Review
doi: 10.1016/j.jcin.2010.12.016.Emerging genomic applications in coronary artery disease
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- PMID:21596318
- PMCID: PMC6072268
- DOI: 10.1016/j.jcin.2010.12.016
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Review
Emerging genomic applications in coronary artery disease
Samir B Damani et al. JACC Cardiovasc Interv.2011 May.
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Abstract
Over the last 4 years, an unprecedented number of studies illuminating the genomic underpinnings of common "polygenic" diseases including coronary artery disease have been published. Notably, these studies have established numerous deoxyribonucleic acid (DNA) variants within or near chromosome 9p21.3, the LPA, CXADR, and APOE genes, to name a few, as key coronary artery disease and sudden cardiac death susceptibility markers. Most importantly, many of these DNA variants confer over a 2-fold increase in risk for coronary artery disease, myocardial infarction, and ventricular fibrillation. Additionally, loss-of-function variants in the hepatic cytochrome 2C19 system have now been found to be the predominant genetic mediators of clopidogrel antiplatelet response, with variant carriers having a >3-fold increase in risk for stent thrombosis. In the near future, many additional rare polymorphisms, structural variants, and tissue-specific epigenetic features of the human genome including DNA methylation, histone modifications, and chromatin state will emerge as significant contributors to disease pathogenesis and drug response. In aggregate, these findings will have the potential to radically change the practice of cardiovascular medicine. However, only the individual clinician can ultimately enable the translation of these important discoveries to systematic implementation in clinical practice.
Copyright © 2011 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.
Figures
(A) Autologous chromosome with evenly spaced microsatellites(B) Segment of DNA between microsatellite markers. Single nucleotide polymorphisms are noted (A,B,C…) within the DNA segment. Tag SNP’s (C,H,K) travel with other noted SNP’s as blocks (haplotypes) and can serve as a surrogate for these haplotypes and more importantly disease causing genes in close proximity.(C) DNA segment with alternative alleles and genomic markers of the same genes designated in part B of the figure. Note that the microsatellite markers are not as close in proximity to the genes as the noted SNP’s. *Figure reproduced from - (Figure 2) Damani and Topol. Future use of genomics in coronary artery disease. J Am Coll of Cardiol. 2007;50:1933-40
Lipoprotein(a) consists of an LDL particle and a glycoprotein molecule, Apo(a), attached to the ApoB-100 moiety of the LDL particle through a disulfide bond. Apo(a) size is determined by the number of kringle repeats. *Figure reproduced from - Permission needed (Figure 1)Danesh J and Erqou S (2009) Lipoprotein(a) and coronary disease—moving closer to causalityNat Rev Cardiol doi:10.1038/nrcardio.2009.138
The odds ratios (squares, with the size inversely proportional to the sampling variation) are for the association of the LPA genotype score (no variant alleles, one variant allele, or two variant alleles) with the risk of coronary disease, as measured with the use of “floating absolute risks” which summarize the sampling variation for the three genotype scores without the selection of an arbitrary baseline genotype score. The vertical lines indicate 95% confidence intervals. *Figure reproduced from - Permission needed. Figure 3. Clark et al. NEJM 361;26 December 24, 2009
Postdischarge ischemic events included myocardial infarction, ischemic stroke, stent thrombosis, unplanned revascularization, and cardiovascular death. All analysis adjusted for age, sex, and race. Patients were further stratified into those who were taking clopidogrel when the event occurred or at 1 year of follow-up and those who were not. All analysis adjusted for age, sex, and race. For all patients, hazard ratio (HR)=2.42 (95% confidence interval [CI] 1.18-4.99;P=0.02); for patients taking clopidogrel at the time of event, HR=3.4 (95% CI 1.36-8.46; P=0.004); for patients not taking clopidogrel, HR=1.39 (95% CI 0.39-4.88; P=0.60) *Figure reproduced from *Permission Needed (Figure 4) Shuldiner et al. JAMA. 2009;302(8):849-858
*Figure reproduced from *Permission needed (Figure 2) Sibbing et al. Circulation.2010;121:512-518
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