Chen Heng, Chen Siyuan, Ye Hengni, Guo Xiaogang
Department of Cardiology, The First Affiliated Hospital, Zhejiang University School of Medicine, 79 Qingchun Road, Hangzhou 310003, China.
Stomatology Hospital, School of Stomatology, Zhejiang University School of Medicine, Zhejiang Provincial Clinical Research Center for Oral Diseases, Key Laboratory of Oral Biomedical Research of Zhejiang Province, Cancer Center of Zhejiang University, Hangzhou 310003, China.
J Cardiovasc Dev Dis. 2022 Aug 18;9(8):277. doi: 10.3390/jcdd9080277.
Tissue inhibitor of metalloproteinase 3 (TIMP3) is a protease with high expression levels in the heart and plays an essential role in extracellular matrix turnover by maintaining equilibrium with matrix metalloproteinases. Considerable data in experimental models have demonstrated a protective role of TIMP3 in coronary artery disease (CAD) and myocardial infarction (MI). However, causality remains unexplored in population studies. Here, we sought to decipher the potential causality between TIMP3 and CAD/MI using the Mendelian randomization (MR) method. We extracted summary-level datasets for TIMP3 and CAD/MI from the genome-wide association studies performed in the KORA study and CARDIoGRAMplusC4D consortium, respectively. Seven independent SNPs were obtained as instrumental variables for TIMP3. The MR analyses were replicated using FinnGen datasets, and the main results were combined in meta-analyses. Elevated genetically predicted serum TIMP3 levels were causally associated with a lower risk of CAD [odds ratio (OR), 0.97; 95% confidence interval (CI), 0.95, 0.98; = 5.29 × 10] and MI (OR, 0.96; 95% CI, 0.95, 0.98; = 3.85 × 10). The association patterns persisted in the meta-analyses combining the different datasets (CAD: OR, 0.97; 95% CI, 0.96, 0.99; = 4.37 × 10; MI: OR, 0.97; 95% CI, 0.96, 0.99; = 9.96 × 10) and was broadly consistent across a set of complementary analyses. Evidence of heterogeneity and horizontal pleiotropy was limited for all associations considered. In conclusion, this MR study supports inverse causal associations between serum TIMP3 and the risk of CAD and MI. Strategies for raising TIMP3 levels may offer new avenues for the prevention strategies of atherosclerotic cardiovascular diseases.
金属蛋白酶组织抑制剂3（TIMP3）是一种在心脏中高表达的蛋白酶，通过与基质金属蛋白酶保持平衡，在细胞外基质周转中发挥重要作用。实验模型中的大量数据表明，TIMP3在冠状动脉疾病（CAD）和心肌梗死（MI）中具有保护作用。然而，在人群研究中，因果关系仍未得到探索。在此，我们试图使用孟德尔随机化（MR）方法来解读TIMP3与CAD/MI之间的潜在因果关系。我们分别从在KORA研究和CARDIoGRAMplusC4D联盟中进行的全基因组关联研究中提取了TIMP3和CAD/MI的汇总水平数据集。获得了7个独立的单核苷酸多态性（SNP）作为TIMP3的工具变量。使用芬兰基因组数据集重复进行MR分析，并将主要结果合并进行荟萃分析。遗传预测的血清TIMP3水平升高与CAD风险降低存在因果关联[比值比（OR），0.97；95%置信区间（CI），0.95，0.98；P = 5.29×10⁻⁵]以及MI风险降低（OR，0.96；95%CI，0.95，0.98；P = 3.85×10⁻⁴）。在合并不同数据集的荟萃分析中，关联模式持续存在（CAD：OR，0.97；95%CI，0.96，0.99；P = 4.37×10⁻³；MI：OR，0.97；95%CI，0.96，0.99；P = 9.96×10⁻²），并且在一系列补充分析中大致一致。对于所有考虑的关联，异质性和水平多效性的证据有限。总之，这项MR研究支持血清TIMP3与CAD和MI风险之间的反向因果关联。提高TIMP3水平的策略可能为动脉粥样硬化性心血管疾病的预防策略提供新途径。
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