scholarly journals Genome-Wide Variants Associated With Longitudinal Survival Outcomes Among Individuals With Coronary Artery Disease

2021 ◽  
Vol 12 ◽  
Author(s):  
Jennifer R. Dungan ◽  
Xue Qin ◽  
Melissa Hurdle ◽  
Carol S. Haynes ◽  
Elizabeth R. Hauser ◽  
...  
Keyword(s):  
Coronary Artery Disease ◽  
Coronary Artery ◽  
Candidate Genes ◽  
Meta Analysis ◽  
Survival Outcomes ◽  
Genome Wide ◽  
A Genome ◽  
Clinical Covariates ◽  
All Cause Mortality ◽  
Artery Disease

ObjectiveCoronary artery disease (CAD) is an age-associated condition that greatly increases the risk of mortality. The purpose of this study was to identify gene variants associated with all-cause mortality among individuals with clinically phenotyped CAD using a genome-wide screening approach.Approach and ResultsWe performed discovery (n = 1,099), replication (n = 404), and meta-analyses (N = 1,503) for association of genomic variants with survival outcome using secondary data from White participants with CAD from two GWAS sub-studies of the Duke Catheterization Genetics Biorepository. We modeled time from catheterization to death or last follow-up (median 7.1 years, max 12 years) using Cox multivariable regression analysis. Target statistical screening thresholds were p × 10–8 for the discovery phase and Bonferroni-calculated p-values for the replication (p < 5.3 × 10–4) and meta-analysis (p < 1.6 × 10–3) phases. Genome-wide analysis of 785,945 autosomal SNPs revealed two SNPs (rs13007553 and rs587936) that had the same direction of effect across all three phases of the analysis, with suggestive p-value association in discovery and replication and significant meta-analysis association in models adjusted for clinical covariates. The rs13007553 SNP variant, LINC01250, which resides between MYTIL and EIPR1, conferred increased risk for all-cause mortality even after controlling for clinical covariates [HR 1.47, 95% CI 1.17–1.86, p(adj) = 1.07 × 10–3 (discovery), p(adj) = 0.03 (replication), p(adj) = 9.53 × 10–5 (meta-analysis)]. MYT1L is involved in neuronal differentiation. TSSC1 is involved in endosomal recycling and is implicated in breast cancer. The rs587936 variant annotated to DAB2IP was associated with increased survival time [HR 0.65, 95% CI 0.51–0.83, p(adj) = 4.79 × 10–4 (discovery), p(adj) = 0.02 (replication), p(adj) = 2.25 × 10–5 (meta-analysis)]. DAB2IP is a ras/GAP tumor suppressor gene which is highly expressed in vascular tissue. DAB2IP has multiple lines of evidence for protection against atherosclerosis.ConclusionReplicated findings identified two candidate genes for further study regarding association with survival in high-risk CAD patients: novel loci LINC01250 (rs13007553) and biologically relevant candidate DAB2IP (rs587936). These candidates did not overlap with validated longevity candidate genes. Future research could further define the role of common variants in survival outcomes for people with CAD and, ultimately, improve longitudinal outcomes for these patients.

Abstract 447: Deep Transcriptomic Analysis of Human Vascular Cells Identifies Risk Genes for Common Vascular Diseases

2017 ◽  
Vol 37 (suppl_1) ◽  
Author(s):  
Sylvia T Nurnberg ◽  
YoSon Park ◽  
Jordi Vaquero-Garcia ◽  
Milos Pjanic ◽  
Susanna Elwyn ◽  
...  
Keyword(s):  
Coronary Artery Disease ◽  
Coronary Artery ◽  
Genetic Susceptibility ◽  
Meta Analysis ◽  
Genome Wide Association ◽  
Genome Wide ◽  
A Genome ◽  
Allele Specific ◽  
Artery Disease ◽  
Shared Genetic

The most recent Genome-wide Association Study (GWAS) meta-analysis has reported a total of 58 genomic loci to be statistically significantly associated with genetic susceptibility to Coronary Artery Disease (CAD) (Consortium, 2015). Many of these loci also associate with other phenotypes, with the majority being lipid traits (Tada et al., 2014). But also hypertension, stroke (Dichgans et al., 2014) and migraine (Pickrell et al., 2016) appear to share genetic determinants with CAD. To functionally annotate the genomic loci harboring these association SNPs we sequenced the transcriptomes of 20 same donor human coronary artery endothelial (EC) and smooth muscle cell (SMC) lines. Deep RNA-Sequencing was used to assess Differential Gene Expression, Differential Splicing and Allele-Specific Expression. Focusing on GWAS loci for vascular phenotypes (CAD, stroke, migraine) we identified genes which display allele-specific differences in mRNA expression or splicing. We propose these genes as suitable targets for follow up studies. Consortium, C.A.D. (2015). A comprehensive 1000 Genomes-based genome-wide association meta-analysis of coronary artery disease. Nature genetics 47, 1121-1130. Tada, H., Won, H.H., Melander, O., Yang, J., Peloso, G.M., and Kathiresan, S. (2014). Multiple associated variants increase the heritability explained for plasma lipids and coronary artery disease. Circulation Cardiovascular genetics 7, 583-587. Dichgans, M., Malik, R., Konig, I.R., Rosand, J., Clarke, R., Gretarsdottir, S., Thorleifsson, G., Mitchell, B.D., Assimes, T.L., Levi, C., et al. (2014). Shared genetic susceptibility to ischemic stroke and coronary artery disease: a genome-wide analysis of common variants. Stroke; a journal of cerebral circulation 45, 24-36. Pickrell, J.K., Berisa, T., Liu, J.Z., Segurel, L., Tung, J.Y., and Hinds, D.A. (2016). Detection and interpretation of shared genetic influences on 42 human traits. Nature genetics 48, 709-717.

scholarly journals Corrigendum: Genome-Wide Variants Associated With Longitudinal Survival Outcomes Among Individuals With Coronary Artery Disease

2021 ◽  
Vol 12 ◽  
Author(s):  
Jennifer R. Dungan ◽  
Xue Qin ◽  
Melissa Hurdle ◽  
Carol S. Haynes ◽  
Elizabeth R. Hauser ◽  
...  
Keyword(s):  
Coronary Artery Disease ◽  
Coronary Artery ◽  
Survival Outcomes ◽  
Genome Wide ◽  
Artery Disease

scholarly journals Validation of a Genome-Wide Polygenic Score for Coronary Artery Disease in South Asians

2020 ◽  
Vol 76 (6) ◽  
pp. 703-714 ◽  
Author(s):  
Minxian Wang ◽  
Ramesh Menon ◽  
Sanghamitra Mishra ◽  
Aniruddh P. Patel ◽  
Mark Chaffin ◽  
...  
Keyword(s):  
Coronary Artery Disease ◽  
Coronary Artery ◽  
South Asians ◽  
Polygenic Score ◽  
Genome Wide ◽  
A Genome ◽  
Artery Disease

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

Rheumatoid Arthritis and Coronary Artery Disease: Genetic Analyses Do Not Support a Causal Relation

2016 ◽  
Vol 44 (1) ◽  
pp. 4-10 ◽  
Author(s):  
Henning Jansen ◽  
Christina Willenborg ◽  
Wolfgang Lieb ◽  
Lingyao Zeng ◽  
Paola Gloria Ferrario ◽  
...  
Keyword(s):  
Rheumatoid Arthritis ◽  
Coronary Artery Disease ◽  
Coronary Artery ◽  
Inflammatory Diseases ◽  
Causal Relation ◽  
Meta Analysis ◽  
Density Lipoprotein ◽  
Nucleotide Polymorphisms ◽  
Genome Wide ◽  
Artery Disease

Objective.Inflammatory diseases, specifically rheumatoid arthritis (RA), are assumed to increase the risk of coronary artery disease (CAD). More recently, multiple single-nucleotide polymorphisms (SNP) associated with RA risk were identified. If causal mechanisms affecting risks of RA and CAD are overlapping, risk alleles for RA might also increase the risk of CAD.Methods.Sixty-one SNP associating with RA in genome-wide significant analyses were tested for association with CAD in CARDIoGRAM (Coronary ARtery DIsease Genome wide Replication and Meta-analysis), a metaanalysis including genome-wide association data (22,233 CAD cases, 64,762 controls). In parallel, a set of SNP being associated with low-density lipoprotein cholesterol (LDL-C) was tested as a positive control.Results.Twenty-nine RA-associated SNP displayed a directionality-consistent association with CAD (OR range 1.002–1.073), whereas 32 RA-associated SNP were not associated with CAD (OR range 0.96–0.99 per RA risk-increasing allele). The proportion (48%) of directionality-consistent associated SNP equaled the proportion expected by chance (50%, p = 0.09). Of only 5 RA-associated SNP showing p values for CAD < 0.05, 4 loci (C5orf30, IL-6R, PTPN22, and RAD51B) showed directionality-consistent effects on CAD, and 1 (rs10774624, locus SH2B3) reached study-wide significance (p = 7.29E-06). By contrast, and as a proof of concept, 46 (74%) out of 62 LDL-C–associated SNP displayed a directionality-consistent association with CAD, a proportion that was significantly different from 50% (p = 5.9E-05).Conclusion.We found no evidence that RA-associated SNP as a group are associated with CAD. Even though we were not able to study potential effects of all genetic variants individually, shared nongenetic factors may more plausibly explain the observed coincidence of the 2 conditions.

scholarly journals Shared genetic risk between migraine and coronary artery disease: A genome-wide analysis of common variants

PLoS ONE ◽  
2017 ◽  
Vol 12 (9) ◽  
pp. e0185663 ◽  
Author(s):  
Bendik S. Winsvold ◽  
Francesco Bettella ◽  
Aree Witoelar ◽  
Verneri Anttila ◽  
Padhraig Gormley ◽  
...  
Keyword(s):  
Coronary Artery Disease ◽  
Coronary Artery ◽  
Genetic Risk ◽  
Common Variants ◽  
Genome Wide Analysis ◽  
Genome Wide ◽  
A Genome ◽  
Artery Disease ◽  
Shared Genetic
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