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Background: Understanding the effect of lifestyle and genetic risk on the lifetime risk of coronary heart disease (CHD) is important to improving public health initiatives. Our objective was to quantify remaining lifetime risk and years free of CHD according to polygenic risk and the American Heart Association’s Life’s Simple 7 (LS7) guidelines in a population-based cohort study. Methods: Our analysis included data from participants of the ARIC (Atherosclerosis Risk in Communities) study: 8372 White and 2314 Black participants; 45 years of age and older; and free of CHD at baseline examination. A polygenic risk score (PRS) comprised more than 6 million genetic variants was categorized into low (80th percentile). An overall LS7 score was calculated at baseline and categorized into “poor,” “intermediate,” and “ideal” cardiovascular health. Lifetime risk and CHD-free years were computed according to polygenic risk and LS7 categories. Results: The overall remaining lifetime risk was 27%, ranging from 16.6% in individuals with an ideal LS7 score to 43.1% for individuals with a poor LS7 score. The association of PRS with lifetime risk differed according to ancestry. In White participants, remaining lifetime risk ranged from 19.8% to 39.3% according to increasing PRS categories. Individuals with a high PRS and poor LS7 had a remaining lifetime risk of 67.1% and 15.9 fewer CHD-free years than did those with intermediate polygenic risk and LS7 scores. In the high-PRS group, ideal LS7 was associated with 20.2 more CHD-free years compared with poor LS7. In Black participants, remaining lifetime risk ranged from 19.1% to 28.6% according to increasing PRS category. Similar lifetime risk estimates were observed for individuals of poor LS7 regardless of PRS category. In the high-PRS group, an ideal LS7 score was associated with only 4.5 more CHD-free years compared with a poor LS7 score. Conclusions: Ideal adherence to LS7 recommendations was associated with lower lifetime risk of CHD for all individuals, especially in those with high genetic susceptibility. In Black participants, adherence to LS7 guidelines contributed to lifetime risk of CHD more so than current PRSs. Improved PRSs are needed to properly evaluate genetic susceptibility for CHD in diverse populations.

Both the health burden and genetic heritability of blood pressure are well-established, yet only a fraction of blood pressure genes have been identified. Epigenetic changes in or near genes related to blood pressure may explain part of its variance and provide new insights into the biological mechanisms involved in blood pressure regulation. DNA methylation measured on the Infinium HumanMethylation450 BeadChip was tested for association with systolic and diastolic blood pressure in individuals of European (EA) and African ancestry (AA) in the ARIC, CHS, FHS, GENOA, GOLDN, NAS, LBC1936, RS-III, and TwinsUK cohorts (N-total=9,828; N-EA=6,650, N-AA=3,178). In each cohort, linear mixed models were used to estimate associations adjusting for age, sex, blood cell counts, BMI, smoking, and ancestry, as well as surrogate variables and technical covariates to control for batch effects. Effect estimates from all cohorts were combined using inverse variance fixed effects meta-analysis; heterogeneity of effects in race- and sex-stratified analyses was not observed. Thirty-one methylation probes were found to be significantly associated with blood pressure after Bonferroni correction (p Our findings suggest a novel genetic regulation of known blood pressure systems through heritable DNA methylation.

Introduction: Inflammation plays a key role in atherosclerosis. We hypothesized that uninvestigated inflammatory markers may predict the risk of coronary heart disease (CHD). Methods: We investigated the association of 16 inflammatory biomarkers with the risk of CHD in a random subset of 839 CHD free individuals in a prospective population-based cohort study. A Bonferroni corrected p-value of 3.1х10 -3 was used as a threshold of statistical significance. We additionally tested whether the association of any identified marker was independent of traditional CHD risk factors and previously studied inflammatory markers. Results: Mean age at baseline was 72.8 years. During a median follow-up of 10.6 years, 99 cases of incident CHD were observed. Among all novel inflammatory biomarkers, neutrophil derived human s100a12 (EN-RAGE) showed the strongest association with the risk of CHD (p-value 2.0х10 -3 ). In the age and sex adjusted model, each standard deviation increase in the natural log-transformed EN-RAGE was associated with 37% higher risk of incident CHD (Hazard ratio (HR): 1.37; 95% confidence interval (CI) CI: 1.12 - 1.67). After further adjustment for established cardiovascular risk factors, the effect estimates attenuated slightly (HR: 1.30; 95% CI: 1.06 - 1.59). Adjustment for ten previously studied inflammatory markers did not attenuate the association (HR: 1.41; 95% CI: 1.12 - 1.77). Excluding individuals with prevalent type 2 diabetes, impaired kidney function or individuals using antihypertensive medication did not change the effect estimates. Conclusions: Our results highlight EN-RAGE as a novel inflammatory marker for CHD independent of traditional CHD risk factors and inflammatory markers, suggesting a specific inflammatory risk pathway for CHD.