학술논문
Regulatory variants in TCF7L2 are associated with thoracic aortic aneurysm.
Document Type
Article
Author
Roychowdhury, Tanmoy; Lu, Haocheng; Hornsby, Whitney E.; Crone, Bradley; Wang, Gao T.; Guo, Dong-chuan; Sendamarai, Anoop K.; Devineni, Poornima; Lin, Maoxuan; Zhou, Wei; Graham, Sarah E.; Wolford, Brooke N.; Surakka, Ida; Wang, Zhenguo; Chang, Lin; Zhang, Jifeng; Mathis, Michael; Brummett, Chad M.; Melendez, Tori L.; Shea, Michael J.
Source
Subject
*THORACIC aneurysms
*VASCULAR smooth muscle
*THORACIC aorta
*GENOME-wide association studies
*TYPE 2 diabetes
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Language
ISSN
0002-9297
Abstract
Thoracic aortic aneurysm (TAA) is characterized by dilation of the aortic root or ascending/descending aorta. TAA is a heritable disease that can be potentially life threatening. While 10%–20% of TAA cases are caused by rare, pathogenic variants in single genes, the origin of the majority of TAA cases remains unknown. A previous study implicated common variants in FBN1 with TAA disease risk. Here, we report a genome-wide scan of 1,351 TAA-affected individuals and 18,295 control individuals from the Cardiovascular Health Improvement Project and Michigan Genomics Initiative at the University of Michigan. We identified a genome-wide significant association with TAA for variants within the third intron of TCF7L2 following replication with meta-analysis of four additional independent cohorts. Common variants in this locus are the strongest known genetic risk factor for type 2 diabetes. Although evidence indicates the presence of different causal variants for TAA and type 2 diabetes at this locus, we observed an opposite direction of effect. The genetic association for TAA colocalizes with an aortic eQTL of TCF7L2 , suggesting a functional relationship. These analyses predict an association of higher expression of TCF7L2 with TAA disease risk. In vitro , we show that upregulation of TCF7L2 is associated with BCL2 repression promoting vascular smooth muscle cell apoptosis, a key driver of TAA disease. [ABSTRACT FROM AUTHOR]