背景：观察性研究表明胶质母细胞瘤与循环炎症蛋白之间存在潜在相关性。需要进一步调查以确定这两个因素之间的因果关系。方法：我们使用全基因组关联研究 (GWAS) 对 91 种循环炎症相关蛋白 (N = 14,824) 进行孟德尔随机化 (MR) 分析，以评估它们对胶质母细胞瘤的因果影响。胶质母细胞瘤的 GWAS 摘要数据包括 243 例病例和 287,137 例对照。逆方差加权（IVW）方法被用作评估因果关系的主要分析方法。另外四种 MR 方法 [简单模式、MR-Egger、加权中值和加权模式] 用于补充 IVW 结果。此外，还进行了多项敏感性分析来评估异质性、水平多效性和稳定性。还进行了反向 MR 分析。对来自癌症基因组图谱 (TCGA) 的胶质母细胞瘤转录组数据进行分析，以验证通过 MR 获得的结果，同时进行通路和功能富集分析以预测潜在的潜在机制。结果：我们在正向 MR 分析中采用反方差加权方法的结果提供了强有力的证据，支持胶质母细胞瘤与循环中胱抑素 D 水平升高以及成纤维细胞生长因子 21 (FGF21) 水平降低之间的潜在关联。此外，我们的反向 MR 分析显示，胶质母细胞瘤可能导致血液中 C-X-C 基序趋化因子 9 (CXCL9) 和白细胞介素 33 (IL-33) 浓度增加。转录组分析表明，FGF21 表达与发生胶质母细胞瘤的风险呈负相关，而风险增加则与 CXCL9 和 IL-33 水平升高相关。通路和功能富集分析表明 Cystatin D 可能通过细胞内蛋白质转运对胶质母细胞瘤发挥作用，而 FGF21 可能通过葡萄糖反应机制影响胶质母细胞瘤。结论：这些结果表明 FGF21 是胶质母细胞瘤易感性的一个重要因素。胶质母细胞瘤还会影响 C-X-C 基序趋化因子 9 和 Interleukin-33 等炎症蛋白的表达，为胶质母细胞瘤发生机制和临床研究提供新的见解。版权所有 © 2024 Lin、Gao、Huang、Wu 和 She。

Background: Observational studies have indicated a potential correlation between glioblastoma and circulating inflammatory proteins. Further investigation is required to establish a causal relationship between these two factors. Methods: We performed a Mendelian randomization (MR) analysis using genome-wide association study (GWAS) summary of 91 circulating inflammation-related proteins (N = 14,824) to assess their causal impact on glioblastoma. The GWAS summary data for glioblastoma included 243 cases and 287,137 controls. The inverse variance weighted (IVW) method was used as the primary analytical method to assess causality. Four additional MR methods [simple mode, MR-Egger, weighted median, and weighted mode] were used to supplement the IVW results. Furthermore, several sensitivity analyses were performed to assess heterogeneity, horizontal pleiotropy, and stability. Reverse MR analysis was also performed. glioblastoma transcriptomic data from The Cancer Genome Atlas (TCGA) were analyzed to validate the findings obtained through MR, while pathway and functional enrichment analyses were conducted to predict the potential underlying mechanisms. Results: Our findings from employing the inverse variance weighted method in our forward MR analysis provide robust evidence supporting a potential association between glioblastoma and elevated levels of Cystatin D, as well as decreased levels of fibroblast growth factor 21 (FGF21) in the circulation. Moreover, our reverse MR analysis revealed that glioblastoma may contribute to increased concentrations of C-X-C motif chemokine 9 (CXCL9) and Interleukin-33 (IL-33) in the bloodstream. Transcriptomic analysis showed that FGF21 expression was inversely associated with the risk of developing glioblastoma, whereas an increased risk was linked to elevated levels of CXCL9 and IL-33. Pathway and functional enrichment analyses suggested that Cystatin D might exert its effects on glioblastoma through intracellular protein transport, whereas FGF21 might affect glioblastoma via glucose response mechanisms. Conclusion: These results indicate that FGF21 is a significant factor in glioblastoma susceptibility. Glioblastoma also affects the expression of inflammatory proteins such as C-X-C motif chemokine 9 and Interleukin-33, providing new insights into the mechanisms of glioblastoma genesis and clinical research.Copyright © 2024 Lin, Gao, Huang, Wu and She.