Whole Exome Sequencing to Identify Genetic Variants Associated with Raised Atherosclerotic Lesions in Young Persons

Abstract We investigated the influence of genetic variants on atherosclerosis using whole exome sequencing in cases and controls from the autopsy study “Pathobiological Determinants of Atherosclerosis in Youth (PDAY)”. We identified a PDAY case group with the highest total amounts of raised lesions...

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Autores principales: James E. Hixson, Goo Jun, Lawrence C. Shimmin, Yizhi Wang, Guoqiang Yu, Chunhong Mao, Andrew S. Warren, Timothy D. Howard, Richard S. Vander Heide, Jennifer Van Eyk, Yue Wang, David M. Herrington
Formato: article
Lenguaje:EN
Publicado: Nature Portfolio 2017
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Acceso en línea:https://doaj.org/article/485c84a505f64a21bc57f4bf322cab09
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Sumario:Abstract We investigated the influence of genetic variants on atherosclerosis using whole exome sequencing in cases and controls from the autopsy study “Pathobiological Determinants of Atherosclerosis in Youth (PDAY)”. We identified a PDAY case group with the highest total amounts of raised lesions (n = 359) for comparisons with a control group with no detectable raised lesions (n = 626). In addition to the standard exome capture, we included genome-wide proximal promoter regions that contain sequences that regulate gene expression. Our statistical analyses included single variant analysis for common variants (MAF > 0.01) and rare variant analysis for low frequency and rare variants (MAF < 0.05). In addition, we investigated known CAD genes previously identified by meta-analysis of GWAS studies. We did not identify individual common variants that reached exome-wide significance using single variant analysis. In analysis limited to 60 CAD genes, we detected strong associations with COL4A2/COL4A1 that also previously showed associations with myocardial infarction and arterial stiffness, as well as coronary artery calcification. Likewise, rare variant analysis did not identify genes that reached exome-wide significance. Among the 60 CAD genes, the strongest association was with NBEAL1 that was also identified in gene-based analysis of whole exome sequencing for early onset myocardial infarction.