Inflammatory biomarkers and delirium: a Mendelian randomization study

Background: 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. Methods: A bidirectional two-sample Mendelian randomization (MR) was performed. Genetic instruments associated with peripheral tumor necrosis factora (TNF-alpha) C-reactive protein (CRP), interleukin (IL)-1 alpha, IL-1b, IL-2, IL-8, IL-6, soluble IL-6 receptor alpha (sIL-6R alpha), and soluble gp130 were identified in three di erent 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 e ects 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 r(2) < 0.001 for each of the exposures. Reverse causation was also performed. The inverse-variance weightedmethod (IVW), MR-Eggermethod, weightedmedianmethod, MR-Egger regression, and MR Pleiotropy RESidual Sum were used for MR analyses. Results: At the genome-wide significant level (P < 5e-8, r(2) < 0.001), genetically predicted sIL-6R alpha 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-6Ra and delirium became nonsignificant 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 e ects of peripheral TNF-alpha, CRP, IL-1 alpha, IL1b, 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 e ect of deliriumon these inflammatory biomarkers could be found (all P > 0.05). Conclusion: The results of this MR analysis did not support that peripheral TNF-alpha, CRP, IL-1a, IL-1b, IL-2, IL-6, sIL-6R alpha, 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.