scholarly journals Association of polygenic risk scores for coronary artery disease with subsequent events amongst established cases

2019 ◽  
Author(s):  
Laurence J. Howe ◽  
Frank Dudbridge ◽  
A. Floriaan Schmidt ◽  
Chris Finan ◽  
Spiros Denaxas ◽  
...  
Keyword(s):  
Coronary Artery Disease ◽  
Coronary Artery ◽  
Risk Scores ◽  
List Type ◽  
Genome Wide Association Studies ◽  
Inverse Association ◽  
Uk Biobank ◽  
Polygenic Risk ◽  
Increased Risk ◽  
Artery Disease

AbstractBackgroundThere is growing evidence that polygenic risk scores (PRS) can be used to identify individuals at high lifetime risk of coronary artery disease (CAD). Whether they can also be used to stratify risk of subsequent events among those surviving a first CAD event remains uncertain.MethodsUsing two subsamples of UK Biobank, defined at baseline as prevalent CAD (N=10,287) and without CAD (N=393,108), we evaluated associations between a CAD PRS and incident cardiovascular and fatal outcomes, during a median follow up of 7.8 years.ResultsA 1 S.D. higher PRS was associated with increased risk of incident MI in participants without CAD (OR 1.33; 95% C.I. 1.29, 1.38), but the effect estimate was markedly attenuated in those with prevalent CAD (OR 1.15; 95% C.I. 1.06, 1.25); heterogeneity P =0.0012. Additionally, among prevalent CAD cases, we found evidence of an inverse association between the CAD PRS and risk of all-cause death (OR 0.91; 95% C.I. 0.85, 0.98) compared to those without CAD (OR 1.01; 95% C.I. 0.99, 1.03); heterogeneity P =0.0041. A similar inverse association was found for ischaemic stroke (Prevalent CAD (OR 0.78; 95% C.I. 0.67, 0.90); without CAD (OR 1.09; 95% C.I. 1.04, 1.15), heterogeneity P <0.001).ConclusionsBias induced by case stratification and survival into UK Biobank may attenuate, or reverse, associations of polygenic risk scores derived from case-control studies or populations initially free of disease. Polygenic risk scores for subsequent events should be derived from new genome wide association studies conducted in patients with established disease.Key messagesCAD PRS are positively associated with incident myocardial infarction risk amongst established CAD cases.However, the effect size is attenuated compared to estimates from CAD-free populations.CAD PRS are inversely associated with mortality and stroke risk amongst established CAD cases.These associations may reflect index event bias induced by stratifying on case status.Dedicated GWAS of coronary disease progression are required to improve prediction of subsequent event risk.

scholarly journals Polygenic risk scores for coronary artery disease and subsequent event risk amongst established cases

2020 ◽  
Vol 29 (8) ◽  
pp. 1388-1395
Author(s):  
Laurence J Howe ◽  
Frank Dudbridge ◽  
Amand F Schmidt ◽  
Chris Finan ◽  
Spiros Denaxas ◽  
...  
Keyword(s):  
Coronary Artery Disease ◽  
Coronary Artery ◽  
Risk Scores ◽  
Effect Estimate ◽  
Inverse Association ◽  
Uk Biobank ◽  
Case Control Studies ◽  
Polygenic Risk ◽  
Increased Risk ◽  
Artery Disease

Abstract Background There is growing evidence that polygenic risk scores (PRSs) can identify individuals with elevated lifetime risk of coronary artery disease (CAD). Whether they can also be used to stratify the risk of subsequent events among those surviving a first CAD event remain uncertain, with possible biological differences between CAD onset and progression, and the potential for index event bias. Methods Using two baseline subsamples of UK Biobank: prevalent CAD cases (N = 10 287) and individuals without CAD (N = 393 108), we evaluated associations between a CAD PRS and incident cardiovascular and fatal outcomes. Results A 1 SD higher PRS was associated with an increased risk of incident myocardial infarction (MI) in participants without CAD (OR 1.33; 95% CI 1.29, 1.38), but the effect estimate was markedly attenuated in those with prevalent CAD (OR 1.15; 95% CI 1.06, 1.25) and heterogeneity P = 0.0012. Additionally, among prevalent CAD cases, we found an evidence of an inverse association between the CAD PRS and risk of all-cause death (OR 0.91; 95% CI 0.85, 0.98) compared with those without CAD (OR 1.01; 95% CI 0.99, 1.03) and heterogeneity P = 0.0041. A similar inverse association was found for ischaemic stroke [prevalent CAD (OR 0.78; 95% CI 0.67, 0.90); without CAD (OR 1.09; 95% CI 1.04, 1.15), heterogeneity P &lt; 0.001]. Conclusions Bias induced by case stratification and survival into UK Biobank may distort the associations of PRS derived from case-control studies or populations initially free of disease. Differentiating between effects of possible biases and genuine biological heterogeneity is a major challenge in disease progression research.

scholarly journals Polygenic background modifies penetrance of monogenic variants conferring risk for coronary artery disease, breast cancer, or colorectal cancer

2019 ◽  
Author(s):  
Akl C. Fahed ◽  
Minxian Wang ◽  
Julian R. Homburger ◽  
Aniruddh P. Patel ◽  
Alexander G. Bick ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Colorectal Cancer ◽  
Coronary Artery Disease ◽  
Coronary Artery ◽  
Case Control ◽  
Uk Biobank ◽  
Polygenic Risk ◽  
Risk Variants ◽  
Increased Risk ◽  
Artery Disease

ABSTRACTBackgroundGenetic variation can predispose to disease both through (i) monogenic risk variants in specific genes that disrupt a specific physiologic pathway and have a large effect on disease risk and (ii) polygenic risk that involves large numbers of variants of small effect that affect many different pathways. Few studies have explored the interaction between monogenic risk variants and polygenic risk.MethodsWe identified monogenic risk variants and calculated polygenic scores for three diseases, coronary artery disease, breast cancer, and colorectal cancer, in three study populations — case-control cohorts for coronary artery disease (UK Biobank; N=12,879) and breast cancer (Color Genomics; N=19,264), and an independent cohort of 49,738 additional UK Biobank participants.ResultsIn the coronary artery disease case-control cohort, increased risk for carriers of a monogenic variant ranged from 1.3-fold for those in the lowest polygenic score quintile to 12.6-fold for those in the highest. For breast cancer, increased risk ranged from 2.4 to 6.9-fold across polygenic score quintiles. Among the 49,738 UK Biobank participants who carried a monogenic risk variant, the probability of disease at age 75 years was strongly modified by polygenic risk. Across individuals in the lowest to highest percentiles of polygenic risk, the probability of disease ranged from 17% to 78% for coronary artery disease; 13% to 76% for breast cancer; and 11% to 80% for colon cancer.ConclusionsFor three important genomic conditions, polygenic risk powerfully modifies the risk conferred by monogenic risk variants.

scholarly journals Validation of genome-wide polygenic risk scores for coronary artery disease in French Canadians

2019 ◽  
Author(s):  
Florian Wünnemann ◽  
Ken Sin Lo ◽  
Alexandra Langford-Avelar ◽  
David Busseuil ◽  
Marie-Pierre Dubé ◽  
...  
Keyword(s):  
Coronary Artery Disease ◽  
Coronary Artery ◽  
Risk Scores ◽  
French Canadian ◽  
French Canadians ◽  
Polygenic Risk ◽  
Genome Wide ◽  
Artery Disease ◽  
The Impact ◽  
Cad Risk

AbstractCoronary artery disease (CAD) represents one of the leading causes of morbidity and mortality worldwide. Given the healthcare risks and societal impacts associated with CAD, their clinical management would benefit from improved prevention and prediction tools. Polygenic risk scores (PRS) based on an individual’s genome sequence are emerging as potentially powerful biomarkers to predict the risk to develop CAD. Two recently derived genome-wide PRS have shown high specificity and sensitivity to identify CAD cases in European-ancestry participants from the UK Biobank. However, validation of the PRS predictive power and transferability in other populations is now required to support their clinical utility. We calculated both PRS (GPSCAD and metaGRSCAD) in French-Canadian individuals from three cohorts totaling 3639 prevalent CAD cases and 7382 controls, and tested their power to predict prevalent, incident and recurrent CAD. We also estimated the impact of the founder French-Canadian familial hypercholesterolemia deletion (LDLR delta > 15kb deletion) on CAD risk in one of these cohorts and used this estimate to calibrate the impact of the PRS. Our results confirm the ability of both PRS to predict prevalent CAD comparable to the original reports (area under the curve (AUC) = 0.72-0.84). Furthermore, the PRS identified about 6-7% of individuals at CAD risk similar to carriers of the LDLR delta > 15kb mutation, consistent with previous estimates. However, the PRS did not perform as well in predicting incident (AUC= 0.56 - 0.60) or recurrent (AUC= 0.56 - 0.60) CAD. This result suggests that additional work is warranted to better understand how ascertainment biases and study design impact PRS for CAD. Collectively, our results confirm that novel, genome-wide PRS are able to predict CAD in French-Canadians; with further improvements, this is likely to pave the way towards more targeted strategies to predict and prevent CAD-related adverse events.

Polygenic Risk Scores in Coronary Artery Disease and Atrial Fibrillation

2020 ◽  
Vol 29 (4) ◽  
pp. 634-640 ◽  
Author(s):  
Patrick A. Gladding ◽  
Malcolm Legget ◽  
Diane Fatkin ◽  
Peter Larsen ◽  
Robert Doughty
Keyword(s):  
Atrial Fibrillation ◽  
Coronary Artery Disease ◽  
Coronary Artery ◽  
Risk Scores ◽  
Polygenic Risk ◽  
Artery Disease

Abstract 16105: Depression Modulates Polygenic Risk of Cardiovascular and Cardiometabolic Disease

Circulation ◽  
2020 ◽  
Vol 142 (Suppl_3) ◽  
Author(s):  
Michael C Honigberg ◽  
Amy Sarma ◽  
Nandita Scott ◽  
Malissa J Wood ◽  
Pradeep Natarajan
Keyword(s):  
Atrial Fibrillation ◽  
Coronary Artery Disease ◽  
Coronary Artery ◽  
Health Behaviors ◽  
Genetic Risk ◽  
Cardiometabolic Disease ◽  
Uk Biobank ◽  
Polygenic Risk ◽  
Artery Disease ◽  
The Uk

Introduction: Depression is associated with an increased risk of coronary artery disease (CAD). Whether depression modifies genetic risk of cardiovascular and cardiometabolic disease is unknown. Methods: We included genotyped, unrelated European ancestry individuals in the UK Biobank. Using genome-wide significant single nucleotide polymorphisms (SNPs) from studies external to the UK Biobank, we generated polygenic risk scores (PRS) for coronary artery disease (CAD, 74 SNPs), hypertension (75 SNPs), type 2 diabetes (T2D, 64 SNPs), atrial fibrillation (25 SNPs), and ischemic stroke (11 SNPs). Participants were stratified by PRS for each condition as low (quintile 1), intermediate (quintiles 2-4), and high (quintile 5) genetic risk. Cox models tested the association of depression frequency with each incident condition among individuals with high PRS, with adjustment for age, sex, the first 20 principal components, genotyping array, and Townsend deprivation index. Additional models further adjusted for health behaviors (exercise, tobacco and alcohol use, vegetable and fresh fruit intake) and tested associations across the PRS spectrum. Results: Among 348,083 individuals, 78,664 (22.6%) reported depression in the past 2 weeks, including 14,776 (4.2%) with depression more than half of days. Depression burden modified the risk of incident CAD across the spectrum of CAD polygenic risk (Figure 1A). Among individuals with high PRS, lack of depression was associated with lower risk of incident CAD (HR 0.70, 95% 0.58-0.86), hypertension (HR 0.58, 95% CI 0.50-0.67), T2D (HR 0.48, 95% CI 0.41-0.55), and atrial fibrillation (HR 0.74, 95% CI 0.62-0.89) compared to those with a high burden of depression. These risk reductions were minimally attenuated after further adjustment for health behaviors (Figure 1B). Conclusions: Lower burden of depression was associated was decreased risks of cardiovascular disease among individuals at high genetic cardiovascular risk.

Recent success in the discovery of coronary artery disease genes

2011 ◽  
Vol 89 (8) ◽  
pp. 609-615 ◽  
Author(s):  
Robert Roberts ◽  
Li Chen ◽  
George A. Wells ◽  
Alexandre F.R. Stewart
Keyword(s):  
Coronary Artery Disease ◽  
Coronary Artery ◽  
Association Studies ◽  
Short Interval ◽  
Minimal Risk ◽  
Genome Wide Association Studies ◽  
Common Diseases ◽  
Multiple Genes ◽  
Increased Risk ◽  
Artery Disease

For more than 50 years, epidemiological studies have indicated that genetic predisposition accounts for approximately 50% of the susceptibility to coronary artery disease (CAD) and its sequelae, including myocardial infarction. Since common diseases such as CAD are caused by multiple genes, the age-old method of linkage analysis used to map monogenic Mendelian disorders in families unfortunately lacks the required sensitivity. The technology to identify genes predisposing individuals to CAD and other common diseases did not become available until 2005. This technology provided computerized arrays containing hundreds of thousands of DNA markers in the form of single-nucleotide polymorphisms (SNPs). This made it possible to pursue an unbiased approach referred to as genome-wide association studies. The first gene for CAD was simultaneously identified by 2 independent groups in 2007. In a very short interval, a total of 23 loci were mapped that were linked to increased risk for CAD. The results of these studies confirm that CAD is caused by multiple genes, each contributing minimal risk. The most exciting and novel findings are that these loci do not act through known risk factors for CAD and that the loci are more likely to be in DNA regions that regulate transcription rather than being in coding regions for protein.

scholarly journals Cis-epistasis at the LPA locus and risk of coronary artery disease

2019 ◽  
Author(s):  
Lingyao Zeng ◽  
Nazanin Mirza-Schreiber ◽  
Claudia Lamina ◽  
Stefan Coassin ◽  
Christopher P. Nelson ◽  
...  
Keyword(s):  
Coronary Artery Disease ◽  
Coronary Artery ◽  
Association Studies ◽  
Arterial Disease ◽  
Genome Wide Association Studies ◽  
Interaction Patterns ◽  
Cardiovascular Risks ◽  
Increased Risk ◽  
Artery Disease ◽  
Cad Risk

AbstractIdentification of epistasis affecting complex human traits has been challenging. Focusing on known coronary artery disease (CAD) risk loci, we explore pairwise statistical interactions between 8,068 SNPs from ten CAD genome-wide association studies (n=30,180). We discovered rs1800769 and rs9458001 in the vicinity of the LPA locus to interact in modulating CAD risk (P=1.75×10−13). Specific genotypes (e.g., rs1800769 CT) displayed either significantly decreased or increased risk for CAD in the context of genotypes of the respective other SNP (e.g., rs9458001 GG vs. AA). In the UK Biobank (n=450,112) significant interaction of this SNP pair was replicated for CAD (P=3.09×10−22), and was also found for aortic valve stenosis (P=6.95×10−7) and peripheral arterial disease (P=2.32×10−4). Identical interaction patterns affected circulating lipoprotein(a) (n=5,953; P=8.7×10−32) and hepatic apolipoprotein(a) (apo(a)) expression (n=522, P=2.6×10−11). We further interrogated potential biological implications of the variants and propose a mechanism explaining epistasis that ultimately may translate to substantial cardiovascular risks.

Coronary artery disease and myocardial infarction

2020 ◽  
pp. 349-354
Author(s):  
Perry Elliott ◽  
Pier D. Lambiase ◽  
Dhavendra Kumar
Keyword(s):  
Myocardial Infarction ◽  
Coronary Artery Disease ◽  
Coronary Artery ◽  
Association Studies ◽  
Risk Scores ◽  
Candidate Gene Approach ◽  
Polygenic Risk ◽  
Mendelian Disorders ◽  
Genomic Studies ◽  
Artery Disease

This chapter covers coronary artery disease (CAD) and myocardial infarction, starting with an introduction to the main causal and treatable risk factors for CAD and myocardial infarction, then goes on to discuss the Mendelian disorders associated with CAD (e.g. Tangier disease, sitosterolaemia, etc.) Association studies based on the candidate gene approach are discussed along with genomic studies, e.g. polygenic risk scores.

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