Regulatory variants in TCF7L2 are associated with thoracic aortic aneurysm.
СтатьяПоддержка NIH: внешняя программаПоддержка исследования: вне правительства СШАПоддержка правительства СШАНазвание и аннотация: Перевод пока не подготовлен
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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, Kim Karen Meekyong, Deeb G Michael, Patel Himanshu J, Eliason Jonathan, Eagle Kim A, Yang Bo, Ganesh Santhi K, Brumpton Ben, Åsvold Bjørn Olav, Skogholt Anne Heidi, Hveem Kristian, VA Million Veteran Program, Pyarajan Saiju, Klarin Derek, Tsao Philip S, Damrauer Scott M, Leal Suzanne M, Milewicz Dianna M, Chen Y Eugene, Garcia-Barrio Minerva T, Willer Cristen J
Аннотация
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.