Yusufujiang Aishanjiang, Zeng Shan, Li Hongyan
Department of Graduate School, Xinjiang Medical University, Ürümqi, China.
Department of Neurology, People's Hospital of Xinjiang Uygur Autonomous Region, Ürümqi, China.
Front Aging Neurosci. 2024 Jun 5;16:1380483. doi: 10.3389/fnagi.2024.1380483. eCollection 2024.
Parkinson's disease (PD), the second most prevalent neurodegenerative condition, has a multifaceted etiology. Cathepsin-cysteine proteases situated within lysosomes participate in a range of physiological and pathological processes, including the degradation of harmful proteins. Prior research has pointed towards a potential link between cathepsins and PD; however, the precise causal relationship between the cathepsin family and PD remains unclear.
This study employed univariate and multivariate Mendelian randomization (MR) analyses to explore the causal relationship between the nine cathepsins and Parkinson's disease (PD) risk. For the primary analysis, genome-wide association study (GWAS) summary statistics for the plasma levels of the nine cathepsins and PD was obtained from the INTERVAL study and the International Parkinson's Disease Genomics Consortium. GWAS for PD replication analysis were obtained from the FinnGen consortium, and a meta-analysis was performed for the primary and replication analyses to evaluate the association between genetically predicted cathepsin plasma levels and PD risk. After identifying significant MR estimates, genetic co-localization analyses were conducted to determine whether shared or distinct causal variants influenced both cathepsins and PD.
Elevated cathepsin B levels were associated with a decreased risk of PD in univariate MR analysis (odds ratio [OR] = 0.890, 95% confidence interval [CI]: 0.831-0.954, pFDR = 0.009). However, there was no indication that PD affected cathepsin B levels (OR = 0.965, 95% CI: 0.858-1.087, = 0.852). In addition, after adjusting for the remaining cathepsins, cathepsin B levels independently and significantly contributed to the reduced risk of PD in multivariate MR analysis (OR = 0.887, 95% CI: 0.823-0.957, = 0.002). The results of the replication MR analysis with the FinnGen GWAS for PD (OR = 0.921, 95% CI: 0.860-0.987, = 0.020) and meta-analysis (OR = 0.905, 95% CI: 0.862-0.951, < 0.001) were consistent with those of the primary analysis. Colocalization analysis did not provide any evidence of a shared causal variant between cathepsins and PD (PP.H4.abf = 0.005).
This genetic investigation supports the hypothesis that cathepsin B exerts a protective effect against PD. The quantification of cathepsin B levels could potentially serve as a predictive biomarker for susceptibility to PD, providing new insights into the pathomechanisms of the disease and possible interventions.
帕金森病（PD）是第二常见的神经退行性疾病，病因是多方面的。溶酶体内的组织蛋白酶 - 半胱氨酸蛋白酶参与一系列生理和病理过程，包括有害蛋白质的降解。先前的研究指出组织蛋白酶与PD之间可能存在联系；然而，组织蛋白酶家族与PD之间的确切因果关系仍不清楚。
本研究采用单变量和多变量孟德尔随机化（MR）分析来探讨9种组织蛋白酶与帕金森病（PD）风险之间的因果关系。对于主要分析，从INTERVAL研究和国际帕金森病基因组学联盟获得了9种组织蛋白酶血浆水平和PD的全基因组关联研究（GWAS）汇总统计数据。用于PD复制分析的GWAS数据来自芬兰基因组联盟，并对主要分析和复制分析进行了荟萃分析，以评估遗传预测的组织蛋白酶血浆水平与PD风险之间的关联。在确定显著的MR估计值后，进行了遗传共定位分析，以确定共享或不同的因果变异是否影响组织蛋白酶和PD。
在单变量MR分析中，组织蛋白酶B水平升高与PD风险降低相关（优势比[OR] = 0.890，95%置信区间[CI]：0.831 - 0.954，pFDR = 0.009）。然而，没有迹象表明PD会影响组织蛋白酶B水平（OR = 0.965，95% CI：0.858 - 1.087，p = 0.852）。此外，在对其余组织蛋白酶进行调整后，在多变量MR分析中，组织蛋白酶B水平独立且显著地导致了PD风险的降低（OR = 0.887，95% CI：0.823 - 0.957，p = 0.002）。使用芬兰基因组联盟的PD GWAS进行的复制MR分析结果（OR = 0.921，95% CI：0.860 - 0.987，p = 0.020）和荟萃分析结果（OR = 0.905，95% CI：0.862 - 0.951，p < 0.001）与主要分析结果一致。共定位分析没有提供组织蛋白酶和PD之间共享因果变异的任何证据（PP.H4.abf = 0.005）。
这项基因研究支持组织蛋白酶B对PD具有保护作用的假设。组织蛋白酶B水平的量化可能潜在地作为PD易感性的预测生物标志物，为该疾病的发病机制和可能的干预措施提供新的见解。
