A Mendelian Randomization Study and Experimental Validation Investigating the Potential Relationship Among Interleukin-6 Receptor Subunit Beta, Obesity, and Alzheimer's Disease

IF 2.7 3区心理学 Q2 BEHAVIORAL SCIENCES

Brain and Behavior Pub Date : 2025-09-16 DOI:10.1002/brb3.70772

Yu Liu, Nan Song, Qun Wang, Peng Cui, Dongyu Min

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Abstract

Objective

This study employs Mendelian randomization (MR) aimed at systematically evaluating the relationship among interleukin-6 receptor subunit beta, obesity, and Alzheimer's disease (AD). We conducted animal studies to validate the reliability of the MR analytical outcomes.

Methods

The pooled data for the interleukin-6 receptor subunit beta originated from the genome-wide association study (GWAS) dataset, which included a total of 10,534,735 participants. Obesity pooled data were from the GWAS dataset (case n = 23,971 and control n = 388,084) and AD pooled data from the GWAS database (case n = 39,106 and control n = 46,828). The aforementioned data sets facilitated MR causal analysis. First, utilize the inverse variance weighting (IVW) method for analysis and enhance it with MR-Egger regression and weighted median approaches, and a sensitivity analysis was performed by MR-multiple effect residuals and outliers (MR-Presso), Cochran Q test, and Leave-one (LOO) analysis. We established an obesity model by feeding 6-week-old male ApoE^−/− mice a high-fat diet for 16 weeks. In contrast, C57BL/6 control mice were fed a normal diet for the same duration. An AD model was established by feeding 3-month-old APP/PS1 mice a normal diet for 24 weeks. We harvested serum and hippocampal tissue from the mice for enzyme-linked immunosorbent assay (ELISA).

Results

MR analysis indicated that a genetically predicted increase in interleukin-6 receptor subunit beta raises the risk of AD (OR = 1.064, 95% CI: 1.021–1.109, p = 0.003). The exposure factor interleukin-6 receptor subunit beta served as a protective element against obesity (OR = 0.9372,95%CI:0.8921–0.9847, p = 0.010). Obesity showed an adverse relationship with AD. As the body mass index (BMI) increased, the risk of developing AD decreased (OR = 0.9299, 95% CI: 0.8939–0.9674, p ＜0.001). ELISA findings revealed that the levels of interleukin-6 receptor subunit beta (gp130), oncostatin-M (OSM), and IL-6 in serum and hippocampus decreased in obesity, whereas they increased in AD, aligning with the results of the MR Analysis.

Conclusion

In summary, our extensive Mendelian randomization data suggest that increased levels of the interleukin-6 receptor subunit beta may be associated with a reduced risk of obesity, and consequently, may increase the risk of AD.

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白介素-6受体亚单位β、肥胖和阿尔茨海默病之间潜在关系的孟德尔随机研究和实验验证

目的：本研究采用孟德尔随机化方法，旨在系统评价白细胞介素-6受体亚单位β与肥胖和阿尔茨海默病（AD）之间的关系。我们进行了动物实验来验证MR分析结果的可靠性。方法：白细胞介素-6受体亚基β的汇总数据来自全基因组关联研究（GWAS）数据集，该数据集共包括10,534,735名参与者。肥胖合并数据来自GWAS数据集（病例n = 23,971，对照组n = 388,084）， AD合并数据来自GWAS数据库（病例n = 39,106，对照组n = 46,828）。上述数据集有助于MR因果分析。首先，利用方差反加权法（IVW）进行分析，并用MR-Egger回归和加权中位数法进行强化，并通过MR-multiple effects残差和异常值（MR-Presso）、Cochran Q检验和Leave-one （LOO）分析进行敏感性分析。我们通过给6周龄雄性ApoE-/-小鼠高脂饮食16周，建立肥胖模型。C57BL/6对照小鼠饲喂相同时间的正常饲料。采用正常饲料喂养3月龄APP/PS1小鼠24周，建立AD模型。我们采集小鼠血清和海马组织进行酶联免疫吸附试验（ELISA）。结果：MR分析显示，基因预测的白介素-6受体亚单位β增加会增加AD的风险（OR = 1.064, 95% CI: 1.021-1.109, p = 0.003）。暴露因子白介素-6受体亚单位β对肥胖有保护作用（OR = 0.9372,95%CI:0.8921-0.9847, p = 0.010）。肥胖与AD呈负相关。随着身体质量指数（BMI）的增加，发生AD的风险降低（OR = 0.9299, 95% CI: 0.8939 ~ 0.9674, p <0.001）。ELISA结果显示，肥胖患者血清和海马中白细胞介素-6受体亚单位β (gp130)、癌抑素- m （OSM）和IL-6水平降低，而AD患者血清和海马中IL-6水平升高，与MR分析结果一致。结论：总之，我们广泛的孟德尔随机化数据表明，白细胞介素-6受体亚基β水平的升高可能与肥胖风险的降低有关，因此可能增加AD的风险。

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来源期刊

Brain and Behavior BEHAVIORAL SCIENCES-NEUROSCIENCES

CiteScore

5.30

自引率

0.00%

发文量

352

审稿时长

14 weeks

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