■组织蛋白酶与帕金森病(PD)之间的观察性关联已在先前的研究中得到部分探索。然而,因果关系尚不清楚.在这项研究中,我们的目的是利用孟德尔随机化(MR)分析研究组织蛋白酶和PD之间的因果关系,并阐明它们相互作用的潜在机制.
■利用双向双样本MR和多变量MR,我们系统地研究了9种组织蛋白酶与PD之间的因果关系.与组织蛋白酶有关的数据来自综合流行病学单位(IEU)开放式GWAS项目,而与PD相关的数据来自FinnGen数据库的R9和R10版本。使用的主要分析方法是逆方差加权(IVW),最初使用R9的PD数据进行MR分析,并辅以一系列敏感性分析。随后,对R10数据集进行复制分析,和荟萃分析用于合并来自两个数据集的发现。为了探索组织蛋白酶可能影响PD的潜在机制,对具有α-突触核蛋白的显著组织蛋白酶进行MR分析。利用PD数据对α-突触核蛋白相关基因的表达数量性状位点(eQTL)数据进行MR分析和共定位分析。
■正向MR分析显示更多的组织蛋白酶B(CTSB)与较低的PD风险相关(OR=0.898,95CI:0.834-0.966,p=0.004),而更多的组织蛋白酶H(CTSH)(OR=1.076,95CI:1.007-1.149,p=0.029)和更多的组织蛋白酶S(CTSS)(OR=1.076,95CI:1.007-1.150,p=0.030)与PD风险增加相关。荟萃分析验证了这些关联。多变量MR结果与校正前一致。在双向MR分析中未观察到显著结果。在对潜在机制的调查中,我们的研究结果表明,CTSB显著降低α-突触核蛋白水平(OR=0.909,95CI:0.841~0.983,p=0.017).同时,eQTLMR和共定位分析均阐明了α-突触核蛋白和PD之间的遗传确定的正相关。
■总而言之,这项MR研究获得了有力的证据,表明CTSB水平升高与PD风险降低之间存在关联,由α-突触核蛋白水平的下调介导。相反,CTSH和CTSS水平升高与PD风险增加相关.这些发现为PD的病理生理机制提供了新的见解,并确定了疾病预防和治疗的潜在药物靶标,值得进一步的临床研究。
UNASSIGNED: The observational association between
cathepsin and Parkinson\'s disease (PD) has been partially explored in previous research. However, the causal relationship remains unclear. In this
study, our objective is to investigate the causal link between
cathepsin and PD using Mendelian randomization (MR) analysis and elucidate the underlying mechanisms governing their interaction.
UNASSIGNED: Utilizing bidirectional two-sample MR and multivariable MR, we systematically investigates the causal relationship between nine cathepsins and PD. The data pertaining to cathepsins were obtained from the Integrative Epidemiology Unit (IEU) Open GWAS Project, while data related to PD were sourced from versions R9 and R10 of the FinnGen database. The primary analytical method utilized was the inverse variance weighted (IVW), with MR analysis initially conducted using PD data from R9, complemented by a series of sensitivity analyses. Subsequently, replication analysis was performed on the R10 dataset, and meta-analysis were employed to merge the findings from both datasets. To explore potential mechanisms by which Cathepsins may impact PD, MR analyses were performed on significant Cathepsins with alpha-synuclein. MR analysis and colocalization analysis were conducted on expression quantitative trait loci (eQTL) data of gene related to alpha-synuclein with PD data.
UNASSIGNED: Forward MR analyses revealed more cathepsin B (CTSB) associated with less PD risk (OR = 0.898, 95%CI: 0.834-0.966, p = 0.004), while more
cathepsin H (CTSH) (OR = 1.076, 95%CI: 1.007-1.149, p = 0.029) and more
cathepsin S (CTSS) (OR = 1.076, 95%CI: 1.007-1.150, p = 0.030) associated with increasing PD risk. Meta-analyses validated these associations. Multivariate MR Results were consistent with those before adjustment. No significant results were observed in bidirectional MR analysis. In the investigation of the underlying mechanism, our findings demonstrate that CTSB significantly reduces the levels of alpha-synuclein (OR = 0.909, 95%CI: 0.841-0.983, p = 0.017). Concurrently, a genetically determined positive correlation between alpha-synuclein and PD is illuminated by both eQTL MR and colocalization analysis.
UNASSIGNED: In conclusion, this MR
study yields robust evidence suggesting an association between elevated levels of CTSB and reduced PD risk, mediated by the downregulation of alpha-synuclein levels. Conversely, higher levels of CTSH and CTSS are associated with an increased risk of PD. These findings offer novel insights into the pathophysiological mechanisms of PD and identify potential drug targets for disease prevention and treatment warranting further clinical investigations.