Browsing by Author "Vander Heide, Richard S."

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    Bioinformatic Analysis of Coronary Disease Associated SNPs and Genes to Identify Proteins Potentially Involved in the Pathogenesis of Atherosclerosis
    Mao, Chunhong; Howard, Timothy D.; Sullivan, Dan; Fu, Zongming; Yu, Guoqiang; Parker, Sarah J.; Will, Rebecca; Vander Heide, Richard S.; Wang, Yue; Hixson, James; Van Eyk, Jennifer; Herrington, David M. (Open Access Pub, 2017-03-04)
    Factors that contribute to the onset of atherosclerosis may be elucidated by bioinformatic techniques applied to multiple sources of genomic and proteomic data. The results of genome wide association studies, such as the CardioGramPlusC4D study, expression data, such as that available from expression quantitative trait loci (eQTL) databases, along with protein interaction and pathway data available in Ingenuity Pathway Analysis (IPA), constitute a substantial set of data amenable to bioinformatics analysis. This study used bioinformatic analyses of recent genome wide association data to identify a seed set of genes likely associated with atherosclerosis. The set was expanded to include protein interaction candidates to create a network of proteins possibly influencing the onset and progression of atherosclerosis. Local average connectivity (LAC), eigenvector centrality, and betweenness metrics were calculated for the interaction network to identify top gene and protein candidates for a better understanding of the atherosclerotic disease process. The top ranking genes included some known to be involved with cardiovascular disease (APOA1, APOA5, APOB, APOC1, APOC2, APOE, CDKN1A, CXCL12, SCARB1, SMARCA4 and TERT), and others that are less obvious and require further investigation (TP53, MYC, PPARG, YWHAQ, RB1, AR, ESR1, EGFR, UBC and YWHAZ). Collectively these data help define a more focused set of genes that likely play a pivotal role in the pathogenesis of atherosclerosis and are therefore natural targets for novel therapeutic interventions.
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    Whole Exome Sequencing to Identify Genetic Variants Associated with Raised Atherosclerotic Lesions in Young Persons
    Hixson, James E.; Jun, Goo; Shimmin, Lawrence C.; Wang, Yizhi; Yu, Guoqiang; Mao, Chunhong; Warren, Andrew S.; Howard, Timothy D.; Vander Heide, Richard S.; Van Eyk, Jennifer E.; Wang, Yue; Herrington, David M. (Springer Nature, 2017-06-22)
    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 exomewide 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.