遗传调控下免疫相关血浆蛋白对帕金森病的效应

Effect of immune-related plasma proteins under genetic regulation on Parkinson's disease

目的 探讨免疫相关血浆蛋白与帕金森病(Parkinson's disease, PD)的联系。方法 通过对4907种免疫相关血浆蛋白的全基因组关联研究数据进行分析,评估血浆蛋白对PD风险的直接影响。研究还利用单细胞核RNA测序数据进行蛋白表达分析。结果 4种免疫相关蛋白质脑源性多巴胺营养因子(cerebral dopamine neurotrophic factor, CDNF)、组织蛋白酶B(cathepsin B,CTSB)、免疫球蛋白G Fc受体2a(FCGR2A)、血红蛋白β亚基(HBB)与PD风险存在潜在联系;其中,CDNF、CTSB、HBB表达增高有助于降低PD风险(OR=0.871,95%CI:0.779~0.973,P=0.015;OR=0.835,95%CI:0.758~0.920,P=0.001;OR=0.735,95%CI:0.631~0.857,P=0.001),而FCGR2A表达增高与PD风险增高相关(OR=1.137,95%CI:1.058~1.223,P=0.001)。单细胞测序分析蛋白表达及其在脑中不同细胞类型中分布,CDNF、CTSB在大脑的多种细胞中大量表达;FCGR2A主要在大脑小胶质细胞中表达;HBB在大脑中几乎不表达。结论 研究揭示了CDNF、CTSB、FCGR2A及HBB 4种蛋白质与PD风险的潜在关联,强调了PD遗传风险变异通过调节这些免疫相关蛋白表达来影响PD发生。此外,单细胞表达数据揭示相关免疫蛋白在大脑的表达模式。

Objective To explore the connection between immune-related plasma proteins and Parkinson's disease.Methods By analyzing genome-wide association study data of 4907immune-related plasma proteins,we assessed their direct impact on the risk of Parkinson's disease.Single-nucleus RNA sequencing data were also utilized for protein expression analysis.Results Four immune-related proteins,cerebral dopamine neurotrophic factor(CDNF),cathepsin B(CTSB),immunoglobulin G Fc receptor 2a(FCGR2A),and hemoglobin beta subunit(HBB),were identified to be associated with the risk of Parkinson's disease.Among them,increased expression levels of CDNF,CTSB and HBB were found to decrease the risk(OR=0.871,95%CI:0.779-0.973,P=0.015;OR=0.835,95%CI:0.758-0.920,P=0.001;OR=0.735,95%CI:0.631-0.857,P=0.001),whereas increased level of FCGR2Awas associated with a higher risk of PD(OR=1.137,95%CI:1.058-1.223,P=0.001).Single-cell sequencing analyzes protein expression and its distribution among different cell types in the brain.CDNF and CTSB exhibit high expression levels in multiple brain cell types,FCGR2Ais predominantly expressed in brain microglia and HBB shows minimal expression in the brain.Conclusion There are potential links between the four proteins CDNF,CTSB,FCGR2Aand HBB and the risk of Parkinson's disease.Our results emphasize that the genetic risk variants of Parkinson's disease influence the disease's occurrence by modulating the expression of these immune-related proteins.Additionally,single-cell expression data reveal the expression patterns of these target proteins in the brain.