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 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 < 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 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.

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.

Coronary artery disease associated with radiation therapy

Open Medicine ◽  
2010 ◽  
Vol 5 (2) ◽  
pp. 180-183
Author(s):  
Turgay Celık ◽  
Cagdas Yuksel ◽  
Sait Demırkol ◽  
Atila Iyısoy ◽  
Cuneyt Ulutın
Keyword(s):  
Breast Cancer ◽  
Coronary Artery Disease ◽  
Radiation Therapy ◽  
Coronary Artery ◽  
Cardiac Complications ◽  
Curative Intent ◽  
Increased Risk ◽  
Cancer Specific Mortality ◽  
Artery Disease ◽  
Effects Of Radiation

AbstractRecent advancements in curative-intent therapies have led to dramatic improvements in breast cancer-specific mortality but at the direct expense of increased risk of cardiovascular-related mortality. The use of radiation therapy has led to significant improvements in survival for patients treated for breast cancer. However, as patients live longer, the potentially serious adverse effects of radiation on the heart have raised concerns. Coronary artery disease following irradiation is encountered rarely but is one of the most devastating treatable complications.In this article we review the cardiac complications associated with radiation therapy.

scholarly journals An integrated polygenic and clinical risk tool enhances coronary artery disease prediction

2020 ◽  
Author(s):  
Fernando Riveros-Mckay ◽  
Michael E. Weale ◽  
Rachel Moore ◽  
Saskia Selzam ◽  
Eva Krapohl ◽  
...  
Keyword(s):  
Cardiovascular Disease ◽  
Coronary Artery Disease ◽  
Coronary Artery ◽  
High Risk ◽  
Predictive Power ◽  
Low Risk ◽  
Uk Biobank ◽  
Polygenic Risk ◽  
Integrated Risk ◽  
Artery Disease

AbstractBackgroundThere is considerable interest in whether genetic data can be used to improve standard cardiovascular disease risk calculators, as the latter are routinely used in clinical practice to manage preventative treatment.MethodsThis research has been conducted using the UK Biobank (UKB) resource. We developed our own polygenic risk score (PRS) for coronary artery disease (CAD), using novel and established methods to combine published genomewide association study (GWAS) data with data from 114,196 UK Biobank individuals, also leveraging a large resource of other GWAS datasets along with functional information, to aid in the identification of causal variants, and thence define weights for > 8M genetic variants. We utilised a further 60,000 UKB individuals to develop an integrated risk tool (IRT) that combined our PRS with established risk tools (either the American Heart Association/American College of Cardiology’s pooled cohort equations (PCE) or the UK’s QRISK3) which was then tested in an additional, independent, set of 212,563 UKB individuals. We evaluated prediction performance in individuals of European ancestry, both as a whole and stratified by age and sex.FindingsThe novel CAD PRS showed superior predictive power for CAD events, compared to other published PRSs. As an individual risk factor, it has similar predictive power to each of systolic blood pressure, HDL cholesterol, and LDL cholesterol, but is more predictive than total cholesterol and smoking history. Our novel CAD PRS is largely uncorrelated with PCE, QRISK3, and family history, and, when combined with PCE into an integrated risk tool, had superior predictive accuracy. In individuals reclassified as high risk, CAD event rates were markedly and significantly higher compared to those reclassified as low risk. Overall, 9.7% of incident CAD cases were misclassified as low risk by PCE and correctly classified as high risk by the IRT, in contrast to 3.7% misclassified by the IRT and correctly classified by PCE. The overall net reclassification improvement for the IRT was 5.7% (95% CI 4.4−7.0), but when individuals were stratified into four age-by-sex subgroups the improvement was larger for all subgroups (range 7.7%−17.3%), with best performance in younger middle-aged men aged 40–54yo (17.3%, 95% CI 13.0–21.5). Broadly similar results were found using a different risk tool (QRISK3), and also for cardiovascular disease events defined more broadly.InterpretationAn integrated risk tool that includes polygenic risk outperforms current, clinical risk stratification tools, and offers greater opportunity for early interventions. Given the plummeting costs of genetic tests, future iterations of CAD risk tools would be enhanced with the addition of a person’s polygenic risk.FundingGenomics plc

scholarly journals Broad Clinical Manifestations of Polygenic Risk for Coronary Artery Disease in the Women′s Health Initiative

2021 ◽  
Author(s):  
Shoa L. Clarke ◽  
Matthew Parham ◽  
Aladdin H. Shadyab ◽  
Simin Liu ◽  
Charles Kooperberg ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Coronary Artery Disease ◽  
Coronary Artery ◽  
Clinical Manifestations ◽  
Polygenic Risk ◽  
Health Initiative ◽  
Genome Wide ◽  
Artery Disease ◽  
Clinical Measurements ◽  
Cad Risk

Background: The genetic basis for coronary artery disease (CAD) risk is highly complex. Genome-wide polygenic risk scores (PRS) can help to quantify that risk, but the broader impacts of polygenic risk for CAD are not well characterized. Methods: We measured polygenic risk for CAD using the metaGRS, a previously validated genome-wide PRS, in a subset of genotyped participants from the Women′s Health Initiative (WHI) and applied a phenome-wide association study framework to assess associations between the PRS and broad range of blood biomarkers, clinical measurements, and outcomes. Results: Polygenic risk for CAD was associated with a variety of biomarkers, clinical measurements, behaviors, and diagnoses related to traditional risk factors, as well as risk-enhancing factors such as elevated lipoprotein(a), increased central adiposity, earlier age of menopause, and rheumatoid arthritis. Analysis of adjudicated outcomes showed a graded association between atherosclerosis related outcomes, with the highest odds ratios being observed for the most severe manifestations of CAD. Higher polygenic risk for CAD was also associated with decreased risk for any incident cancer, breast cancer, and invasive breast cancer but a younger age of death. Conclusion: Polygenic risk for CAD has broad clinical manifestations, reflected in biomarkers, clinical measurements, behaviors, and diagnoses. Some of these associations may represent direct pathways between genetic risk and CAD while others may reflect pleiotropic effects independent of CAD risk.

scholarly journals Integrated Polygenic Tool Substantially Enhances Coronary Artery Disease Prediction

2021 ◽  
Vol 14 (2) ◽  
Author(s):  
Fernando Riveros-Mckay ◽  
Michael E. Weale ◽  
Rachel Moore ◽  
Saskia Selzam ◽  
Eva Krapohl ◽  
...  
Keyword(s):  
Cardiovascular Disease ◽  
Coronary Artery Disease ◽  
Coronary Artery ◽  
Risk Score ◽  
Disease Risk ◽  
The United States ◽  
Polygenic Risk Score ◽  
Uk Biobank ◽  
Polygenic Risk ◽  
Artery Disease

Background: There is considerable interest in whether genetic data can be used to improve standard cardiovascular disease risk calculators, as the latter are routinely used in clinical practice to manage preventative treatment. Methods: Using the UK Biobank resource, we developed our own polygenic risk score for coronary artery disease (CAD). We used an additional 60 000 UK Biobank individuals to develop an integrated risk tool (IRT) that combined our polygenic risk score with established risk tools (either the American Heart Association/American College of Cardiology pooled cohort equations [PCE] or UK QRISK3), and we tested our IRT in an additional, independent set of 186 451 UK Biobank individuals. Results: The novel CAD polygenic risk score shows superior predictive power for CAD events, compared with other published polygenic risk scores, and is largely uncorrelated with PCE and QRISK3. When combined with PCE into an IRT, it has superior predictive accuracy. Overall, 10.4% of incident CAD cases were misclassified as low risk by PCE and correctly classified as high risk by the IRT, compared with 4.4% misclassified by the IRT and correctly classified by PCE. The overall net reclassification improvement for the IRT was 5.9% (95% CI, 4.7–7.0). When individuals were stratified into age-by-sex subgroups, the improvement was larger for all subgroups (range, 8.3%–15.4%), with the best performance in 40- to 54-year-old men (15.4% [95% CI, 11.6–19.3]). Comparable results were found using a different risk tool (QRISK3) and also a broader definition of cardiovascular disease. Use of the IRT is estimated to avoid up to 12 000 deaths in the United States over a 5-year period. Conclusions: An IRT that includes polygenic risk outperforms current risk stratification tools and offers greater opportunity for early interventions. Given the plummeting costs of genetic tests, future iterations of CAD risk tools would be enhanced with the addition of a person’s polygenic risk.

scholarly journals Association of the ATG9B gene polymorphisms with coronary artery disease susceptibility: A case-control study

2019 ◽  
Vol 11 (2) ◽  
pp. 109-115 ◽  
Author(s):  
Mahsa Mehrabi Pour ◽  
Mahboobeh Nasiri ◽  
Hajar Kamfiroozie ◽  
Mohammad Javad Zibaeenezhad
Keyword(s):  
Coronary Artery Disease ◽  
Coronary Artery ◽  
Gene Polymorphisms ◽  
Case Control Study ◽  
Case Control ◽  
Proper Function ◽  
Arms Pcr ◽  
Increased Risk ◽  
Artery Disease ◽  
Control Study

Introduction: Endothelial nitric oxide synthase (eNOS), the main regulator of cardiac cell functioning, is regulated post-transcriptionally by autophagy-related 9B (ATG9B) gene. The proper function of the heart is partly determined by the intact interaction of these molecules. The present study aimed to investigate the effects of ATG9B rs2373929 and rs7830 gene polymorphisms on the predisposition to coronary artery disease (CAD). Methods: In this hospital-based case-control study, 150 patients with CAD compared with 150 healthy subjects for the genotype distributions of rs2373929 and rs7830 polymorphisms using T-ARMS PCR and ARMS PCR, respectively. Results: Considering rs2373929 polymorphism, increased risk of CAD observed in the presence of TT genotype (OR: 3.65; 95% CI: 1.77-7.53; P < 0.001) and also in the recessive model for T allele (OR: 3.41; 95% CI: 1.76- 6.60; P < 0.001). The frequency of the T allele was higher in cases compared to controls (OR: 1.71; 95% CI: 1.24-2.28; P = 0.001). The genotype and allele frequencies of the rs7830 polymorphism did not differ between the two study groups. Conclusion: The ATG9B gene rs2373929 polymorphism might involve in the pathogenesis of the CAD and can be considered as a screening molecular marker in the subjects prone to CAD.

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