both genetic and lifestyle factors contribute to individual-level risk of coronary artery disease. The extent to which increased genetic risk can be offset by a healthy lifestyle is unknown.

Methods: Using a polygenic score of DNA sequence polymorphisms, we quantified genetic risk for coronary artery disease in three prospective cohorts - 7814 participants in the Atherosclerosis Risk in Communities (ARIC) study, 21,222 in the Women's Genome Health Study (WGHS), and 22,389 in the Malmö Diet and Cancer Study (MDCS) - and in 4260 participants in the cross-sectional BioImage Study for whom genotype and covariate data were available. We also determined adherence to a healthy lifestyle among the participants using a scoring system consisting of four factors: no current smoking, no obesity, regular physical activity, and a healthy diet.

Results: 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) (hazard ratio, 1.91; 95% confidence interval [CI], 1.75 to 2.09). A favorable lifestyle (defined as at least three of the four healthy lifestyle factors) 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 a 46% lower relative risk of coronary events than an unfavorable lifestyle (hazard ratio, 0.54; 95% CI, 0.47 to 0.63). This finding corresponded to a reduction in the standardized 10-year incidence of coronary events from 10.7% for an unfavorable lifestyle to 5.1% for a favorable lifestyle in ARIC, from 4.6% to 2.0% in WGHS, and from 8.2% to 5.3% in MDCS. In the BioImage Study, a favorable lifestyle was associated with significantly less coronary-artery calcification within each genetic risk category.

Conclusions: Across four studies involving 55,685 participants, genetic and lifestyle factors were independently associated with susceptibility to coronary artery disease. Among participants at high genetic risk, a favorable lifestyle was associated with a nearly 50% lower relative risk of coronary artery disease than was an unfavorable lifestyle. (Funded by the National Institutes of Health and others.).

Figure 1. Standardized Coronary Events Rates, According to Genetic and Lifestyle Risk in the Prospective Cohorts

Shown are the standardized rates of coronary events, according to the genetic risk and lifestyle risk of participants in the Atherosclerosis Risk in Communities (ARIC) cohort, the Women’s Genome Health Study (WGHS) cohort, and the Malmö Diet and Cancer Study (MDCS) cohort. The 95% confidence intervals for the hazard ratios are provided in parentheses. Cox regression models were adjusted for age, sex (in ARIC and MDCS), randomization to receive vitamin E or aspirin (in WGHS), education level, and principal components of ancestry (in ARIC and WGHS). Standardization was performed to cohort-specific population averages for each covariate.

Figure 2. Risk of Coronary Events, According to Genetic and Lifestyle Risk in the Prospective Cohorts

Shown are adjusted hazard ratios for coronary events in each of the three prospective cohorts, according to genetic risk and lifestyle risk. In these comparisons, participants at low genetic risk with a favorable lifestyle served as the reference group. There was no evidence of a significant interaction between genetic and lifestyle risk factors (P = 0.38 for interaction in the Atherosclerosis Risk in Communities (ARIC) cohort, P = 0.31 in the Women’s Genome Health Study (WGHS) cohort, and P = 0.24 in the Malmö Diet and Cancer Study (MDCS) cohort). Unadjusted incidence rates are reported per 1000 person-years of follow-up. A random-effects meta-analysis was used to combine cohort-specific results.

Figure 3. 10-Year Coronary Event Rates, According to Lifestyle and Genetic Risk in the Prospective Cohorts

Shown are standardized 10-year cumulative incidence rates for coronary events in the three prospective cohorts, according to lifestyle and genetic risk. Standardization was performed to cohort-specific population averages for each covariate. The I bars represent 95% confidence intervals.

Figure 4. Coronary-Artery Calcification Score in the BioImage Study, According to Lifestyle and Genetic Risk

Among the participants in the BioImage Study, a standardized score for coronary-artery calcification was determined by means of linear regression after adjustment for age, sex, education level, and principal components of ancestry. Standardization was performed on the basis of study averages for each covariate. Average standardized coronary-artery calcification scores are expressed in Agatston units, with higher scores indicating an increased burden of coronary atherosclerosis. The I bars represent 95% confidence intervals.