PDF(Pubmed)
Abstract：
Background: Cardiovascular diseases (CVDs) are the leading age-related disorders worldwide, with their prevalence increasing annually. Cathepsins are protein-degrading enzymes essential for processes such as intracellular protein breakdown, apoptosis, and immune responses. Recent studies suggest a potential link between cathepsins and CVDs, yet the exact causal relationship remains to be elucidated. To address this, we propose using Mendelian randomization (MR) to explore the causal relationships between cathepsins and CVDs. Methods: We obtained single nucleotide polymorphism (SNP) data for cathepsins from the INTERVAL study, a publicly accessible genome-wide association study (GWAS) dataset. Outcome SNP data were sourced from seven distinct GWAS datasets, ensuring a comprehensive analysis across multiple cardiovascular outcomes. For MR analysis, we primarily employed the inverse variance weighted (IVW) method, known for its efficiency when all SNPs are valid instruments. This was supplemented by the weighted median and MR-Egger methods to provide robustness against potential violations of MR assumptions, such as pleiotropy. The IVW method offers precision and efficiency, the weighted median method adds robustness against invalid instruments, and the MR-Egger method helps identify and correct for pleiotropic biases. Cochran\'s Q test was utilized to assess heterogeneity, and sensitivity analyses were conducted using MR-PRESSO and the leave-one-out approach. Results: The strength of the associations between exposure and outcome was measured using odds ratios (ORs), and results were presented with 95% confidence intervals (CIs). The cathepsin E increases the risk of myocardial infarction (MI) (OR = 1.053%, 95% CI: 1.007-1.101, p = 0.024) and ischemic stroke (IS) (OR = 1.06%, 95% CI: 1.019-1.103, p = 0.004). Conversely, cathepsin L2 decreases the risk of chronic heart failure (CHF) (OR = 0.922%, 95% CI: 0.859-0.99, p = 0.025) and atrial fibrillation (AF) (OR = 0.956%, 95% CI: 0.918-0.996, p = 0.033). Cathepsin O was associated with an increased risk of IS (OR = 1.054%, 95% CI: 1.008-1.102, p = 0.021) and AF (OR = 1.058%, 95% CI: 1.02-1.098, p = 0.002). Conclusion: Our MR analysis reveals that cathepsin E is a risk factor for MI and IS, cathepsin L2 offers protective effects against CHF and AF, and cathepsin O increases the risk for IS and AF.
摘要：
背景：心血管疾病（CVDs）是全球主要的与年龄相关的疾病，他们的患病率每年都在增加。组织蛋白酶是细胞内蛋白质分解过程所必需的蛋白质降解酶，凋亡，和免疫反应。最近的研究表明，组织蛋白酶和心血管疾病之间存在潜在的联系，然而，确切的因果关系仍有待阐明。为了解决这个问题，我们建议使用孟德尔随机化(MR)来探索组织蛋白酶和CVD之间的因果关系.方法：我们从INTERVAL研究中获得了组织蛋白酶的单核苷酸多态性（SNP）数据，可公开获取的全基因组关联研究(GWAS)数据集.结果SNP数据来自七个不同的GWAS数据集，确保对多种心血管结局进行全面分析。对于MR分析，我们主要采用逆方差加权(IVW)方法，当所有SNP都是有效工具时，以其效率而闻名。通过加权中位数和MR-Egger方法进行了补充，以提供对可能违反MR假设的稳健性。比如多功能性。IVW方法提供了精度和效率，加权中位数方法增加了对无效工具的鲁棒性，MR-Egger方法有助于识别和纠正多效性偏差。Cochran的Q检验用于评估异质性，使用MR-PRESSO和留一法进行敏感性分析。结果：使用比值比(OR)衡量暴露与结果之间的关联强度，结果以95%置信区间(CI)表示。组织蛋白酶E增加心肌梗死(MI)的风险(OR=1.053%,95%CI：1.007-1.101，p=0.024）和缺血性卒中（IS）（OR=1.06%，95%CI：1.019-1.103，p=0.004）。相反，组织蛋白酶L2降低慢性心力衰竭（CHF）的风险（OR=0.922%，95%CI:0.859-0.99,p=0.025)和心房颤动(AF)(OR=0.956%,95%CI：0.918-0.996，p=0.033）。组织蛋白酶O与IS风险增加相关(OR=1.054%,95%CI：1.008-1.102，p=0.021）和AF（OR=1.058%，95%CI：1.02-1.098，p=0.002）。结论：我们的MR分析显示组织蛋白酶E是MI和IS的危险因素，组织蛋白酶L2对CHF和AF具有保护作用，和组织蛋白酶O增加IS和AF的风险。
