BME Seminar Series: Mete Civelek, PhD, University of Virginia

All dates for this event occur in the past.

In-person 2000 Fontana Labs
https://osu.zoom.us/j/96668659430?pwd=Wm1NNU55cFJtWlhyM3Rvc1BLYUtZQT09
Password: 531165
United States

Mete Civelek, PhD
Associate Professor
Department of Biomedical Engineering
University of Virginia

Abstract:

"Systems Genetics Analysis of Smooth Muscle Cell Phenotypes"

Recent meta-analyses of genome-wide association studies (GWAS) have identified over 200 loci associated with coronary artery disease. The majority of these loci are in non-coding regions and are predicted to regulate gene expression. Given that vascular smooth muscle cells (SMCs) play critical roles in the development and progression of CAD, we used a systems genetics approach to identify the subset of the CAD GWAS risk loci that are associated with the regulation of cellular and molecular phenotypes of SMCs that represent various stages of atherosclerosis. We isolated SMCs from the ascending aortas of 151 heart transplant donors with diverse genetic ancestries and cultured them in quiescent and proliferative conditions. We genotyped them for ~6.3 million single nucleotide polymorphisms (SNPs). We measured the extent of migration, proliferation, and calcification, as well as gene expression. We calculated the associations of SNPs with cellular phenotypes, mRNA expression, mRNA splicing and circular RNA expression. To predict the causal cellular and molecular mechanisms of GWAS loci, we overlapped the genetic loci associated with cellular phenotypes and gene expression with vascular disease-related GWAS loci using Bayesian colocalization approaches. We identified 79 CAD loci associated with migration, proliferation, or calcification. Further, 84 and 164 CAD loci were associated with SMC mRNA expression and splicing, respectively. Lastly, to identify the relevance of circRNAs in cardiovascular disease, we overlapped genetic loci associated with circRNA expression with vascular disease-related GWAS loci. We identified 14 blood pressure, one myocardial infarction, and three coronary artery disease loci, which were associated with a circRNA transcript but not an mRNA transcript. Collectively, our results predicted candidate causal genes affecting various atherosclerosis-relevant SMC phenotypes that modulate the genetic risk for CAD. Some of the loci act differentially in quiescent and proliferative SMC phenotypes emulating different stages of atherosclerosis. They also have distinct effects in males and females, and some are SMC-specific. Our results provide evidence for the complexity of the cellular and molecular mechanisms of CAD loci.

Bio: 

Dr. Mete Civelek is an Associate Professor of Biomedical Engineering at the University of Virginia. He is also a resident faculty member of the Center for Public Health Genomics and the chair of the Diversity, Equity, and Inclusion Committee of the BME department. He received his Ph.D. in Bioengineering from the University of Pennsylvania and was a postdoctoral fellow in Human Genetics at the University of California Los Angeles.  His laboratory focuses on identifying the genetic mechanisms that lead to increased susceptibility to cardiovascular and metabolic diseases. His work is supported by the American Heart Association, American Diabetes Association, Leducq Foundation, National Institute of Diabetes and Digestive and Kidney Diseases, and National Heart Lung and Blood Institute. He is a fellow of the American Heart Association, chair of the Program Committee of the American Society of Human Genetics, and a member of the leadership team of the HHMI-supported Driving Change Program, which aims to generate a transformative change to enable students from all backgrounds to excel in STEM, at the University of Virginia.

 

 

Category: Seminar Series