Metabolic syndrome (MetSyn) is a group of metabolic conditions that occur together and promote the development of cardiovascular disease (CVD) and type 2 diabetes. Although various criteria for defining MetSyn exist, disease conditions include abdominal obesity, insulin resistance, elevated serum triglyceride levels, depressed serum high-density lipoprotein (HDL) levels, elevated blood glucose levels and hypertension. The incidence of MetSyn is predicted to increase as obesity has become a worldwide epidemic. This increase may have detrimental effects and may actually reverse the trend of decreasing CVD in the US. Recent genome-wide association studies (GWAS) have identified over 400 genomic loci that are associated with obesity, diabetes, CVD and cardiometabolic traits. However, most of the underlying genes and the related mechanisms of how these loci contribute to the disease process remain unknown. This proposal outlines an integrated systems genetics approach to identify causal genes and pathways underlying the GWAS loci by combining data from extensively phenotyped human and mouse cohorts that are part of the Metabolic Syndrome in Men (METSIM) and Hybrid Mouse Diversity Panel (HMDP) studies, respectively. It also outlines an extensive career development plan for Dr. Mete Civelek to complete postdoctoral training under the mentorship of Dr. Aldons Lusis and transition to an independent academic position by establishing a multi-disciplinary research program in cardiovascular pathophysiology. During the K99 phase of the award, the PI will measure adipose mRNA and microRNA abundance using expression arrays and next generation profiling from the human subjects which will be genotyped using high density SNP arrays. Similar measurements will be performed in mice. Significant genotype-expression trait associations at GWAS loci will be used to predict genes causally involved in the development of disease. Co- expression networks will be constructed from expression data and will be used to predict the relationships of causal genes with known pathways. Having predicted the causal genes and their functions during the K99 phase of the award, the PI will then test these predictions, using in vitro and in vivo experiments during the R00 phase of the award. The preliminary results have identified CPEB4, which encodes an RNA binding protein, as the causal gene underlying the significant association signal in the chromosome 5 locus for waist-to-hip ratio in humans. In vitro studies and bioinformatics approaches will identify the mRNAs that are targeted by this RNA binding protein. In vivo studies using adipocyte specific Cpeb4 transgenic and knock-out mice will identify its role in the regulation of fat mass and associated metabolic traits. The overall goal of the proposed studies is to integrate system biology and molecular analysis in both in vitro and in vivo experiments, leading to mechanistic understandings of the gene networks that are perturbed by disease-associated genetic variants that result in cardiometabolic disorders.

Public Health Relevance

Metabolic Syndrome is a primary cause of cardiovascular disease and diabetes. Understanding the biologic networks that underlie the complex interactions in metabolic syndrome traits is required for disease prevention, diagnosis, and treatment.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Career Transition Award (K99)
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Special Emphasis Panel (ZHL1-CSR-P (O1))
Program Officer
Carlson, Drew E
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University of California Los Angeles
Internal Medicine/Medicine
Schools of Medicine
Los Angeles
United States
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Dennis, J; Truong, V; Aïssi, D et al. (2016) Single nucleotide polymorphisms in an intergenic chromosome 2q region associated with tissue factor pathway inhibitor plasma levels and venous thromboembolism. J Thromb Haemost 14:1960-1970
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Kenagy, Richard D; Civelek, Mete; Kikuchi, Shinsuke et al. (2016) Scavenger receptor class A member 5 (SCARA5) and suprabasin (SBSN) are hub genes of coexpression network modules associated with peripheral vein graft patency. J Vasc Surg 64:202-209.e6
Codoni, Veronica; Blum, Yuna; Civelek, Mete et al. (2016) Preservation Analysis of Macrophage Gene Coexpression Between Human and Mouse Identifies PARK2 as a Genetically Controlled Master Regulator of Oxidative Phosphorylation in Humans. G3 (Bethesda) 6:3361-3371
Briot, Anaïs; Civelek, Mete; Seki, Atsuko et al. (2015) Endothelial NOTCH1 is suppressed by circulating lipids and antagonizes inflammation during atherosclerosis. J Exp Med 212:2147-63
Brænne, Ingrid; Civelek, Mete; Vilne, Baiba et al. (2015) Prediction of Causal Candidate Genes in Coronary Artery Disease Loci. Arterioscler Thromb Vasc Biol 35:2207-17
Soccio, Raymond E; Chen, Eric R; Rajapurkar, Satyajit R et al. (2015) Genetic Variation Determines PPAR? Function and Anti-diabetic Drug Response In Vivo. Cell 162:33-44
Bennett, Brian J; Davis, Richard C; Civelek, Mete et al. (2015) Genetic Architecture of Atherosclerosis in Mice: A Systems Genetics Analysis of Common Inbred Strains. PLoS Genet 11:e1005711
Roman, Tamara S; Marvelle, Amanda F; Fogarty, Marie P et al. (2015) Multiple Hepatic Regulatory Variants at the GALNT2 GWAS Locus Associated with High-Density Lipoprotein Cholesterol. Am J Hum Genet 97:801-15

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