scholarly journals Polygenic Risk for Coronary Artery Disease in the Scottish and English Population

2021 ◽  
Author(s):  
Chuhua Yang ◽  
Fabian Starnecker ◽  
Shichao Pang ◽  
Zhifen Chen ◽  
Ulrich Güldener ◽  
...  
Keyword(s):  
Coronary Artery Disease ◽  
Coronary Artery ◽  
Risk Score ◽  
Individual Risk ◽  
Risk Alleles ◽  
Genome Wide ◽  
Common Genetic Variants ◽  
Weighted Genetic Risk Score ◽  
Artery Disease ◽  
Cad Risk

Abstract Background: Epidemiological studies have repeatedly observed a markedly higher risk for coronary artery disease (CAD) in Scotland as compared to England. Up to now, it is unclear whether environmental or genetic factors might explain this phenomenon. Methods: Studying UK Biobank we assessed CAD risk based on the Framingham risk score (FRS) and common genetic variants to explore the respective contribution to CAD prevalence in Scotland (n=31,963) and England (n=317,889). We calculated FRS based on sex, age, body mass index, total cholesterol, high density lipoprotein cholesterol, systolic blood pressure, antihypertensive medication, smoking status, and diabetes. We determined the allele frequency of published genome-wide significant risk CAD alleles and a weighted genetic risk score (wGRS) for quantifying genetic CAD risk.Results: Prevalence of CAD was 16% higher in Scotland as compared to England (8.98% vs. 7.68%, P<0.001). By contrast, the FRS predicted a less than 1% higher CAD risk in Scotland (12.5±10.5 vs.12.6±10.6, P=0.03). Likewise, the overall number genome-wide significant variants affecting CAD risk (157.6±7.7 and 157.5±7.7; P=0.12) and a wGRS for CAD (2.49±0.25 in both populations, P=0.14) were remarkably similar in the English and Scottish population. Interestingly, we observed substantial differences with respect to the allele frequencies of individual risk variants. Of the previously described 163 genome-wide significant variants studied here 35 had higher frequencies in Scotland whereas 37 had higher frequencies in England (P<0.001 each).Conclusions: Neither the traditional risk factors included in the FRS nor a GRS based on established common risk alleles explained the higher CAD prevalence in Scotland. However, we observed marked differences in the distribution of individual risk alleles which emphasizes that even geographically and ethnically closely related populations may display relevant differences in the genetic architecture of a common disease.

scholarly journals Polygenic risk for coronary artery disease in the Scottish and English population

2021 ◽  
Vol 21 (1) ◽  
Author(s):  
Chuhua Yang ◽  
Fabian Starnecker ◽  
Shichao Pang ◽  
Zhifen Chen ◽  
Ulrich Güldener ◽  
...  
Keyword(s):  
Coronary Artery Disease ◽  
Coronary Artery ◽  
Risk Score ◽  
Genetic Risk ◽  
Genetic Risk Score ◽  
Individual Risk ◽  
Risk Alleles ◽  
Genome Wide ◽  
Artery Disease ◽  
Cad Risk

Abstract Background Epidemiological studies have repeatedly observed a markedly higher risk for coronary artery disease (CAD) in Scotland as compared to England. Up to now, it is unclear whether environmental or genetic factors might explain this phenomenon. Methods Using UK Biobank (UKB) data, we assessed CAD risk, based on the Framingham risk score (FRS) and common genetic variants, to explore the respective contribution to CAD prevalence in Scotland (n = 31,963) and England (n = 317,889). We calculated FRS based on sex, age, body mass index (BMI), total cholesterol (TC), high density lipoprotein cholesterol (HDL-C), systolic blood pressure (SBP), antihypertensive medication, smoking status, and diabetes. We determined the allele frequency of published genome-wide significant risk CAD alleles and a weighted genetic risk score (wGRS) for quantifying genetic CAD risk. Results Prevalence of CAD was 16% higher in Scotland as compared to England (8.98% vs. 7.68%, P < 0.001). However, the FRS only predicted a marginally higher CAD risk (less than 1%) in Scotland (12.5 ± 10.5 vs.12.6 ± 10.6, P = 0.03). Likewise, the overall number of genome-wide significant variants affecting CAD risk (157.6 ± 7.7 and 157.5 ± 7.7; P = 0.12) and a wGRS for CAD (2.49 ± 0.25 in both populations, P = 0.14) were remarkably similar in the English and Scottish population. Interestingly, we observed substantial differences in the allele frequencies of individual risk variants. Of the previously described 163 genome-wide significant variants studied here, 35 variants had higher frequencies in Scotland, whereas 37 had higher frequencies in England (P < 0.001 each). Conclusions Neither the traditional risk factors included in the FRS nor a genetic risk score (GRS) based on established common risk alleles explained the higher CAD prevalence in Scotland. However, we observed marked differences in the distribution of individual risk alleles, which emphasizes that even geographically and ethnically closely related populations may display relevant differences in the genetic architecture of a common disease.

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.

scholarly journals Acromegaly per se does not increase the risk for coronary artery disease

2010 ◽  
Vol 162 (5) ◽  
pp. 879-886 ◽  
Author(s):  
Hiroyoshi Akutsu ◽  
Jürgen Kreutzer ◽  
Gerald Wasmeier ◽  
Dieter Ropers ◽  
Christian Rost ◽  
...  
Keyword(s):  
Coronary Artery Disease ◽  
Coronary Artery ◽  
Risk Score ◽  
Successful Treatment ◽  
Cardiac Computed Tomography ◽  
Agatston Score ◽  
Per Se ◽  
Artery Disease ◽  
Cad Risk ◽  
Gh Excess

ContextInformation about the risk and course of coronary artery disease (CAD) in acromegaly is limited.ObjectiveTo evaluate CAD risk in acromegalic patients at diagnosis and after successful treatment during follow-up.Subjects and methodsTwenty-five consecutive patients (age 45.1±10.6 years, 15 women) were studied at the time of diagnosis, and 19 patients were re-evaluated after 4.6±1.1 years. The European Society of Cardiology (ESC) risk score was calculated, and a cardiac computed tomography was performed for detection and quantification (Agatston score (AS)) of coronary artery calcium (CACs). Fifty age-, sex-, and CAD risk-matched subjects and CAC data from the population-based Heinz Nixdorf Recall (HNR) study served as controls.ResultsIn 21 of the 25 patients, the 10-year risk of developing CAD according to the ESC risk score was low (<10%) and high (>20%) in four patients. The AS was lower than in controls (2.6±7.9 vs 66±182;P=0.014) and less patients had a positive CAC (AS>0) (20 vs 48%,P=0.024), which in the acromegalic patients was less than expected from the HNR study. The AS did not correlate with GH excess or disease duration. In 19 acromegalic patients, who were in remission and re-evaluated after 4.6±1.1 years, the ESC risk (P=0.102) and the AS (P=0.173) did not change significantly and no symptomatic CAD event occurred.ConclusionCAD risk in newly diagnosed acromegalic patients was low and remained stable after successful treatment. CAC was lower than in controls suggesting that GH excessper sedoes not carry an additional CAD risk.

4259Discovery of the first genome-wide significant risk loci for syncope and collapse

2019 ◽  
Vol 40 (Supplement_1) ◽  
Author(s):  
G Ahlberg ◽  
K Hadji-Turdeghal ◽  
L Andreasen ◽  
C M Hagen ◽  
J Ghouse ◽  
...  
Keyword(s):  
Coronary Artery Disease ◽  
Coronary Artery ◽  
Cerebral Arteries ◽  
European Ancestry ◽  
Carrier Status ◽  
Genome Wide ◽  
Common Genetic Variants ◽  
A Genome ◽  
Artery Disease ◽  
The Brain

Abstract Background Syncope is a common condition in the general population causing frequent hospitalisation and visits to the emergency department. Family aggregation and twin studies have previously indicated that syncope and collapse has a heritable component. Purpose We investigated whether common genetic variants predispose to syncope and collapse. Methods We used genome-wide association data on syncope and collapse for 408,961 individuals with European ancestry from the UK Biobank study. In a replication study, the Integrative Psychiatric Research Consortium (iPSYCH) cohort (n=86,189) was used to investigate the risk of incident syncope stratified by genotype carrier status. Results We report on a genome-wide significant locus on chromosome 2q32.1 with the lead SNP rs12465214 (odds ratio [OR] = 1.13, 95% confidence interval [CI] = 1.10–1.17, P=5.8x10–15; Figure 1a). This association was replicated in the iPSYCH cohort, where homozygous carriers of the C allele conferred an increased hazard ratio (HR=1.30, CI: 1.15–1.46, P=1.68x10–5; Figure 1b). LD score regression demonstrated a significant genetic correlation (rg) with coronary artery disease (rg=0.41, P=6.99x10–15) and related phenotypes such as angina and hypertension (Figure 1c). Analyses of eQTL (P=4x10–8) and epigenetic chromatin states revealed that variation in this locus likely affects expression of the gene ZNF804A, which resides in its proximity (Figure 1d). A qPCR analysis showed that ZNF804A was mostly expressed in the brain. A lower level of ZNF804A expression was also detected in the cerebral arteries. ZNF804A was not expressed in heart tissue. Figure 1 Conclusion rs12465214 is associated with syncope and collapse. Variation in this locus likely modulates the expression of the nearby gene ZNF804A through eQTLs and chromatin interactions. ZNF804A is mainly expressed in the brain and cerebral arteries. However, the precise function of ZNF804A is unknown. Furthermore, syncope and collapse is a polygenetic trait and share a significant genetic overlap with coronary artery disease, angina and hypertension. Acknowledgement/Funding This work was supported by grants from The John and Birthe Meyer Foundation, The Research Foundation of the Heart Centre, Rigshospitalet, The Research

scholarly journals B-PO02-164 GENOME-WIDE POLYGENIC RISK SCORE PREDICTS SUDDEN ARRHYTHMIC DEATH IN PATIENTS WITH CORONARY ARTERY DISEASE

Heart Rhythm ◽  
2021 ◽  
Vol 18 (8) ◽  
pp. S164-S165
Author(s):  
Roopinder K. Sandhu ◽  
Jacqueline Dron ◽  
Yunxian Liu ◽  
Manickavasagar Vinayagamoorthy ◽  
Nancy R. Cook ◽  
...  
Keyword(s):  
Coronary Artery Disease ◽  
Coronary Artery ◽  
Risk Score ◽  
Polygenic Risk Score ◽  
Polygenic Risk ◽  
Arrhythmic Death ◽  
Genome Wide ◽  
Artery Disease

scholarly journals Sexual Differences in Genetic Predisposition of Coronary Artery Disease

2020 ◽  
Author(s):  
Yunfeng Huang ◽  
Qin Hui ◽  
Marta Gwinn ◽  
Yi-Juan Hu ◽  
Arshed A. Quyyumi ◽  
...  
Keyword(s):  
Coronary Artery Disease ◽  
Coronary Artery ◽  
Risk Score ◽  
Genetic Risk ◽  
Genetic Risk Score ◽  
Risk Scores ◽  
Men And Women ◽  
High Genetic Risk ◽  
Genome Wide ◽  
Artery Disease

Background - The genomic structure that contributes to the risk of coronary artery disease (CAD) can be evaluated as a risk score of multiple variants. However, sex differences have not been fully examined in applications of genetic risk score of CAD. Methods - Using data from the UK Biobank, we constructed a CAD genetic risk score based on all known loci, three mediating trait-based (blood pressure, lipids, body mass index) sub-scores, and a genome-wide polygenic risk score based on 1.1 million variants. The differences in genetic associations with prevalent and incident CAD between men and women were investigated among 317,509 unrelated individuals of European ancestry. We also assessed interactions with sex for 161 individual loci included in the comprehensive genetic risk score. Results - For both prevalent and incident CAD, the associations of comprehensive and genome-wide genetic risk scores were stronger among men than women. Using a score of 161 loci, we observed a 2.4 times higher risk for incident CAD comparing men with high genetic risk to men with low genetic risk, but an 80 percent greater risk comparing women with high genetic risk to women with low genetic risk. (interaction p=0.002). Of the three sub-scores, the blood pressure-associated sub-score exhibited sex differences (interaction p=0.0004 per SD increase in sub-score). Analysis of individual variants identified a novel gene-sex interaction at locus 21q22.11 . Conclusions - Sexual differences in genetic predisposition should be considered in future studies of coronary artery disease, and genetic risk scores should not be assumed to perform equally well in men and women.

Abstract 3451: Risk for Coronary Artery Disease at the 9p21.3 Locus Is Abolished by a Protective Locus at 8p21.3 Identified by a Genome-Wide Association Study

Circulation ◽  
2008 ◽  
Vol 118 (suppl_18) ◽  
Author(s):  
Alexandre F Stewart ◽  
Ruth McPherson ◽  
Li Chen ◽  
Kathryn Williams ◽  
Heather Doelle ◽  
...  
Keyword(s):  
Coronary Artery Disease ◽  
Coronary Artery ◽  
Genome Wide Association ◽  
Genome Wide Association Studies ◽  
Genome Wide ◽  
A Genome ◽  
Genomic Study ◽  
Risk Locus ◽  
Artery Disease ◽  
Cad Risk

Background : Coronary artery disease (CAD) is the leading cause of death in the western world. The only common genetic risk locus identified to date by us and others in genome wide association studies (GWAS) resides at 9p21.3. Methods: The Ottawa Heart Genomic Study compared genotypes of 1,542 early onset CAD patients (average 49y) and 1,455 elderly control Caucasians (average 75y). Results: Here, we report two protective haplotypes in the 3′ region of the lipoprotein lipase (LPL) gene at 8p21.3. LPL promotes lipolysis of circulating triglycerides (TG) and increases levels of atheroprotective high density lipoprotein (HDL) cholesterol. Since the 8p21.3 haplotypes are protective, we tested their interaction with the 9p21.3 risk allele. The rs10503669 haplotype associated with elevated TG and HDL levels but did not affect risk from 9p21.3. In contrast, the rs17411031 haplotype was not associated with TG or HDL levels and showed a significant interaction that abolished 9p21.3 risk independent of known risk factors. The interaction was confirmed using data of the Wellcome Trust Case Control Consortium. Excluding carriers of the interacting allele, accuracy of 9p21.3 to predict CAD risk is dramatically improved. Conclusion: Identification of the first modifier gene of the 9p21.3 risk locus for CAD improves CAD risk assessment and provides novel insight into coronary atherosclerosis. This protective 8p21.3 locus may provide a target for novel therapy.

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.

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