Improved Prediction of Cardiovascular Disease Based on a Panel of Single Nucleotide Polymorphisms Identified Through Genome-Wide Association Studies

Davies, R. W.; Dandona, Sonny; Stewart, Alexandre F.R.; Chen, Li; Ellis, Stephan G.; Tang, W.H. Wilson; Hazen, Stanley L.; Roberts, Robert; McPherson, Ruth; Wells, George A.

doi:10.1161/circgenetics.110.946269

Cited by 98 publications

(76 citation statements)

References 25 publications

(29 reference statements)

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“…Similarly in another study, a 13 SNPs score was associated with the first MI event (Ripatti et al, 2010). While some researchers were able to improve the net reclassification by the inclusion of GRS, the improvement remained modest (Davies et al, 2010;Lluís-Ganella et al, 2010), and even some failed to show a significant change in net reclassification index (Paynter et al, 2010;Ripatti et al, 2010).…”

Section: When Tested Directly For Cad Risk Prediction Different Grsmentioning

confidence: 85%

Genetic risk analysis of coronary artery disease in Pakistani subjects using a genetic risk score of 21 variants

et al. 2017

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Back ground and Aims: Conventional risk factors like age, gender, blood lipids, hypertension and smoking have been the basis of coronary artery disease (CAD) risk prediction algorithms, but provide only modest discrimination. A genetic risk score (GRS) may provide improved discrimination over and above conventional risk factors alone. The current study analysed the genetic risk of CAD in Pakistani subjects using a GRS of 21 loci in 18 genes and examined whether its association with blood lipids in this cohort.Methods: 625 subjects were genotyped for the variants, NOS3 rs1799983, SMAD3 rs17228212, APOBrs1042031, LPArs3798220, LPA rs10455872, SORT1rs646776, APOE rs429358, GLUL rs10911021 and FTO rs9939609 (by TaqMan) and MIA3 rs17465637,CDKN2A rs10757274, DAB2IP rs7025486, CXCL12 rs1746048, ACE rs4341, APOA5 rs662799, CETP rs708272, MRAS rs9818870, LPL rs328,LPL rs1801177, PCSK9 rs11591147and APOE rs7412 (by KASPar technique).Results: Individually, risk allele frequencies were not significantly higher in cases than controls (p>0.05) except for APOB rs1042031 and FTO rs9939609 (p=0.007 and 0.003 respectively), and did not associate with CAD except rs1042031 and rs993969 (p=0.01 and 0.009 respectively). However, the GRS of 21 SNPs was significantly higher in cases than controls (17.53±2.52 vs16.64±2.44, p<0.001) and was associated with CAD risk. CAD risk in the top quintile of GRS was 2.96 (95% CI 1.71-5.13). Atherogenic blood lipid levels showed significant positive association with GRS. Conclusion:The GRS was quantitatively associated with d CAD risk and showed association with blood lipid levels, suggesting that the mechanism of these variants is likely to be in part at least through creating an atherogenic lipid profile in subjects carrying high numbers of risk alleles.

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Section: When Tested Directly For Cad Risk Prediction Different Grsmentioning

confidence: 85%

Genetic risk analysis of coronary artery disease in Pakistani subjects using a genetic risk score of 21 variants

et al. 2017

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“…There have been many attempts to assess various configurations from the single genetic risk variant 9p21 112 to combinations of ≤13 variants. [113][114][115][116][117] All of these studies show a good correlation between the genetic risk variants and the risk of CAD with some improvement in the prediction of CAD. However, the conventional criteria for significant improvement is judged on whether it changes the net reclassification index or improves discrimination by the conventional ethics, referred to as C-index.…”

Section: Clinical Application Of Genetic Risk Variants For the Prevenmentioning

confidence: 94%

Genetics of Coronary Artery Disease

Roberts

2014

Circulation Research

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100

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Abstract:There is almost no data on the genetics of acute coronary syndromes, so this review discusses primarily the 50 genetic risk variants associated with coronary artery disease that are of genome-wide significance in the discovery population and replicated in an independent population. All of these risk variants are extremely common with more than half occurring in >50% of the general population. They increased only minimally the relative risk for coronary artery disease. The most striking finding is that 35 of the 50 risk variants act independently of known risk factors, indicating there are several pathways yet to be appreciated, contributing to the pathogenesis of coronary atherosclerosis and myocardial infarction. All of the genetic variants seem to act through atherosclerosis, except for the ABO blood groups, which show that A and B are associated with increased risk for myocardial infarction, mediated by a prolonged von Willebrand plasma half life leading to thrombosis. The potential molecular mechanisms of 9p21 are discussed, including cell cycle kinase inhibitors. Discovery of risk variants associated with PCSK9 has led to the development of novel treatment for plasma low-density lipoprotein cholesterol. A monoclonal antibody inhibiting PCSK9 has already undergone phase I and II clinical trials, showing it is a potent inhibitor of low-density lipoprotein cholesterol and is mediated through more rapid removal of low-density lipoprotein cholesterol from the plasma. This therapy complements that of statin therapy, which inhibits the synthesis of cholesterol. The benefits of Mendelian randomization to assess safety and efficacy and their limitations are discussed along with future directions.

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“…87 After adjusting for LDL-C levels, this association was completely attenuated in WHII but not in BWHHS. The value of a GRS for CAD risk prediction beyond conventional risk factors has improved beyond previous studies considering a small number of risk variants 88,89 beyond those related to plasma lipid traits to more recent analyses incorporating a more comprehensive list of recently identified CAD loci. [90][91][92] Tikkanen et al 92 constructed a GRS consisting of 28 CAD genetic variants and in 24 124 participants, in 4 populationbased, prospective cohorts, determined its association with incident cardiovascular disease events for a mean 12-year follow-up period.…”

Section: Utility Of a Genetic Risk Score For Risk Assessment And Treamentioning

confidence: 99%

Genetics of Coronary Artery Disease

McPherson

Tybjærg‐Hansen

2016

Circulation Research

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314

203

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Genetic factors contribute importantly to the risk of coronary artery disease (CAD), and in the past decade, there has been major progress in this area. The tools applied include genome-wide association studies encompassing >200 000 individuals complemented by bioinformatic approaches, including 1000 Genomes imputation, expression quantitative trait locus analyses, and interrogation of Encyclopedia of DNA Elements, Roadmap, and other data sets. close to 60 common SNPs (minor allele frequency>0.05) associated with CAD risk and reaching genomewide significance (P<5×10 −8 ) have been identified. Furthermore, a total of 202 independent signals in 109 loci have achieved a false discovery rate (q<0.05) and together explain 28% of the estimated heritability of CAD. These data have been used successfully to create genetic risk scores that can improve risk prediction beyond conventional risk factors and identify those individuals who will benefit most from statin therapy. Such information also has important applications in clinical medicine and drug discovery by using a Mendelian randomization approach to interrogate the causal nature of many factors found to associate with CAD risk in epidemiological studies. In contrast to genome-wide association studies, whole-exome sequencing has provided valuable information directly relevant to genes with known roles in plasma lipoprotein metabolism but has, thus far, failed to identify other rare coding variants linked to CAD. Overall, recent studies have led to a broader understanding of the genetic architecture of CAD and demonstrate that it largely derives from the cumulative effect of multiple common risk alleles individually of small effect size rather than rare variants with large effects on CAD risk. Despite this success, there has been limited progress in understanding the function of the novel loci; the majority of which are in noncoding regions of the genome. (Circ Res. 2016;118:564-578.

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Improved Prediction of Cardiovascular Disease Based on a Panel of Single Nucleotide Polymorphisms Identified Through Genome-Wide Association Studies

Cited by 98 publications

References 25 publications

Genetic risk analysis of coronary artery disease in Pakistani subjects using a genetic risk score of 21 variants

Genetic risk analysis of coronary artery disease in Pakistani subjects using a genetic risk score of 21 variants

Genetics of Coronary Artery Disease

Genetics of Coronary Artery Disease

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