Interethnic analyses of blood pressure loci in populations of East Asian and European descent

Blood pressure (BP) is a major risk factor for cardiovascular disease and more than 200 genetic loci associated with BP are known. Here, we perform a multi-stage genome-wide association study for BP ( max N = 289,038) principally in East Asians and meta-analysis in East Asians and Europeans. We report 19 new genetic loci and ancestry-specific BP variants, conforming to a common ancestry-specific variant association model. At 10 unique loci, distinct non-rare ancestry-specific variants colocalize within the same linkage disequilibrium block despite the significantly discordant effects for the proxy shared variants between the ethnic groups. The genome-wide transethnic correlation of causal-variant effect-sizes is 0.898 and 0.851 for systolic and diastolic BP, respectively. Some of the ancestry-specific association signals are also influenced by a selective sweep. Our results provide new evidence for the role of common ancestry-specific variants and natural selection in ethnic differences in complex traits such as BP.</p

Identification of 64 Novel Genetic Loci Provides an Expanded View on the Genetic Architecture of Coronary Artery Disease

Rationale: Coronary artery disease (CAD) is a complex phenotype driven by genetic and environmental factors. Ninety-seven genetic risk loci have been identified to date, but the identification of additional susceptibility loci might be important to enhance our understanding of the genetic architecture of CAD. Objective: To expand the number of genome-wide significant loci, catalog functional insights, and enhance our understanding of the genetic architecture of CAD. Methods and Results: We performed a genome-wide association study in 34541 CAD cases and 261984 controls of UK Biobank resource followed by replication in 88192 cases and 162544 controls from CARDIoGRAMplusC4D. We identified 75 loci that replicated and were genome-wide significant (P Conclusions: We identified 64 novel genetic risk loci for CAD and performed fine mapping of all 161 risk loci to obtain a credible set of causal variants. The large expansion of reconstituted gene sets argues in favor of an expanded omnigenic model view on the genetic architecture of CAD

ukbpheno v1.0:An R package for phenotyping health-related outcomes in the UK Biobank

The complexity and volume of data associated with population-based cohorts means that generating health-related outcomes can be challenging. Using one such cohort, the UK Biobank—a major open access resource—we present a protocol to efficiently integrate the main dataset and record-level data files, to harmonize and process the data using an R package named “ukbpheno”. We describe how to use the package to generate binary phenotypes in a standardized and machine-actionable manner

Validation and comparison of 28 risk prediction models for coronary artery disease

Aims Risk prediction models (RPMs) for coronary artery disease (CAD), using variables to calculate CAD risk, are potentially valuable tools in prevention strategies. However, their use in the clinical practice is limited by a lack of poor model description, external validation, and head-to-head comparisons. Methods and results CAD RPMs were identified through Tufts PACE CPM Registry and a systematic PubMed search. Every RPM was externally validated in the three cohorts (the UK Biobank, LifeLines, and PREVEND studies) for the primary endpoint myocardial infarction (MI) and secondary endpoint CAD, consisting of MI, percutaneous coronary intervention, and coronary artery bypass grafting. Model discrimination (C-index), calibration (intercept and regression slope), and accuracy (Brier score) were assessed and compared head-to-head between RPMs. Linear regression analysis was performed to evaluate predictive factors to estimate calibration ability of an RPM. Eleven articles containing 28 CAD RPMs were included. No single best-performing RPM could be identified across all cohorts and outcomes. Most RPMs yielded fair discrimination ability: mean C-index of RPMs was 0.706 +/- 0.049, 0.778 +/- 0.097, and 0.729 +/- 0.074 (P < 0.01) for prediction of MI in UK Biobank, LifeLines, and PREVEND, respectively. Endpoint incidence in the original development cohorts was identified as a significant predictor for external validation performance. Conclusion Performance of CAD RPMs was comparable upon validation in three large cohorts, based on which no specific RPM can be recommended for predicting CAD risk

Active Tobacco Smoking Impairs Cardiac Systolic Function

Tobacco smoking is a well-established risk factor for cardiovascular disease, but its direct effect on myocardial structure and function remains unclear. This study investigated the effects of smoking using a nested matched case-control study design. 5,668 participants of the UK Biobank study who underwent cardiovascular magnetic resonance imaging were screened for inclusion. 102 smokers (56 males) with a median age of 56 years were matched to non-smokers based on sex, age, and body surface area. Manual post-processing and feature tracking analyses were performed to determine left ventricular (LV) and right ventricular (RV) structure and function measures. Linear regression analyses were performed to determine the effect of tobacco smoking on imaging measures. Tobacco smoking was associated with increased LV and RV end-systolic volume (4.98 +/- 2.08mL, 5.19 +/- 2.62mL, P=0.018, 0.049 respectively), reduced LV and RV ejection fraction (beta: -2.21 +/- 0.82%, -2.06 +/- 0.87%, P=0.007, 0.019 respectively), and reduced absolute measures of LV peak global longitudinal, radial, and circumferential strain (beta: 0.86 +/- 0.30%, -2.52 +/- 0.99%, 1.05 +/- 0.32%, P=0.004, 0.011, 0.001 respectively). Effect sizes were larger in daily smokers compared to occasional smokers. In a general Caucasian population without known clinical cardiovascular disease, active tobacco smoking was dose dependently associated with impaired cardiac systolic function

Pharmacoepigenetics in Heart Failure

Epigenetics studies inheritable changes of genes and gene expression that do not concern DNA nucleotide variation. Such modifications include DNA methylation, several forms of histone modification, and microRNAs. From recent studies, we know not only that genetic changes account for heritable phenotypic variation, but that epigenetic changes also play an important role in the variation of predisposition to disease and to drug response. In this review, we discuss recent evidence of epigenetic changes that play an important role in the development of cardiac hypertrophy and heart failure and may dictate response to therapy