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 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

scholarly journals A Genome-Wide Association Study Identifies LIPA as a Susceptibility Gene for Coronary Artery Disease

2011 ◽  
Vol 4 (4) ◽  
pp. 403-412 ◽  
Author(s):  
Philipp S. Wild ◽  
Tanja Zeller ◽  
Arne Schillert ◽  
Silke Szymczak ◽  
Christoph R. Sinning ◽  
...  
Keyword(s):  
Coronary Artery Disease ◽  
Coronary Artery ◽  
Association Study ◽  
Genome Wide Association Study ◽  
Susceptibility Gene ◽  
Genome Wide Association ◽  
Genome Wide ◽  
A Genome ◽  
Artery Disease

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.

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