在观察性研究中，炎症生物标志物与个体谵妄症状的关联性尚存在争议。本研究调查了炎症生物标志物与发展谵妄的风险之间的关系。通过双向双样本Mendelian随机化(MR)进行了分析。在欧洲人群中的三个不同的大型汇总全基因组关联研究(GWAS)中，确定了与外周肿瘤坏死因子-α(TNF-α)、C-反应蛋白(CRP)、白细胞介素-1α(IL-1α)、白细胞介素-1β(IL-1β)、白细胞介素-2(IL-2)、白细胞介素-8(IL-8)、白细胞介素-6(IL-6)、可溶性白细胞介素-6受体α(sIL-6Rα)和可溶性gp130相关的遗传工具。谵妄且不由酒精和其他精神活性物质引起的总结水平统计数据来自FinnGen联盟(2612例个案和325306例对照组)。使用在全基因组水平(P < 5e-8和P < 5e-6)上具有显著关联的工具变体，采用r2 < 0.001的等位基因频率连锁不平衡聚类方法进行估计的因果效应。同时进行了反向因果分析。MR分析使用了逆方差加权法(IVW)、MR-Egger法、加权中位数法、MR-Egger回归法和MR多性研究残差和总和。在全基因组水平(P < 5e-8，r2 < 0.001)上，基因预测的sIL-6Rα与发生谵妄的风险显著相关，三个GWAS数据源中的单核苷酸多态性(SNPs)不超过3个(ORWaldratio = 0.89，95% CI: 0.79-0.96，PWaldratio = 0.0016; ORIVW = 0.88，95% CI: 0.79-0.97，PIVW = 0.008; ORIVW = 0.88，95% CI: 0.80-0.96，PIVW = 0.004)。当使用较为开放的P值阈值< 5e-6时，sIL-6Rα与谵妄的因果关系变得不显著(all PIVW > 0.05)。在两个全基因组显著水平(P < 5e-8和P < 5e-6)上，我们没有发现外周TNF-α、CRP、IL-1α、IL-1β、IL-2、IL-6、IL-8和可溶性gp130对谵妄有实质性的影响(all P > 0.05)。MR-Egger截距和MR-PRESSO结果表明，没有单核苷酸多态性有可能具有多效性(all P > 0.05)。至于反向因果分析，没有找到谵妄对这些炎症生物标志物的影响的证据(all P > 0.05)。本MR分析的结果不支持外周TNF-α、CRP、IL-1α、IL-1β、IL-2、IL-6、sIL-6Rα、可溶性gp130和IL-8与谵妄有因果关联。需要进一步研究炎症因子在谵妄发病机制中的作用。版权所有 © 2023 Yu, Li, Li and Ge.

The association between inflammatory biomarkers and individual delirium symptoms remains controversial in observational studies. We investigated the relationship between inflammatory biomarkers and the risk of developing delirium.A bidirectional two-sample Mendelian randomization (MR) was performed. Genetic instruments associated with peripheral tumor necrosis factor-a (TNF-a) C-reactive protein (CRP), interleukin (IL)-1α, IL-1β, IL-2, IL-8, IL-6, soluble IL-6 receptor alpha (sIL-6Rα), and soluble gp130 were identified in three different large summary genome-wide association studies (GWAS) conducted in the European population. Summary-level statistics for delirium not induced by alcohol and other psychoactive substances were obtained from the FinnGen consortium (2,612 cases and 325,306 controls). The estimated causal effects were performed using instruments' variants at the genome-wide significant level (P < 5e-8 and P < 5e-6), applying a linkage disequilibrium clumping approach with a threshold of r2 < 0.001 for each of the exposures. Reverse causation was also performed. The inverse-variance weighted method (IVW), MR-Egger method, weighted median method, MR-Egger regression, and MR Pleiotropy RESidual Sum were used for MR analyses.At the genome-wide significant level (P < 5e-8, r2 < 0.001), genetically predicted sIL-6Rα was significantly associated with a decreased risk of delirium with less than three single-nucleotide polymorphisms (SNPs) in all three GWAS data sources (ORWaldratio = 0.89, 95% CI: 0.79-0.96, PWaldratio = 0.0016; ORIVW = 0.88, 95% CI: 0.79-0.97, PIVW = 0.008; ORIVW = 0.88, 95% CI: 0.80-0.96, PIVW = 0.004). The causal relationship between sIL-6Rα and delirium became non-significant when a more liberal threshold of P of < 5e-6 was applied (all PIVW > 0.05). At the two genome-wide significance levels (P < 5e-8 and P < 5e-6), we found no evidence for the causal effects of peripheral TNF-α, CRP, IL-1α, IL-1β, IL-2, IL-6, IL-8, and soluble gp130 on delirium (all P > 0.05). The MR-Egger intercept and MR-PRESSO results indicated that no SNP had possible pleiotropy (all P > 0.05). Regarding the reverse, no evidence for an effect of delirium on these inflammatory biomarkers could be found (all P > 0.05).The results of this MR analysis did not support that peripheral TNF-α, CRP, IL-1α, IL-1β, IL-2, IL-6, sIL-6Rα, soluble gp130, and IL-8 were causally associated with delirium. More research is needed to explore the role of inflammatory factors in the pathogenesis of delirium.Copyright © 2023 Yu, Li, Li and Ge.