Department of Internal Medicine, Division of Cardiovascular Medicine, University of Michigan, Ann Arbor, MI 48109, USA.
Department of Computational Medicine and Bioinformatics, University of Michigan, Ann Arbor, MI 48109, USA.
Am J Hum Genet. 2021 Sep 2;108(9):1578-1589. doi: 10.1016/j.ajhg.2021.06.016. Epub 2021 Jul 14.
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.
胸主动脉瘤（TAA）的特征是主动脉根部或升主动脉/降主动脉扩张。TAA 是一种遗传性疾病，可能对生命构成威胁。虽然 10%-20%的 TAA 病例是由单个基因中罕见的致病性变异引起的，但大多数 TAA 病例的起源仍然未知。先前的研究表明，FBN1 中的常见变异与 TAA 疾病风险有关。在这里，我们报告了对 1351 名 TAA 受影响个体和 18295 名对照个体进行的全基因组扫描，这些个体来自密歇根大学心血管健康改善项目和密歇根基因组倡议。我们在对另外四个独立队列进行荟萃分析后，在 TCF7L2 的第三个内含子内发现了与 TAA 相关的全基因组显著关联。该基因座中的常见变异是 2 型糖尿病最强的已知遗传风险因素。尽管证据表明该基因座上存在 TAA 和 2 型糖尿病的不同因果变异，但我们观察到了相反的效果。TAA 的遗传关联与 TCF7L2 的主动脉 eQTL 重合，表明存在功能关系。这些分析预测 TCF7L2 表达升高与 TAA 疾病风险相关。在体外，我们表明 TCF7L2 的上调与 BCL2 抑制有关，促进血管平滑肌细胞凋亡，这是 TAA 疾病的关键驱动因素。
