Bai Chao, Yang Wenwen, Qi Guangwei, Yang Liuyu, Wu Qingrui, Peng Jieguang, Wang Ning, Liu Tao
Vascular and Thyroid Surgery, The First Affiliated Hospital of Xinjiang Medical University, Urumqi, Xinjiang, China.
Postdoctoral Research Station of Public Health and Preventive Medicine, Xinjiang Medical University, Urumqi, Xinjiang, China.
Front Endocrinol (Lausanne). 2025 Jan 14;15:1429121. doi: 10.3389/fendo.2024.1429121. eCollection 2024.
Diabetic neuropathy (DN), a common and debilitating complication of diabetes, significantly impairs the quality of life of affected individuals. While multiple studies have indicated changes in the expression of specific matrix metalloproteinases (MMPs) in patients with DN, and basic research has reported the impact of MMPs on DN, there is a lack of systematic research and the causal relationship remains unclear. The objective of this research is to investigate the casual relationship between MMPs and DN through two-sample Mendelian randomization (MR).
Data for this investigation were derived from genome-wide association studies (GWAS) of MMPs and DN. For the analysis using two-sample MR, methods such as inverse variance weighted (IVW), weighted median, weighted mode, and MR-Egger were utilized, with IVW serving as the primary measure for determining causative impacts. To evaluate the analysis' heterogeneity and potential pleiotropy, sensitivity examinations including MR-PRESSO analysis, Cochran's Q test, and the leave-one-out test were conducted.
IVW analysis revealed that genetically decreased serum MMP-2 level were causally associated with a high risk of DN (OR = 0.88, 95% CI: 0.79-0.99, P = 0.026). Genetically elevated serum MMP-16 level were causally associated with a high risk of DN (OR = 1.15, 95% CI: 1.01-1.32, P = 0.038). Genetic prediction results showed no causal association between other MMPs (MMP14/17/9/12/7/3) and DN. Sensitivity analyses showed no significant heterogeneity or pleiotropy.
In summary, this research uncovered a genetic causal relationship between heightened MMP-16 levels and reduced MMP-2 concentrations, and DN risk. These discoveries offer new perspectives on the role of MMPs in DN etiology and establish a foundational premise for further investigations into MMP-targeted therapeutic interventions.
糖尿病神经病变（DN）是糖尿病常见且使人衰弱的并发症，严重损害患者的生活质量。尽管多项研究表明DN患者体内特定基质金属蛋白酶（MMPs）的表达有变化，且基础研究报道了MMPs对DN的影响，但缺乏系统研究，因果关系仍不明确。本研究的目的是通过两样本孟德尔随机化（MR）研究MMPs与DN之间的因果关系。
本研究的数据来自MMPs和DN的全基因组关联研究（GWAS）。对于两样本MR分析，采用了逆方差加权（IVW）、加权中位数、加权模式和MR-Egger等方法，其中IVW作为确定因果影响的主要指标。为评估分析的异质性和潜在多效性，进行了包括MR-PRESSO分析、 Cochr an's Q检验和留一法检验在内的敏感性检验。
IVW分析显示，遗传决定的血清MMP-2水平降低与DN高风险存在因果关系（OR = 0.88，95% CI：0.79 - 0.99，P = 0.026）。遗传决定的血清MMP-16水平升高与DN高风险存在因果关系（OR = 1.15，95% CI：1.01 - 1.32，P = 0.038）。基因预测结果显示其他MMPs（MMP14/17/9/12/7/3）与DN之间无因果关系。敏感性分析未显示显著的异质性或多效性。
总之，本研究揭示了MMP-16水平升高、MMP-2浓度降低与DN风险之间的遗传因果关系。这些发现为MMPs在DN病因学中的作用提供了新视角，并为进一步研究以MMPs为靶点的治疗干预奠定了基础。
