A Mendelian randomization study investigating the causal role of inflammation on Parkinson's disease.
A Mendelian randomization study investigating the causal role of inflammation on Parkinson's disease.
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DOI：
10.1093/brain/awac193
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发表时间：
2022-10-21
期刊：
影响因子：
14.5
通讯作者：
Del Greco, Fabiola M.
中科院分区：
文献类型：
--
作者：
Bottigliengo, Daniele;Foco, Luisa;Seibler, Philip;Klein, Christine;Koenig, Inke R.;Del Greco, Fabiola M.
关键词：
越来越多的证据表明炎症是帕金森病发病机制中的决定因素，但其在帕金森神经变性中的作用仍然难以捉摸。目前尚不清楚炎症级联反应是多巴胺神经元死亡的原因还是后果。在本研究中，我们的目的是进行深入的统计调查的因果关系炎症和帕金森病使用两个样本孟德尔随机设计。使用迄今为止在欧洲人群中进行的最大全基因组关联研究（样本量范围为13 955至204 402例）的汇总水平数据选择遗传工具，用于以下炎症生物标志物：C反应蛋白、白细胞介素-6、白细胞介素1受体拮抗剂和肿瘤坏死因子α。帕金森病（56306例和1417791例对照）和帕金森病发病年龄（28568例）的遗传关联数据来自国际帕金森病基因组学联盟。在初步分析中，使用逆方差加权法对强（P值< 5 × 10−8; F统计量> 10）和独立（连锁不平衡r2 < 0.001）遗传工具的因果关系进行估计。在敏感性分析中，我们使用稳健的孟德尔随机化方法并在去除多效性遗传变异后估计因果效应。还探讨了反向因果关系。我们对不同的炎症生物标志物数据源重复分析，以检查结果的一致性。在白细胞介素-6选择的所有三个数据来源中，我们发现帕金森病发病年龄较早与白细胞介素-6浓度增加相关的统计学证据[每增加1个对数单位的年差=-2.364，95%置信区间（CI）=-4.789-0.060;每增加1个对数单位的年差= −2.011，95%CI = −3.706至−0.317;每增加1个对数单位的年差= −1.569，95%CI = −2.891至−0.247]。我们没有观察到任何统计学证据表明C反应蛋白、白细胞介素1受体拮抗剂和肿瘤坏死因子α对帕金森病及其发病年龄的因果关系。排除可能的多效性遗传变异后的结果与主要分析的结果一致。在调查反向因果关系时，我们没有发现帕金森病或发病年龄对任何炎症生物标志物的因果影响的证据。我们发现了帕金森病的发病与白细胞介素-6之间存在因果关系的证据。这项研究的结果表明，白细胞介素-6细胞因子的促炎活性可能是前驱帕金森病的决定因素。Bottigliengo等人使用双样本孟德尔随机化设计研究了炎症与帕金森病之间的因果关系。他们表明，较高的IL-6水平与帕金森病发病时的年轻年龄有关，这表明IL-6水平升高可能是疾病前驱症状的一部分。
There is increasing evidence for inflammation as a determinant in the pathogenesis of Parkinson’s disease, but its role in parkinsonian neurodegeneration remains elusive. It is not clear whether inflammatory cascades are causes or consequences of dopamine neuron death. In the present study, we aim to perform an in-depth statistical investigation of the causal relationship between inflammation and Parkinson’s disease using a two-sample Mendelian randomization design. Genetic instruments were selected using summary-level data from the largest genome-wide association studies to date (sample size ranging from 13 955 to 204 402 individuals) conducted on a European population for the following inflammation biomarkers: C-reactive protein, interleukin-6, interleukin 1 receptor antagonist and tumour necrosis factor α. Genetic association data on Parkinson’s disease (56 306 cases and 1 417 791 controls) and age at onset of Parkinson’s disease (28 568 cases) were obtained from the International Parkinson’s Disease Genomics Consortium. On primary analysis, causal associations were estimated on sets of strong (P-value < 5 × 10−8; F-statistic > 10) and independent (linkage disequilibrium r2 < 0.001) genetic instruments using the inverse-variance weighted method. In sensitivity analysis, we estimated causal effects using robust Mendelian randomization methods and after removing pleiotropic genetic variants. Reverse causation was also explored. We repeated the analysis on different data sources for inflammatory biomarkers to check the consistency of the findings. In all the three data sources selected for interleukin-6, we found statistical evidence for an earlier age at onset of Parkinson’s disease associated with increased interleukin-6 concentration [years difference per 1 log-unit increase = −2.364, 95% confidence interval (CI) = −4.789–0.060; years difference per 1 log-unit increase = −2.011, 95% CI = −3.706 to −0.317; years difference per 1 log-unit increase = −1.569, 95% CI = −2.891 to −0.247]. We did not observe any statistical evidence for causal effects of C-reactive protein, interleukin 1 receptor antagonist and tumour necrosis factor α on both Parkinson’s disease and its age at onset. Results after excluding possible pleiotropic genetic variants were consistent with findings from primary analyses. When investigating reverse causation, we did not find evidence for a causal effect of Parkinson’s disease or age at onset on any biomarkers of inflammation. We found evidence for a causal association between the onset of Parkinson’s disease and interleukin-6. The findings of this study suggest that the pro-inflammatory activity of the interleukin-6 cytokine could be a determinant of prodromal Parkinson’s disease. Bottigliengo et al. investigate the causal relationship between inflammation and Parkinson’s disease using a two-sample Mendelian randomization design. They show that higher IL-6 levels are associated with younger age at onset of Parkinson's disease, suggesting that elevated IL-6 levels could be part of the disease prodrome.
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