High blood pressure is a highly heritable and modifiable risk factor for cardiovascular disease. We report the largest genetic association study of blood pressure traits (systolic, diastolic, pulse pressure) to date in over one million people of European ancestry. We identify 535 novel blood pressure loci that not only offer new biological insights into blood pressure regulation but also reveal shared genetic architecture between blood pressure and lifestyle exposures. Our findings identify new biological pathways for blood pressure regulation with potential for improved cardiovascular disease prevention in the future.

BackgroundCoronary artery disease (CAD) has substantial heritability and a polygenic architecture. However, the potential of genomic risk scores to help predict CAD outcomes has not been evaluated comprehensively, because available studies have involved limited genomic scope and limited sample sizes.ObjectivesThis study sought to construct a genomic risk score for CAD and to estimate its potential as a screening tool for primary prevention.MethodsUsing a meta-analytic approach to combine large-scale, genome-wide, and targeted genetic association data, we developed a new genomic risk score for CAD (metaGRS) consisting of 1.7 million genetic variants. We externally tested metaGRS, both by itself and in combination with available data on conventional risk factors, in 22,242 CAD cases and 460,387 noncases from the UK Biobank.ResultsThe hazard ratio (HR) for CAD was 1.71 (95% confidence interval [CI]: 1.68 to 1.73) per SD increase in metaGRS, an association larger than any other externally tested genetic risk score previously published. The metaGRS stratified individuals into significantly different life course trajectories of CAD risk, with those in the top 20% of metaGRS distribution having an HR of 4.17 (95% CI: 3.97 to 4.38) compared with those in the bottom 20%. The corresponding HR was 2.83 (95% CI: 2.61 to 3.07) among individuals on lipid-lowering or antihypertensive medications. The metaGRS had a higher C-index (C = 0.623; 95% CI: 0.615 to 0.631) for incident CAD than any of 6 conventional factors (smoking, diabetes, hypertension, body mass index, self-reported high cholesterol, and family history). For men in the top 20% of metaGRS with >2 conventional factors, 10% cumulative risk of CAD was reached by 48 years of age.ConclusionsThe genomic score developed and evaluated here substantially advances the concept of using genomic information to stratify individuals with different trajectories of CAD risk and highlights the potential for genomic screening in early life to complement conventional risk prediction.

Context Previous reviews of associations of apolipoprotein E (apoE) genotype and coronary disease have been dominated by smaller studies that are liable to biases.Objective To reassess associations of apoE genotypes with circulating lipid levels and with coronary risk. Data SourcesWe conducted an updated meta-analysis including both published and previously unreported studies, using MEDLINE, EMBASE, BIOSIS, Science Citation Index, and the Chinese National Knowledge Infrastructure Database published between January 1970 and January 2007, reference lists of articles retrieved, and a registry of relevant studies. Study SelectionEighty-two studies of lipid levels (86 067 healthy participants) and 121 studies of coronary outcomes (37 850 cases and 82 727 controls) were identified, with prespecified principal focus on studies with at least 1000 healthy participants for lipids and those with at least 500 coronary outcomes.Data Extraction Information on genotype frequencies, lipid levels, coronary outcomes, and laboratory and population characteristics were recorded independently by 2 investigators and/or supplied by study investigators. ResultsIn the most extreme comparison, people with the ε2/ε2 genotype had 1.14 mmol/L (95% confidence interval [CI], 0.87-1.40 mmol/L [44.0 mg/dL; 95% CI; 33.6-51.1 mg/dL]) or about 31% (95% CI, 23%-38%) lower mean lowdensity lipoprotein cholesterol (LDL-C) values than those with the ε4/ε4 genotype. There were approximately linear relationships of apoE genotypes (when ordered ε2/ε2, ε2/ε3, ε2/ε4, ε3/ε3, ε3/ε4, ε4/ε4) with LDL-C and with coronary risk. The relationship with high-density lipoprotein cholesterol was inverse and shallow and that with triglycerides was nonlinear and largely confined to the ε2/ε2 genotype. Compared with ε3/ε3, the odds ratio for coronary disease was 0.80 (95% CI, 0.70-0.90) in ε2 carriers and was 1.06 (95% CI, 0.99-1.13) in ε4 carriers. ConclusionsThere are approximately linear relationships of apoE genotypes with both LDL-C levels and coronary risk. Compared with individuals with the ε3/ε3 genotype, ε2 carriers have a 20% lower risk of coronary heart disease and ε4 carriers have a slightly higher risk.