循环细胞因子浓度对阿尔茨海默病风险和认知功能的因果效应。
Causal effects of circulating cytokine concentrations on risk of Alzheimer's disease and cognitive function.
作者信息
Pagoni Panagiota, Korologou-Linden Roxanna S, Howe Laura D, Davey Smith George, Ben-Shlomo Yoav, Stergiakouli Evie, Anderson Emma L
机构信息
MRC Integrative Epidemiology Unit, University of Bristol, Bristol, UK; Population Health Sciences, Bristol Medical School, University of Bristol, Bristol, UK.
MRC Integrative Epidemiology Unit, University of Bristol, Bristol, UK; Population Health Sciences, Bristol Medical School, University of Bristol, Bristol, UK.
出版信息
Brain Behav Immun. 2022 Aug;104:54-64. doi: 10.1016/j.bbi.2022.05.006. Epub 2022 May 14.
BACKGROUND
There is considerable evidence suggesting a role of neuroinflammation in the pathogenesis of Alzheimer's disease. Establishing causality is challenging due to bias from reverse causation and residual confounding.
METHODS
We used two-sample MR to explore causal effects of circulating cytokine concentrations on Alzheimer's disease risk and cognitive function. We employed genetic variants from the largest publicly available genome-wide association studies (GWASs) of cytokine concentrations (N = 8,293), Alzheimer's disease (71,880 cases/383,378 controls), prospective memory (N = 152,605 to 462,302), reaction time (N = 454,157 to 459,523) and fluid intelligence (N = 149,051).
RESULTS
Evidence suggest that 1 standard deviation (SD) increase in levels of CTACK (CCL27) (OR = 1.09 95%CI: 1.01 to 1.19, p = 0.03) increased risk of Alzheimer's disease. There was weak evidence of a causal effect of MIP-1b (CCL4) (OR = 1.04 95% CI: 0.99 to 1.09, p = 0.08), Eotaxin (OR = 1.08 95% CI: 0.99 to 1.17, p = 0.10), GROa (CXCL1) (OR = 1.04 95% CI: 0.99 to 1.10, p = 0.15), MIG (CXCL9) (OR = 1.17 95% CI: 0.97 to 1.41, p = 0.10), IL-8 (Wald ratio: OR = 1.21 95% CI: 0.97 to 1.51, p = 0.09) and IL-2 (Wald Ratio: OR = 1.21 95% CI: 0.94 to 1.56, p = 0.14) on Alzheimer's disease risk. A 1 SD increase in concentration of Eotaxin (IVW: OR = 1.05 95% CI: 0.98 to 1.13, p = 0.14), IL-8 (OR = 1.21 95% CI: 1.07 to 1.37, p = 0.003) and MCP1 (OR = 1.07 95% CI: 1.03 to 1.13, p = 0.003) were associated with lower fluid intelligence, and IL-4 (OR = 0.86 95%CI: 0.79 to 0.98, p = 0.02) with higher.
CONCLUSIONS
Our findings suggest a causal role of cytokines in the pathogenesis of Alzheimer's disease and fluid intelligence.
背景
有大量证据表明神经炎症在阿尔茨海默病的发病机制中起作用。由于反向因果关系和残余混杂因素导致的偏差，确定因果关系具有挑战性。
方法
我们使用两样本孟德尔随机化方法来探究循环细胞因子浓度对阿尔茨海默病风险和认知功能的因果效应。我们采用了来自公开可用的最大规模细胞因子浓度全基因组关联研究（GWAS）（N = 8293）、阿尔茨海默病（71880例/383378例对照）、前瞻性记忆（N = 152605至462302）、反应时间（N = 454157至459523）和流体智力（N = 149051）的基因变异。
结果
有证据表明，CTACK（CCL27）水平增加1个标准差（SD）（比值比[OR]=1.09，95%置信区间[CI]：1.01至1.19，p = 0.03）会增加患阿尔茨海默病的风险。有微弱证据表明MIP-1b（CCL4）（OR = 1.04，95% CI：0.99至1.09，p = 0.08）、嗜酸性粒细胞趋化因子（OR = 1.08，95% CI：0.99至1.17，p = 0.10）、生长调节致癌基因α（CXCL1）（OR = 1.04，95% CI：0.99至1.10，p = 0.15）、巨噬细胞炎性蛋白-γ（CXCL9）（OR = 1.17，95% CI：0.97至1.41，p = 0.10）、白细胞介素-8（Wald比值：OR = 1.21，95% CI：0.97至1.51，p = 0.09）和白细胞介素-2（Wald比值：OR = 1.21，95% CI：0.94至1.56，p = 0.14）对阿尔茨海默病风险有因果效应。嗜酸性粒细胞趋化因子浓度增加1个SD（逆方差加权法：OR = 1.05，95% CI：0.98至1.13，p = 0.14）以及白细胞介素-8（OR = 1.21，95% CI：1.07至1.37，p = 0.003）和单核细胞趋化蛋白-1（OR = 1.07，95% CI：1.03至1.13，p = 0.003）与较低的流体智力相关，而白细胞介素-4（OR = 0.86，95% CI：0.79至0.98，p = 0.02）与较高的流体智力相关。
结论
我们的研究结果表明细胞因子在阿尔茨海默病发病机制和流体智力中起因果作用。
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