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Regulatory variants in TCF7L2 are associated with thoracic aortic aneurysm
Tanmoy Roychowdhury1, Haocheng Lu1, Whitney E Hornsby1
1Department of Internal Medicine, Division of Cardiovascular Medicine, University of Michigan, Ann Arbor, MI 48109, USA.
American Journal of Human Genetics
|July 15, 2021
Summary
Genetic variants in TCF7L2 are linked to thoracic aortic aneurysm (TAA) risk, distinct from their role in type 2 diabetes. Increased TCF7L2 expression promotes cell death, contributing to TAA development.
Area of Science:
- Genetics
- Cardiovascular Disease
- Molecular Biology
Background:
- Thoracic aortic aneurysm (TAA) is a heritable condition involving aortic dilation, with unknown genetic origins for most cases.
- Previous research suggested common variants in FBN1 may influence TAA risk.
- Understanding the genetic basis of TAA is crucial for identifying at-risk individuals and developing targeted therapies.
Purpose of the Study:
- To identify novel genetic risk factors for thoracic aortic aneurysm (TAA).
- To investigate the functional role of identified genetic associations in TAA pathogenesis.
Main Methods:
- Genome-wide association study (GWAS) in 1,351 TAA cases and 18,295 controls.
- Replication and meta-analysis across four independent cohorts.
- In vitro studies to explore the functional impact of TCF7L2 expression.
Main Results:
- A genome-wide significant association between TAA and variants in the third intron of TCF7L2 was identified.
- The TCF7L2 locus shows an opposite direction of effect for TAA compared to type 2 diabetes.
- Genetic association colocalizes with an aortic expression quantitative trait locus (eQTL) for TCF7L2, suggesting higher expression increases TAA risk.
Conclusions:
- Common variants in TCF7L2 represent a significant genetic risk factor for thoracic aortic aneurysm (TAA).
- Upregulation of TCF7L2 promotes vascular smooth muscle cell apoptosis via BCL2 repression, a key mechanism in TAA.
- TCF7L2 plays a distinct role in TAA pathogenesis compared to its established role in type 2 diabetes.
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