Coronary Artery Disease Risk Variants Research Articles

MRAS in coronary artery disease-Unchartered territory.

Genome-wide association studies (GWAS) have identified coronary artery disease (CAD) susceptibility locus on chromosome 3q22.3. This locus contains a cluster of several genes that includes muscle rat sarcoma virus (MRAS). Common MRAS variants are also associated with CAD causing risk factors such as hypertension, dyslipidemia, obesity, and type II diabetes. The MRAS gene is an oncogene that encodes a membrane-bound small GTPase. It is involved in a variety of signaling pathways, regulating cell differentiation and cell survival (mitogen-activated protein kinase [MAPK]/extracellular signal-regulated kinase and phosphatidylinositol 3-kinase) as well as acute phase response signaling (tumor necrosis factor [TNF] and interleukin 6 [IL6] signaling). In this review, we will summarize the role of genetic MRAS variants in the etiology of CAD and its comorbidities with the focus on tissue distribution of MRAS isoforms, cell type/tissue specificity, and mode of action of single nucleotide variants in MRAS associated complex traits. Finally, we postulate that CAD risk variants in the MRAS locus are specific to smooth muscle cells and lead to higher levels of MRAS, particularly in arterial and cardiac tissue, resulting in MAPK-dependent tissue hypertrophy or hyperplasia.

Genome-wide association analysis of plasma lipidome identifies 495 genetic associations

The human plasma lipidome captures risk for cardiometabolic diseases. To discover new lipid-associated variants and understand the link between lipid species and cardiometabolic disorders, we perform univariate and multivariate genome-wide analyses of 179 lipid species in 7174 Finnish individuals. We fine-map the associated loci, prioritize genes, and examine their disease links in 377,277 FinnGen participants. We identify 495 genome-trait associations in 56 genetic loci including 8 novel loci, with a considerable boost provided by the multivariate analysis. For 26 loci, fine-mapping identifies variants with a high causal probability, including 14 coding variants indicating likely causal genes. A phenome-wide analysis across 953 disease endpoints reveals disease associations for 40 lipid loci. For 11 coronary artery disease risk variants, we detect strong associations with lipid species. Our study demonstrates the power of multivariate genetic analysis in correlated lipidomics data and reveals genetic links between diseases and lipid species beyond the standard lipids.

Multiomic Analysis and CRISPR Perturbation Screens Identify Endothelial Cell Programs and Novel Therapeutic Targets for Coronary Artery Disease.

Endothelial cells (EC) are an important mediator of atherosclerosis and vascular disease. Their exposure to atherogenic risk factors such as hypertension and serum cholesterol leads to endothelial dysfunction and many disease-associated processes. Identifying which of these multiple EC functions is causally related to disease risk has been challenging. There is evidence from in vivo models and human sequencing studies that dysregulation of nitric oxide production directly affects risk of coronary artery disease. Human genetics can help prioritize the other EC functions with causal relationships because germline mutations are acquired at birth and serve as a randomized test of which pathways affect disease risk. Though several coronary artery disease risk variants have been linked to EC function, this process has been slow and laborious. Unbiased analyses of EC dysfunction using multiomic approaches promise to identify the causal genetic mechanisms responsible for vascular disease. Here, we review the data from genomic, epigenomic, and transcriptomic studies that prioritize EC-specific causal pathways. New methods that CRISPR (clustered regularly interspaced short palindromic repeats) perturbation technology with genomic, epigenomic, and transcriptomic analysis promise to speed up the characterization of disease-associated genetic variation. We summarize several recent studies in ECs which use high-throughput genetic perturbation to identify disease-relevant pathways and novel mechanisms of disease. These genetically validated pathways can accelerate the identification of drug targets for the prevention and treatment of atherosclerosis.

The FES Gene at the 15q26 Coronary-Artery-Disease Locus Inhibits Atherosclerosis.

Genome-wide association studies have discovered a link between genetic variants on human chromosome 15q26.1 and increased coronary artery disease (CAD) susceptibility; however, the underlying pathobiological mechanism is unclear. This genetic locus contains the FES (FES proto-oncogene, tyrosine kinase) gene encoding a cytoplasmic protein-tyrosine kinase involved in the regulation of cell behavior. We investigated the effect of the 15q26.1 variants on FES expression and whether FES plays a role in atherosclerosis. Analyses of isogenic monocytic cell lines generated by CRISPR (clustered regularly interspaced short palindromic repeats)-mediated genome editing showed that monocytes with an engineered 15q26.1 CAD risk genotype had reduced FES expression. Small-interfering-RNA-mediated knockdown of FES promoted migration of monocytes and vascular smooth muscle cells. A phosphoproteomics analysis showed that FES knockdown altered phosphorylation of a number of proteins known to regulate cell migration. Single-cell RNA-sequencing revealed that in human atherosclerotic plaques, cells that expressed FES were predominately monocytes/macrophages, although several other cell types including smooth muscle cells also expressed FES. There was an association between the 15q26.1 CAD risk genotype and greater numbers of monocytes/macrophage in human atherosclerotic plaques. An animal model study demonstrated that Fes knockout increased atherosclerotic plaque size and within-plaque content of monocytes/macrophages and smooth muscle cells, in apolipoprotein E-deficient mice fed a high fat diet. We provide substantial evidence that the CAD risk variants at the 15q26.1 locus reduce FES expression in monocytes and that FES depletion results in larger atherosclerotic plaques with more monocytes/macrophages and smooth muscle cells. This study is the first demonstration that FES plays a protective role against atherosclerosis and suggests that enhancing FES activity could be a potentially novel therapeutic approach for CAD intervention.

Effects of Coronary Artery Disease-Associated Variants on Vascular Smooth Muscle Cells.

Background:Genome-wide association studies have identified many genetic loci that are robustly associated with coronary artery disease (CAD). However, the underlying biological mechanisms are still unknown for most of these loci, hindering the progress to medical translation. Evidence suggests that the genetic influence on CAD susceptibility may act partly through vascular smooth muscle cells (VSMCs).Methods:We undertook genotyping, RNA sequencing, and cell behavior assays on a large bank of VSMCs (n>1499). Expression quantitative trait locus and splicing quantitative trait locus analyses were performed to identify genes with an expression that was influenced by CAD-associated variants. To identify candidate causal genes for CAD, we ascertained colocalizations of VSMC expression quantitative trait locus signals with CAD association signals by performing causal variants identification in associated regions analysis and the summary data–based mendelian randomization test. Druggability analysis was then performed on the candidate causal genes. CAD risk variants were tested for associations with VSMC proliferation, migration, and apoptosis. Collective effects of multiple CAD-associated variants on VSMC behavior were estimated by polygenic scores.Results:Approximately 60% of the known CAD-associated variants showed statistically significant expression quantitative trait locus or splicing quantitative trait locus effects in VSMCs. Colocalization analyses identified 84 genes with expression quantitative trait locus signals that significantly colocalized with CAD association signals, identifying them as candidate causal genes. Druggability analysis indicated that 38 of the candidate causal genes were druggable, and 13 had evidence of drug-gene interactions. Of the CAD-associated variants tested, 139 showed suggestive associations with VSMC proliferation, migration, or apoptosis. A polygenic score model explained up to 5.94% of variation in several VSMC behavior parameters, consistent with polygenic influences on VSMC behavior.Conclusions:This comprehensive analysis shows that a large percentage of CAD loci can modulate gene expression in VSMCs and influence VSMC behavior. Several candidate causal genes identified are likely to be druggable and thus represent potential therapeutic targets.

Single-nucleus chromatin accessibility profiling highlights regulatory mechanisms of coronary artery disease risk.

Coronary artery disease (CAD) is a complex inflammatory disease involving genetic influences across cell types. Genome-wide association studies have identified over 200 loci associated with CAD, where the majority of risk variants reside in noncoding DNA sequences impacting cis-regulatory elements. Here, we applied single-nucleus assay for transposase-accessible chromatin with sequencing to profile 28,316 nuclei across coronary artery segments from 41 patients with varying stages of CAD, which revealed 14 distinct cellular clusters. We mapped ~320,000 accessible sites across all cells, identified cell-type-specific elements and transcription factors, and prioritized functional CAD risk variants. We identified elements in smooth muscle cell transition states (for example, fibromyocytes) and functional variants predicted to alter smooth muscle cell- and macrophage-specific regulation of MRAS (3q22) and LIPA (10q23), respectively. We further nominated key driver transcription factors such as PRDM16 and TBX2. Together, this single-nucleus atlas provides a critical step towards interpreting regulatory mechanisms across the continuum of CAD risk.

Genetic risk and its role in primary prevention of CAD

Coronary artery disease (CAD) is a pandemic disease and the number one cause of death in the world. Predisposition to CAD is about 50% acquired and 50% genetic. CAD prevention has been proven in randomized clinical trials with statin therapy. However, primary prevention is limited by the lack of biomarkers to detect asymptomatic young individuals at risk. Traditional risk factors (TRFs) such as hypertension or Type 2 Diabetes are age-dependent and often not present until the sixth or seventh decade. In contrast, genetic risk determined at conception is potentially a biomarker to detect young individuals at risk for CAD. The first genetic risk variant for CAD (9p21) was discovered in 2007, and subsequently, over 200 risk variants for CAD were discovered. A genetic risk score (GRS) based on the genetic risk variants for CAD was evaluated in over one million individuals. Retrospective analysis of clinical trials assessing the effect of statin therapy showed that individuals with the highest GRS had the highest risk for cardiac events and also the most benefit from lowering cholesterol. In a recent study of 55,685 individuals, those with the highest GRS (20%) had a 91% higher risk for cardiac events. Furthermore, those with high genetic risk on a favorable lifestyle had 46% fewer cardiac events than those with an unfavorable lifestyle. The GRS is superior and independent of TRFs. Incorporation into clinical practice will be a paradigm shift in preventing this pandemic.

Abstract 113: Cell-specific Chromatin Landscape Of Human Coronary Artery Resolves Mechanisms Of Disease Risk

Coronary artery disease (CAD) is a complex inflammatory disease involving genetic influences across several cell types. Genome-wide association studies (GWAS) have identified over 170 loci associated with CAD, where the majority of risk variants reside in noncoding DNA sequences impacting cis -regulatory elements (CREs). Here, we applied single-cell ATAC-seq to profile 28,316 cells across coronary artery segments from 41 patients with varying stages of CAD, which revealed 14 distinct cellular clusters. We mapped over 320,000 accessible sites across all cells, identified cell type-specific elements, transcription factors, and prioritized functional CAD risk variants via quantitative trait locus and sequence-based predictive modeling. Using differential peak analyses we identified a number of candidate mechanisms for smooth muscle cell transition states (e.g. fibromyocytes). By integrating these profiles with GWAS meta-analysis summary data we resolved cell type-specific putative binding sites for the majority of CAD risk variants. In particular, we prioritized functional variants predicted to alter MEF2 binding in smooth muscle cells at the MRAS locus. We also identify variants predicted to alter macrophage-specific regulation of LIPA. We further employed DNA to gene linkage to nominate disease-associated key driver transcription factors such as PRDM16 and TBX2. Together, this single cell atlas provides a critical step towards interpreting cis -regulatory mechanisms in the vessel wall across the continuum of CAD risk.

Functional fine-mapping of coronary artery disease risk variants identified by single-cell profiling of accessible chromatin in human atherosclerotic lesions

Background and Aims: Genome-wide association studies (GWAS) have identified hundreds of loci associated with coronary artery disease (CAD). Many of these loci are enriched in cis-regulatory elements (CREs) but not linked to cardiometabolic risk factors nor to candidate causal genes, complicating their functional interpretation.

The ABO Locus is Associated with Increased Fibrin Network Formation in Patients with Stable Coronary Artery Disease.

The ABO locus has been associated with increased risk of myocardial infarction (MI) in patients with coronary artery disease (CAD), but the underlying mechanisms are unknown. As altered fibrin clot structure has been demonstrated to predict MI in CAD patients, we examined the association between the ABO risk variant and fibrin clot properties, and investigated the effects of other CAD-associated risk variants. We included 773 stable CAD patients. Patients were genotyped for 45 genome-wide CAD risk variants, including rs495828 at the ABO locus. We used a genetic risk score (GRS) for CAD calculated as the weighted sum of the number of risk alleles based on all 45 variants. Fibrin clot properties were evaluated using a turbidimetric assay. We studied clot maximum absorbance, a measure of clot density and fiber thickness, together with clot lysis time, an indicator of fibrinolysis potential. The rs495828 risk allele was present in 13.2% of patients and associated with higher clot maximum absorbance (adjusted effect size per risk allele: 1.05 [1.01 - 1.09], p = 0.01) but not with clot lysis time (p = 0.97). The rs12936587 (p = 0.04), rs4773144 (p = 0.02), and rs501120 (p = 0.04) were associated with clot lysis time; however, after Bonferroni correction, no significant associations were found between any of the remaining 44 CAD-associated variants and fibrin clot properties. The GRS was not associated with fibrin clot properties (p-values > 0.05). The ABO risk allele was associated with a more compact fibrin network in stable CAD patients, which may represent a mechanism for increased MI risk in ABO risk variant carriers.

Genetic predisposition to coronary artery disease is predictive of recurrent events: a Chinese prospective cohort study.

Evidence of the effects of genetic risk score (GRS) on secondary prevention is scarce and mixed. We investigated whether coronary artery disease (CAD) susceptible loci can be used to predict the risk of major adverse cardiovascular events (MACEs) in a cohort with acute coronary syndromes (ACSs). A total of 1667 patients hospitalized with ACS were enrolled and prospectively followed for a median of 2years. We constructed a weighted GRS comprising 79 CAD risk variants and investigated the association between GRS and MACE using a multivariable cox proportional hazard regression model. The incremental value of adding GRS into the prediction model was assessed by integrated discrimination improvement (IDI) and decision curve analysis (DCA). In the age- and sex-adjusted model, each increase in standard deviation in the GRS was associated with a 33% increased risk of MACE (hazard ratio: 1.33; 95% confidence interval: 1.10-1.61; P = 0.003), with this association not attenuating after further adjustment for traditional cardiovascular risk factors. The addition of GRS to a prediction model of seven clinical risk factors and EPICOR prognostic model slightly improved risk stratification for MACE as calculated by IDI (+1.7%, P = 0.006; +0.3%, P = 0.024, respectively). DCA demonstrated positive net benefits by adding GRS to other models. GRS was associated with MACE after multivariable adjustment in a cohort comprising Chinese ACS patients. Future studies are needed to validate our results and further evaluate the predictive value of GRS in secondary prevention.

Genetic Risk of Coronary Artery Disease, Features of Atherosclerosis, and Coronary Plaque Burden.

BackgroundPolygenic risk scores (PRSs) based on risk variants from genome‐wide association studies predict coronary artery disease (CAD) risk. However, it is unknown whether the PRS is associated with specific CAD characteristics.Methods and ResultsWe consecutively included 1645 patients with suspected stable CAD undergoing coronary computed tomography angiography. A multilocus PRS was calculated as the weighted sum of CAD risk variants. Plaques were evaluated using an 18‐segment model and characterized by stenosis severity and composition (soft [0%‐19% calcified], mixed‐soft [20%‐49% calcified], mixed‐calcified [50%‐79% calcified], or calcified [≥80% calcified]). Coronary artery calcium score and segment stenosis score were used to characterize plaque burden. For each standard deviation increase in the PRS, coronary artery calcium score increased by 78% (P=4.1e‐26) and segment stenosis score increased by 16% (P=2.4e‐29) in the fully adjusted model. The PRS was associated with a higher prevalence of obstructive plaques (odds ratio [OR ]: 1.78, P=5.6e‐16), calcified (OR: 1.69, P=6.5e‐17), mixed‐calcified (OR: 1.67, P=7.3e‐9), mixed‐soft (OR: 1.45, P=1.6e‐6), and soft plaques (OR: 1.49, P=2.5e‐6), and a higher prevalence of plaque in each coronary vessel (all P<1.0e‐4). However, when analyzing data on a plaque level (3007 segments with plaque in 849 patients) the PRS was not associated with stenosis severity, plaque composition, or localization (all P>0.05).ConclusionsOur results suggest that polygenic risk based on large genome‐wide association studies increases CAD risk through an increased burden of coronary atherosclerosis rather than promoting specific plaque features.Clinical Trial Registration URL: https://www.clinicaltrials.gov. Unique identifier: NCT02264717.

P870A genetic risk score is associated with increased coronary plaque burden but not specific plaque features: a coronary computed tomography study

Abstract Background Genetic risk scores (GRSs) based on risk variants identified from genome-wide association studies (GWASs) predict coronary artery disease (CAD) risk. However, it is unknown whether the GRS is associated with coronary plaque burden or specific high-risk plaque features responsible for the clinical disease onset. Purpose To investigate if a GRS is associated with coronary plaque burden and specific plaque characteristics, in patients with suspected stable CAD referred for coronary computed tomography angiography (CTA). Methods We consecutively included and genotyped 1645 patients undergoing coronary CTA. Using LDPred, a previously validated GRS was calculated as the weighted sum of the number of CAD risk variants identified from the CARDIoGRAMplusC4D GWAS meta-analysis. Plaques were evaluated using an 18-segment model and characterized by stenosis severity (0%, 1–49%, 50–69%, 70–100%) and composition (calcified (&gt;80% calcified), mixed-calcified (50–80% calcified), mixed-soft (20–50% calcified), or soft (&lt;20% calcified)). The segment stenosis score and the coronary artery calcium score (CACS) were used as measures of plaque burden. Multivariate regression models were used to assess the effect per standard deviation (SD) of the GRS with adjustment for age, sex, hypertension, hypercholesterolemia, BMI, chest pain symptoms, and active smoking. Results For each SD increase in the GRS, the segment stenosis score increased with 49% (p=8.6e-27) and CACS increased with 110% (p=2.3e-24). The GRS was associated with a higher risk of plaque stenosis &gt;50% (OR: 1.74, p=3.2e-15), calcified (OR: 1.65, p=3.0e-16), mixed-calcified (OR: 1.64, p=1.5e-8), mixed-soft (OR: 1.44, p=1.6e-6), and soft plaques (OR: 1.40, p=3.0e-6), and all coronary vessels were more often affected with plaques (all p-values &lt;1.0e-4). When analyzing the plaque characteristics (3007 plaques in 849 patients), the GRS was associated with stenosis severity (OR per severity category: 1.15 (p=0.005), but not with extent of calcification, proximal location, or presence in any of the major coronary vessels (all p-values &gt;0.05). GRS and Plaque burden Conclusion The GRS was strongly associated with the extent and severity of CAD at coronary CTA, but not any specific plaque characteristics per se. The results may suggest that polygenic risk based on large CAD-GWAS increases CAD risk through increased coronary plaque burden rather than specific plaque features.

P2713A genetic risk score improves discrimination of hemodynamically obstructive coronary artery disease (CAD) beyond the CAD Consortium scores in patients at low-to-intermediate risk of CAD

Abstract Background Genetic risk scores (GRSs), based on variants identified in genome-wide association studies (GWAS), have been shown to predict risk of coronary artery disease (CAD). However, the clinical potential remains unknown. Purpose To investigate whether a GRS improves discrimination of hemodynamically obstructive CAD beyond the CAD Consortium scores and coronary artery calcium score (CACS) in patients referred for coronary computed tomography angiography (CTA). Methods We consecutively included and genotyped 1645 patients undergoing CACS scoring and coronary CTA on a suspicion of CAD. Using LDPred, a recently validated GRS was calculated as the weighted sum of the number of CAD risk variants identified from the CARDIoGRAMplusC4D GWAS meta-analysis. Patients with a ≥50% stenosis on CTA further underwent invasive coronary angiography (ICA) with fractional flow reserve (FFR). Hemodynamically obstructive CAD was defined as a visual ICA stenosis &gt;90%, FFR &lt;0.80, or a quantitative coronary analysis stenosis &gt;50% if FFR was not feasible. Discrimination was evaluated by receiver-operating characteristics. Results Median age was 57 (interquartile range 50–64) years and 799 (49%) were males. Hemodynamically obstructive CAD was present in 14 (4%) with a low GRS (&lt;20th percentile), 91 (9%) with an intermediate GRS (20th–80th percentile) and 53 (16%) with a high GRS (&gt;80th percentile) (p&lt;0.0001). Adding the GRS improved the area under the receiver-operating curve (AUC) on top of the CAD Consortium basic score (from 0.67 to 0.72, p=0.0052), and the CAD Consortium clinical score (0.70 to 0.74, p=0.0084), but not on top of the CAD Consortium clinical score + CACS (0.85 to 0.86, p=0.30). Improvement in discrimination on top of the CAD Consortium scores was predominantly driven by females ≤57 years (CAD Consortium basic score ± GRS: 0.60 to 0.78, p=0.0004; CAD Consortium clinical score ± GRS: 0.63 to 0.78, p=0.0007). The GRS did not improve discrimination in any subgroups including CACS (CAD Consortium clinical score + CACS ± GRS: all p-values &gt;0.05). Conclusion A GRS improves discrimination of hemodynamically obstructive CAD beyond CAD consortium scores, particularly in young women. However, the additive discriminative value is attenuated in models including CACS.

The ABO locus is associated with increased platelet aggregation in patients with stable coronary artery disease

BackgroundGenome-wide association studies of patients with coronary artery disease (CAD) suggest that several risk loci increase the risk of CAD and myocardial infarction (MI) equally. In contrast, the ABO locus is stronger associated with MI than with CAD, but the underlying mechanisms are unknown. PurposeTo investigate the association between the ABO risk variant and platelet activation and aggregation. Moreover, to explore the effects of other CAD-associated risk variants. MethodsWe included 879 stable CAD patients receiving low-dose aspirin. All patients were genotyped for 45 genome-wide significant CAD risk variants, including rs495828 at the ABO locus. A genetic risk score (GRS) was calculated to assess the combined risk of all genetic variants. Serum soluble P-selectin (sP-selectin) and thromboxane B2 were used as measures of platelet activation, and platelet aggregation was assessed by multiple electrode aggregometry (MEA) using arachidonic acid and collagen as agonists and VerifyNow. ResultsThe rs495828 CAD risk allele was associated with higher MEA platelet aggregation; arachidonic acid: 14.9% (6.7–23.7%, p = 0.0002) higher AUC (Area Under aggregation Curve) per risk allele, and collagen: 13.1% (5.8%–20.9%, p = 0.0003). Conversely, sP-selectin levels were 7.5% (3.1%–11.7%, p = 0.001) lower per risk allele. Rs495828 genotypes were not associated with aggregation assessed by VerifyNow (p = 0.30) or S-thromboxane B2 levels (p = 0.98). None of the remaining variants or the GRS were associated with platelet activation or aggregation. ConclusionsThe ABO risk allele was associated with increased platelet aggregation as assessed by MEA. This finding may contribute to explain the increased MI risk in ABO risk variant carriers.

Genetic Risk Stratification: Tipping Point for Global Primary Prevention of Coronary Artery Disease.

In 2003, Wald and Law1 predicted that coronary artery disease (CAD) would be markedly attenuated if not eliminated. CAD is a preventable disease based on randomized, placebo-controlled clinical trials that consistently showed 30% to 40% reduction in cardiac events with decreased plasma cholesterol.1 Epidemiologists claimed for decades that 40% to 50% of predisposition for CAD is genetic. Discovery of the first genetic risk variant in 2007 has led to an avalanche of >90 genetic risk variants predisposing to CAD, each of genome-wide significance and replicated in independent populations,2 but each with relatively low individual effect sizes. The total individual genetic risk burden for CAD is proportional to the number of genetic risk variants inherited. These variants account for ≈25% of genetic predisposition to CAD, which is less than the predicted 40%, signaling that more genetic risk variants are yet to be discovered. It is interesting to note that only one third of the genetic risk variants for CAD mediate their risk through known conventional risk factors. Exploration of the unknown pathways mediating the risk conferred by these genetic variants is already enabling new insights into the pathogenesis of coronary atherosclerosis (eg, inflammation, lack of protection of high-density lipoprotein cholesterol) and novel targets for the development of specific drugs. A major impetus for our pursuit of genetic risk variants was to better predict those at higher risk for CAD who would benefit most from preventive measures, particularly primary prevention. The genetic …

Evaluation of 71 Coronary Artery Disease Risk Variants in a Multiethnic Cohort.

BackgroundCoronary heart disease (CHD) is the most common cause of death worldwide. Previous studies have identified numerous common CHD susceptibility loci, with the vast majority identified in populations of European ancestry. How well these findings transfer to other racial/ethnic populations remains unclear.Methods and ResultsWe examined the generalizability of the associations with 71 known CHD loci in African American, Latino and Japanese men and women in the Multiethnic Cohort (6,035 cases and 11,251 controls). In the combined multiethnic sample, 78% of the loci demonstrated odds ratios that were directionally consistent with those previously reported (p = 2 × 10−6), with this fraction ranging from 59% in Japanese to 70% in Latinos. The number of nominally significant associations across all susceptibility regions ranged from only 1 in Japanese to 11 in African Americans with the most statistically significant association observed through locus fine-mapping noted for rs3832016 (OR = 1.16, p = 2.5×10−5) in the SORT1 region on chromosome 1p13. Lastly, we examined the cumulative predictive effect of CHD SNPs across populations with improved power by creating genetic risk scores (GRSs) that summarize an individual’s aggregated exposure to risk variants. We found the GRSs to be significantly associated with risk in African Americans (OR = 1.03 per allele; p = 4.1×10−5) and Latinos (OR = 1.03; p = 2.2 × 10−8), but not in Japanese (OR = 1.01; p = 0.11).ConclusionsWhile a sizable fraction of the known CHD loci appear to generalize in these populations, larger fine-mapping studies will be needed to localize the functional alleles and better define their contribution to CHD risk in these populations.

Genetic Risk Stratification and Prevention of CAD: An Idea Whose Time Is Now.

The latter part of the 20th century was the golden age for genetics, as it focused on linkage analysis in families and discovered genes responsible for >4000 single gene disorders (1). Cardiovascular success included familial hypertrophic cardiomyopathy and atrial fibrillation, as well as Wolff–Parkinson–White, the long QT, and Brugada syndromes (1). A notable feature of the 21st century will be the breakthrough in genetics of polygenic disorders. In the year 2007, we and the Icelandic group simultaneously and independently discovered the first genetic risk variant (9p21) for coronary artery disease (CAD).2 This was followed closely by successes of the Wellcome Trust Group and many other investigators (2). An international collaboration was established to analyze and perform genome-wide association studies for CAD with a sample size of over 200000 cases and controls, referred to as the Coronary Artery Disease Genome-Wide Replication and Meta-Analysis (CARDIoGRAM) consortium. This collaboration provided the necessary expertise, resources, and sample size to identify over 60 genetic variants predisposing to CAD with more to come (2). All these variants are genome-wide significant ( P < 5 × 10−8) and have been replicated in independent populations. This information provided proof of concept for the observations made by epidemiologists decades ago, namely, 40% to 60% of risk for CAD is inherited. Genetic risk variants for CAD, as for all polygenic disorders, have several features in common: they occur commonly, each variant imparts only minimal risk, they occur primarily in nonprotein coding regions of the genome, and the total risk burden for CAD is proportional to the number of independent genetic risk variants rather than the intensity of any one variant. CAD, a pandemic disease, is the number one killer in men and women in the US and throughout the world (2). Someone born today in the …

Genetics-Current and Future Role in the Prevention and Management of Coronary Artery Disease.

The purpose of this study is to review genetic risk variants for coronary artery disease (CAD) and how they will change the management and prevention of CAD currently and in the future. Through the efforts of international consortia, 58 genetic risk variants for CAD of genome-wide significance have been replicated in appropriate independent populations. Only one third of these variants mediate their risk through known conventional risk factors for CAD. Thus, unknown mechanisms contribute to CAD. Secondly, the genetic risk is proportional to the total number of risk variants rather than the intensity of any risk factor. Thirdly, the availability of the genetic risk variants enables one to perform Mendelian randomization (MR) studies since they are randomized at conception, not confounded, fixed for life, and can be used to determine if a risk factor is causative or just a marker. MR can also be used to determine the safety and efficacy of a gene product targeted for drug therapy. Genetic risk variants have been shown to successfully risk stratify for CAD in both primary and secondary preventions. Contrary to dogma, MR documents that plasma HDL-C is not protective of CAD. The use of genetic risk score (GRS) for CAD is shown to be more effective in risk stratifying for CAD than the Framingham risk score and independent of the conventional risk factors including family history. Furthermore, the GRS predicts the response to statin therapy in primary and secondary preventions. The use of GRS could represent a paradigm shift in the prevention of CAD.

Circulation : Clinical Summaries

<i>Circulation</i> : Clinical Summaries