Integrating Genes Affecting Coronary Artery Disease in Functional Networks by Multi-OMICs Approach

Coronary artery disease (CAD) and myocardial infarction (MI) remain among the leading causes of mortality worldwide, urgently demanding a better understanding of disease etiology, and more efficient therapeutic strategies. Genetic predisposition as well as the environment and lifestyle are thought to contribute to disease risk. It is likely that non-linear and complex interactions occur between these multiple factors, involving simultaneous pathological changes in diverse cell types, tissues, and organs, at multiple molecular levels. Recent technological advances have exponentially expanded the breadth of available -omics data, from genome, epigenome, transcriptome, proteome, metabolome to even the microbiome. Integration of multiple layers of information across several -omics domains, i.e., the so-called multi-omics approach, currently holds the promise as a path toward precision medicine. Indeed, a more meaningful interpretation of genotype-phenotype relationships and the development of successful therapeutics tailored to individual patients are urgently needed. In this review, we will summarize recent findings and applications of integrative multi-omics in elucidating the etiology of CAD/MI; with a special focus on established disease susceptibility loci sequentially identified in genome-wide association studies (GWAS) over the last 10 years. Moreover, in addition to the autosomal genome, we will also consider the genetic variation in our “second genome”—the mitochondrial genome. Finally, we will summarize the current challenges in the field and point to future research directions required in order to successfully and effectively apply these approaches for precision medicine

The impact of genome-wide association studies on the pathophysiology and therapy of cardiovascular disease

Funding Information: This work was supported by grants from the Fondation Leducq (CADgenomics: Understanding CAD Genes, 12CVD02), the German Federal Ministry of Education and Research (BMBF) within the framework of the e: Med research and funding concept (e:AtheroSysMed, grant 01ZX1313A-2014) and the European Union Seventh Framework Programme FP7/2007-2013 under grant agreement no. HEALTH-F2-2013-601456 (CVgenes-at-target). Further grants were received from the DFG as part of the Sonderforschungsbereich CRC 1123 (B2). T.K. was supported by a DZHK Rotation Grant. Figures and contain modified image material available at Servier Medical Art under a Creative Commons Attribution 3.0 Unported License. Publisher Copyright: © 2016 The Authors. Published under the terms of the CC BY 4.0 license Copyright: Copyright 2016 Elsevier B.V., All rights reserved.Cardiovascular diseases are leading causes for death worldwide. Genetic disposition jointly with traditional risk factors precipitates their manifestation. Whereas the implications of a positive family history for individual risk have been known for a long time, only in the past few years have genome-wide association studies (GWAS) shed light on the underlying genetic variations. Here, we review these studies designed to increase our understanding of the pathophysiology of cardiovascular diseases, particularly coronary artery disease and myocardial infarction. We focus on the newly established pathways to exemplify the translation from the identification of risk-related genetic variants to new preventive and therapeutic strategies for cardiovascular disease.publishersversionPeer reviewe

Influenza A positive but H1N1 negative myocarditis in a patient coming from a high outbreak region of new influenza

We present the case of a 21 year-old man holidaying on the Spanish island of Mallorca, a region of high outbreak of infections with a new influenza A/H1N1 virus. Symptomatic influenza A infection, but not H1N1 positive, led to myocarditis after intimate contact with a woman with positive H1N1 titer. The electrocardiogram showed T-wave inversions in II, III, aVF and V5, V6. Serum chemistry showed elevated levels of troponin T, increased creatine kinase (CK) and CK myocardial band. Cardiac magnetic resonance imaging revealed mid- -myocardial and subepicardial hyperintensities in the lateral wall, and subepicardial and mid-myocardial areas of gadolinium enhancement in the inferior wall. Despite intimate contact with an H1N1 positive patient, the analyses on H1N1 (H1 A/Brisbane/59/07, H1 A/ /California/7/09swine) were negative, but were positive for common influenza (H3 A/Brisbane/ /10/07). Myocarditis is a rare clinical manifestation of influenza A infection. (Cardiol J 2011; 18, 4: 441–445

Integration of a polygenic score into guideline-recommended prediction of cardiovascular disease

Background and Aims It is not clear how a polygenic risk score (PRS) can be best combined with guideline-recommended tools for cardiovascular disease (CVD) risk prediction, e.g. SCORE2.Methods A PRS for coronary artery disease (CAD) was calculated in participants of UK Biobank (n = 432 981). Within each tenth of the PRS distribution, the odds ratios (ORs)-referred to as PRS-factor-for CVD (i.e. CAD or stroke) were compared between the entire population and subgroups representing the spectrum of clinical risk. Replication was performed in the combined Framingham/Atherosclerosis Risk in Communities (ARIC) populations (n = 10 757). The clinical suitability of a multiplicative model 'SCORE2 x PRS-factor' was tested by risk reclassification.Results In subgroups with highly different clinical risks, CVD ORs were stable within each PRS tenth. SCORE2 and PRS showed no significant interactive effects on CVD risk, which qualified them as multiplicative factors: SCORE2 x PRS-factor = total risk. In UK Biobank, the multiplicative model moved 9.55% of the intermediate (n = 145 337) to high-risk group increasing the individuals in this category by 56.6%. Incident CVD occurred in 8.08% of individuals reclassified by the PRS-factor from intermediate to high risk, which was about two-fold of those remained at intermediate risk (4.08%). Likewise, the PRS-factor shifted 8.29% of individuals from moderate to high risk in Framingham/ARIC.Conclusions This study demonstrates that absolute CVD risk, determined by a clinical risk score, and relative genetic risk, determined by a PRS, provide independent information. The two components may form a simple multiplicative model improving precision of guideline-recommended tools in predicting incident CVD. Structured Graphical Abstract The left panel shows that relative risk related to polygenic disposition [1-10 tenth of the polygenic risk score (PRS) distribution] is independent of having a low, intermediate, or high clinical risk by SCORE2 in the UK Biobank. Thereby, the odds ratio from the PRS (relative risk) can be used as a genetic factor (PRS-factor) to multiply the absolute clinical risk estimate from SCORE2. If this is being done, similar to 10% of the intermediate-risk group is being upgraded to a higher total risk (right panel). Subgroups that were genetically upgraded had incident event rates that were similar to those in the original high-risk groups and substantially increased the overall numbers of individuals correctly assessed to be at high risk. CVD, cardiovascular disease

A comprehensive 1000 Genomes–based genome-wide association meta-analysis of coronary artery disease

Existing knowledge of genetic variants affecting risk of coronary artery disease (CAD) is largely based on genome-wide association studies (GWAS) analysis of common SNPs. Leveraging phased haplotypes from the 1000 Genomes Project, we report a GWAS meta-analysis of 185 thousand CAD cases and controls, interrogating 6.7 million common (MAF>0.05) as well as 2.7 million low frequency (0.005<MAF<0.05) variants. In addition to confirmation of most known CAD loci, we identified 10 novel loci, eight additive and two recessive, that contain candidate genes that newly implicate biological processes in vessel walls. We observed intra-locus allelic heterogeneity but little evidence of low frequency variants with larger effects and no evidence of synthetic association. Our analysis provides a comprehensive survey of the fine genetic architecture of CAD showing that genetic susceptibility to this common disease is largely determined by common SNPs of small effect size

Validation of the 30-Year Framingham Risk Score in a German Population-Based Cohort

The Framingham Risk Score to predict 30-year risk (FRS30y) of cardiovascular disease (CVD) constitutes an important tool for long-term risk prediction. However, due to its complex statistical properties and the paucity of large population-based cohorts with appropriate data, validation of the FRS30y is lacking. A population-based cohort from Southern Germany (N = 3110, 1516 (48.7%) women) was followed up for a median time of 29.5 [18.7, 31.2] years. Discrimination and calibration were assessed for the original, recalibrated and refitted FRS30y version. During follow up, 620 incident CVD events (214 in women) occurred. The FRS30y showed adequate discrimination (original and recalibrated version: Area under the curve (AUC): 78.4 for women and 74.9 for men) but overestimated actual CVD risk (original version: discordance 45.4% for women and 37.3% for men, recalibrated version: 37.6% and 28.6%, respectively). Refitting showed substantial improvement in neither discrimination nor calibration. The performance of FRS30y is adequate for long-term CVD risk prediction and could serve as an important tool in risk communication, especially for younger audiences

729-1 Modulation of Cardiac Hypertrophy by Blockade of the Renin Angiotensin System: Effects on LVH Regression, Gene Expression, and Survival

The aim of the present study was to investigate the contribution of the renin angiotensin system to maintenance of pressure overload left ventricular hypertrophy (LVH). Rats with fixed ascending aortic stenosis were treated with either vehicle (VEH, n=36), hydralazine (HYD, 20mg/kg/d, n=35). ramipril (RAM, 10mg/kg/d, n=35), or losartan (LOS, 40mg/kg/d, n=16) during weeks 6–12 after banding. We have previously demonstrated that compared to sham (n=36), VEH and HYD rats were characterized by a 1.8–1.9-fold increase of left ventricular to body weight ratios (LV/BW). whereas those aortic stenosis rats treated with RAM or LOS displayed a blunted increase of LV/BW (14-fold; p&lt;0.05, each vs. HYD). We now extend these observations demonstrating that myocyte cross sectional widths were increased by 150% in VEH and HYD rats (p&lt;0.001, vs. sham), whereas ramipril and losartan treatment resulted in myocyte widths that were only mildly elevated (53% and 28%, respectively). Furthermore, VEH and HYD displayed a 14–15 fold increase of LV atrial natriuretic peptide (ANP) mRNA as well as a 44% decrease of sarcoplasmatic reticulum (SR) Ca2+-ATPase (p&lt;0.001, vs. sham). In contrast, alterations of ANP and SR-Ca2+-ATPase mRNA levels were significantly blunted by both RAM and LOS. The attenuation of LVH by RAM or LOS was not explained by blood pressure reduction that was similar in the HYD group. Finally, RAM and LOS decreased mortality (6 out of 51 animals; 11%)as compared to 20% in HYD and 31% in VEH groups (p&lt;0.05).In summary, blockade of the renin angiotensin system may promote regression of pressure overload LVH on the macro-, and microscopical, as well as the molecular level by mechanisms that are, in part, independent of hemodynamic drug effects. LVH regression may improve survival despite persisting pressure overload