血浆代谢物介导炎症蛋白对阿尔茨海默病的因果效应：一项孟德尔随机化分析研究

doi:10.12122/j.issn.1673-4254.2026.02.05

摘要/Abstract

摘要：

目的探讨炎症蛋白与阿尔茨海默病（AD）之间的因果关系，并评估血浆代谢物在该关系中的中介作用。方法采用孟德尔随机化（MR）方法进行分析。研究利用公开可获得的全基因组关联研究（GWAS）数据，选取91种炎症蛋白强相关且无反向因果关系的单核苷酸多态性（snp）作为暴露，以AD为结局，进行双向双样本MR分析。通过逆方差加权法（IVW）筛选出与AD存在因果关系的炎症蛋白，进一步基于中介MR分析，以1400种血浆代谢物作为中介变量，评估代谢物在炎症蛋白对AD因果效应中的中介作用。结果初步双向MR分析识别出3种与AD存在潜在正向因果关联且无反向因果关联的炎症蛋白，分别是Axin-1、C-X-C基序趋化因子11（CXCL11）及白细胞介素-12β（IL-12β）。其中，Axin-1水平升高与AD风险呈潜在正向因果效应（OR=1.082，95% CI：1.009~1.159，P=0.026），而CXCL11（OR=0.951，95% CI：0.914~0.990，P=0.026）和IL-12β（OR=0.959，95% CI：0.926~0.994，P=0.026）与AD风险则呈潜在负向因果效应。敏感性分析表明，这些因果关联均无异质性和多效性。在中介分析中，筛选出18种与AD具有潜在因果关联的血浆代谢物，其中3种血浆代谢物在炎症蛋白-AD因果中具有中介效应。甲基-4-羟基苯甲酸硫酸盐在Axin-1与AD之间起到部分中介作用（占比为20.10%）。孕烯三醇硫酸盐在CXCL11与AD之间起到部分中介作用（占比为18.20%）。亚精胺/鸟氨酸比值在IL-12β与AD之间起到重要中介作用，中介效应占比为43.40%。结论本研究首次揭示了特定炎症蛋白通过血浆代谢物影响AD风险的潜在机制，为AD的炎症-代谢交互机制提供了遗传学证据，为AD的早期检测和干预提供了潜在的生物标志物和靶点。

关键词: 炎症蛋白, 血浆代谢物, 孟德尔随机化, 阿尔茨海默病, 中介效应

Abstract:

Objective To investigate the causal relationship between inflammatory proteins and Alzheimer's disease (AD) and the mediating role of plasma metabolites therein. Methods Using Mendelian mandomization (MR) methods and publicly available genome-wide association study (GWAS) data, we selected 91 single nucleotide polymorphisms (SNPs) that were strongly linked to inflammatory proteins without reverse causality with AD as the outcome. A bidirectional two-sample MR analysis was performed. Inflammatory proteins with causal links to AD were identified via inverse variance weighted (IVW) analysis. A mediation MR analysis was then performed using 1400 plasma metabolites to assess their mediating role in this causal pathway. Results The preliminary bidirectional MR analysis identified 3 inflammatory proteins that had a potential positive causal association with AD without reverse causality: Axin-1, C-X-C motif chemokine ligand 11 (CXCL11), and interleukin-12β (IL-12β). Elevated levels of Axin-1 were positively causally associated with AD risk (OR=1.082, 95% CI: 1.009-1.159; P=0.026), while CXCL11 (OR=0.951, 95% CI: 0.914-0.990; P=0.026) and IL-12β (OR=0.959, 95% CI: 0.926-0.994; P=0.026) were negatively causally associated with AD risk. Sensitivity analyses indicated that these causal effects exhibited no heterogeneity or pleiotropy. In the mediation analysis, 18 plasma metabolites with causal links to AD were identified, among which 3 plasma metabolites exhibited mediating effects in the inflammatory protein-AD causal relationship. Methyl-4-hydroxybenzoate sulfate partially mediated the effect between Axin-1 and AD (20.10%). Pregnenetriol sulfate partially mediated the effect between CXCL11 and AD (18.20%). The ratio of spermidine to ornithine played an important mediating role between IL-12β and AD, with a mediating effect of 43.40%. Conclusion This study reveals how specific inflammatory proteins influence AD risk via plasma metabolites and provides genetic evidence for inflammatory-metabolic interactions in AD to facilitate the identification of potential biomarkers and targets for early detection and intervention of AD.

Key words: inflammatory proteins, plasma metabolites, mendelian randomization, Alzheimer's disease, mediating effect

陈梅妹, 黄睿娜, 杨朝阳. 血浆代谢物介导炎症蛋白对阿尔茨海默病的因果效应：一项孟德尔随机化分析研究[J]. 南方医科大学学报, 2026, 46(2): 278-285.

Meimei CHEN, Ruina HUANG, Zhaoyang YANG. Plasma metabolites mediates the causal effect of inflammatory proteins on Alzheimer's disease: a Mendelian randomization study[J]. Journal of Southern Medical University, 2026, 46(2): 278-285.

图/表 9

参考文献 36

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Type	Exposure	Outcome	Nsnp	Beta	SE	P	OR (95% CI)
Inflammation proteins	Axin-1	AD	13	0.079	0.035	0.026	1.082 (1.009-1.159)
	C-X-C motif chemokine 11	AD	39	-0.050	0.020	0.026	0.951 (0.914-0.990)
	Interleukin-12 subunit beta	AD	31	-0.041	0.018	0.026	0.959 (0.926-0.994)
Blood metabolites	Methyl-4-hydroxybenzoate sulfate	AD	21	0.083	0.025	0.003	1.086 (1.034-1.141)
	Epiandrosterone sulfate	AD	24	-0.038	0.014	0.006	0.963 (0.938-0.989)
	11beta-hydroxyandrosterone glucuronide	AD	29	-0.062	0.019	0.003	0.940 (0.906-0.976)
	Pregnenetriol sulfate	AD	8	0.092	0.033	0.006	1.096 (1.027-1.169)
	Palmitoleoylcarnitine (C16:1)	AD	19	0.083	0.026	0.003	1.087 (1.034-1.143)
	Spermidine to ornithine ratio	AD	4	-0.168	0.057	0.006	0.845 (0.756-0.945)
	Phosphate to threonine ratio	AD	7	0.141	0.050	0.006	1.151 (1.043-1.271)
	Citrulline to phosphate ratio	AD	33	-0.053	0.021	0.010	0.948 (0.911-0.987)

Type	Exposure	Outcome	Nsnp	Beta	SE	P	OR (95% CI)
Inflammation proteins	Axin-1	AD	13	0.079	0.035	0.026	1.082 (1.009-1.159)
	C-X-C motif chemokine 11	AD	39	-0.050	0.020	0.026	0.951 (0.914-0.990)
	Interleukin-12 subunit beta	AD	31	-0.041	0.018	0.026	0.959 (0.926-0.994)
Blood metabolites	Methyl-4-hydroxybenzoate sulfate	AD	21	0.083	0.025	0.003	1.086 (1.034-1.141)
	Epiandrosterone sulfate	AD	24	-0.038	0.014	0.006	0.963 (0.938-0.989)
	11beta-hydroxyandrosterone glucuronide	AD	29	-0.062	0.019	0.003	0.940 (0.906-0.976)
	Pregnenetriol sulfate	AD	8	0.092	0.033	0.006	1.096 (1.027-1.169)
	Palmitoleoylcarnitine (C16:1)	AD	19	0.083	0.026	0.003	1.087 (1.034-1.143)
	Spermidine to ornithine ratio	AD	4	-0.168	0.057	0.006	0.845 (0.756-0.945)
	Phosphate to threonine ratio	AD	7	0.141	0.050	0.006	1.151 (1.043-1.271)
	Citrulline to phosphate ratio	AD	33	-0.053	0.021	0.010	0.948 (0.911-0.987)

Outcome	Exposure	MR Egger		Inverse variance weighted
Outcome	Exposure	Q	Q_P	Q	Q_P
AD	Axin-1	11.388	0.411	11.440	0.492
AD	C-X-C motif chemokine 11	40.637	0.313	41.066	0.338
AD	Interleukin-12 subunit beta	30.999	0.365	31.852	0.374

Outcome	Exposure	MR Egger		Inverse variance weighted
Outcome	Exposure	Q	Q_P	Q	Q_P
AD	Axin-1	11.388	0.411	11.440	0.492
AD	C-X-C motif chemokine 11	40.637	0.313	41.066	0.338
AD	Interleukin-12 subunit beta	30.999	0.365	31.852	0.374

Outcome	Exposure	MR-Egger intercept	SE	P
AD	Axin-1	-0.002	0.009	0.826
AD	C-X-C motif chemokine 11	-0.004	0.006	0.536
AD	Interleukin-12 subunit beta	-0.004	0.004	0.379