Liu Yu, Song Nan, Wang Qun, Cui Peng, Min Dongyu
Liaoning University of Chinese Medicine, Shenyang, Liaoning, China.
Affiliated Hospital of Liaoning University of Traditional Chinese Medicine, Shenyang, Liaoning, China.
Brain Behav. 2025 Sep;15(9):e70772. doi: 10.1002/brb3.70772.
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.
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).
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.
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.
本研究采用孟德尔随机化（MR）方法，旨在系统评估白细胞介素-6受体亚基β、肥胖症与阿尔茨海默病（AD）之间的关系。我们进行了动物研究以验证MR分析结果的可靠性。
白细胞介素-6受体亚基β的汇总数据源自全基因组关联研究（GWAS）数据集，该数据集总共包括10,534,735名参与者。肥胖症汇总数据来自GWAS数据集（病例n = 23,971，对照n = 388,084），AD汇总数据来自GWAS数据库（病例n = 39,106，对照n = 46,828）。上述数据集有助于进行MR因果分析。首先，使用逆方差加权（IVW）方法进行分析，并用MR-Egger回归和加权中位数方法进行强化，同时通过MR-多效应残差和异常值（MR-Presso）、 Cochr an Q检验和留一法（LOO）分析进行敏感性分析。我们通过给6周龄雄性ApoE小鼠喂食高脂饮食16周来建立肥胖模型。相比之下，C57BL/6对照小鼠在相同时间段内喂食正常饮食。通过给3月龄APP/PS1小鼠喂食正常饮食24周来建立AD模型。我们从小鼠身上采集血清和海马组织用于酶联免疫吸附测定（ELISA）。
MR分析表明，基因预测的白细胞介素-6受体亚基β水平升高会增加AD风险（OR = 1.064，95% CI：1.021 - 1.109，p = 0.003）。暴露因素白细胞介素-6受体亚基β是预防肥胖症的保护因素（OR = 0.9372，95% CI：0.8921 - 0.9847，p = 0.010）。肥胖症与AD呈负相关。随着体重指数（BMI）增加，患AD的风险降低（OR = 0.9299，95% CI：0.8939 - 0.9674，p＜0.001）。ELISA结果显示，肥胖症小鼠血清和海马中的白细胞介素-6受体亚基β（gp130）、抑瘤素-M（OSM）和IL-6水平降低，而在AD小鼠中则升高，这与MR分析结果一致。
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水平升高可能与肥胖风险降低相关，因此可能增加AD风险。
