基于孟德尔随机化探析肠道菌群与甲状腺功能亢进症的因果关系

樊毓运; 魏军平; 车峰远

doi:10.16766/j.cnki.issn.1674-4152.004033

基于孟德尔随机化探析肠道菌群与甲状腺功能亢进症的因果关系

doi: 10.16766/j.cnki.issn.1674-4152.004033

樊毓运^{1, 2},
魏军平²,
车峰远^3, ,

1.
临沂市人民医院中医内科，山东临沂 276000
2.
中国中医科学院广安门医院内分泌科，北京 100053
3.
临沂市人民医院神经内科

基金项目:

国家自然科学基金面上项目 82074412

齐鲁卫生与健康杰出青年人才专项鲁卫人字〔2020〕3号

山东省中医临床优秀人才项目鲁卫函〔2022〕233号

详细信息

通讯作者:
车峰远，E-mail：che1971@126.com

中图分类号: R581.1
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- 文章访问数: 15
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- 被引次数: 0
出版历程
- 收稿日期: 2024-12-26
- 网络出版日期: 2025-09-04

Analysis of causal relationship between gut microbiota and hyperthyroidism based on Mendelian randomization

FAN Yuyun^{1, 2},
WEI Junping²,
CHE Fengyuan^{3
, ,}

1.
Department of Traditional Chinese Internal Medicine, Linyi People's Hospital, Linyi, Shandong 276000, China

摘要

摘要: 目的探索肠道菌群(GM)与甲状腺功能亢进症(以下简称甲亢)的相关性。方法以MiBioGen数据库的肠道菌群为暴露因素，以甲状腺功能亢进症为结局变量。从IEU OpenGWAS数据库下载甲状腺功能亢进症的UKB数据，以逆方差加权法(IVW)为主，辅助以MR-Egger回归和加权众数法(WM)等进行双样本孟德尔随机化分析，采用β值、OR值等指标评估GM与甲亢之间的因果关系，并进行异质性检验、多效性检验和敏感性分析，然后验证MR分析结果的稳定性和可靠性。结果经孟德尔随机化(MR)分析，发现在119个属水平的肠道菌群中，与甲亢有关且呈负相关的肠道细菌分别为戴阿利斯特杆菌属(OR=0.998，95% CI: 0.996~1.000，P=0.037，β=-0.002)、肠杆菌科的志贺菌属(OR=0.998，95% CI: 0.995~1.000，P=0.026，β=-0.002)和瘤胃球菌科UCG014属(OR=0.998，95% CI: 0.996~1.000，P=0.032，β=-0.002)，其β值均＜0，OR值均＜1且P＜0.05，说明以上3个菌属可能是患者发生甲亢风险的保护性因素。异质性检验(P＞0.05)、水平基因多效性检验(P＞0.05)和敏感性分析结果证明结果可靠。结论戴阿利斯特杆菌属、肠杆菌科的志贺菌属、瘤胃球菌科UCG014属可能减少甲亢发病风险，初步发现了肠道菌群和甲亢间的潜在因果关系。
- 甲状腺功能亢进症 /
- 孟德尔随机化 /
- 逆方差加权法 /
- 肠道菌群 /
- 因果关系
Abstract: Objective To investigate the relationship between human gut microbiota and hyperthyroidism. Methods The gut microbiota of the MiBioGen database was used as the exposure factor, and hyperthyroidism was used as the outcome variable. The GWAS data of hyperthyroidism were downloaded from the IEU Open GWAS database. Two-sample Mendelian randomization analysis was performed using regression models such as inverse variance weighting method, MR-Egger regression and weighted median method. The causal relationship between GM and intestinal flora was evaluated by β-value and odds ratio of effect index and so on. The stability and reliability of the results were verified by leave-one-out method, heterogeneity test and horizontal gene pleiotropic test. Results Mendelian randomization (MR) analysis revealed that, among 119 gut microbiota at the genus level, three bacterial taxa showed a negative association with hyperthyroidism: Dialister (OR=0.998, 95% CI: 0.996-1.000, P=0.037, β=-0.002), Escherichia. Shigella (OR=0.998, 95% CI: 0.996-1.000, P=0.032, β=-0.002), and Ruminococcaceae UCG014 (OR=0.998, 95% CI: 0.996-1.000, P=0.032, β=-0.002). All three genera exhibited β < 0, OR < 1, and P < 0.05, suggesting they may serve as protective factors against hyperthyroidism risk. The results of heterogeneity test (P>0.05), horizontal gene pleiotropic test (P>0.05) and sensitivity analysis proved that the formal results were reliable. Conclusion Dialister, Escherichia. Shigella and Ruminococcaceae UCG014 can reduce the risk of hyperthyroidism, the potential relationship between gut microbiota and hyperthyroidism is found preliminarily.
- Hyperthyroidism /
- Mendelian randomization /
- Inverse variance weight /
- Gut microbiota /
- Causal relationship

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图 1 孟德尔随机化分析流程

Figure 1. Flow chart of MR analysis

下载: 全尺寸图片幻灯片

图 2 肠道菌群与甲亢关联的孟德尔随机化分析效应量散点图

Figure 2. Scatter plot of MR effect size for causal association between gut microbiota and Hyperthyroidism

下载: 全尺寸图片幻灯片

表 1 筛选后代表性工具变量SNPs

Table 1. Representative instrumental variable SNPs after screening

工具变量(SNPs)	其他效应位点	效应位点	暴露因素	R²	F
rs34583783	T	G	Actinomyces	0.002	22.23
rs2715439	T	C	Actinomyces	0.002	20.51
rs7680684	T	C	Adlercreutzia	0.002	24.36
rs2147798	G	C	Adlercreutzia	0.002	23.07
rs11729256	C	T	Akkermansia	0.002	24.97
rs4936098	G	A	Akkermansia	0.001	22.81
rs67281112	C	G	Alistipes	0.001	21.18
rs67705352	G	T	Alistipes	0.001	23.05
rs11769002	A	G	Alistipes	0.001	23.36

下载: 导出CSV

表 2 孟德尔随机化分析后获得3个菌属的分析结果

Table 2. Mendelian randomization analysis yielded results for three bacterial genera

肠道菌属	方法	工具变量数量	β	P值	OR(95% CI)
Dialister	Inverse variance weighted	12	-0.002	0.037	0.998(0.996~1.000)
	MR Egger	12	-0.009	0.057	0.991(0.982~0.999)
	Weighted median	12	-0.002	0.185	0.998(0.995~1.001)
	Simple mode	12	-0.002	0.400	0.997(0.993~1.002)
	Weighted mode	12	0.000	0.944	1.000(0.995~1.005)
Escherichia. Shigella	Inverse variance weighted	15	-0.002	0.026	0.998(0.995~1.00)
	MR Egger	15	-0.003	0.311	0.997(0.990~1.002)
	Weighted median	15	-0.002	0.158	0.998(0.995~1.000)
	Simple mode	15	-0.002	0.392	0.998(0.993~1.002)
	Weighted mode	15	-0.002	0.366	0.998(0.993~1.002)
RuminococcaceaeUCG014	Inverse variance weighted	18	-0.002	0.032	0.998(0.996~1.000)
	MR Egger	18	0.003	0.425	1.000(0.996~1.008)
	Weighted median	18	-0.002	0.185	0.998(0.995~1.000)
	Simple mode	18	-0.002	0.355	0.998(0.993~1.002)
	Weighted mode	18	-0.002	0.425	0.998(0.994~1.002)

下载: 导出CSV

表 3 甲亢相关肠道细菌的异质性和多效性分析结果

Table 3. Heterogeneity and pleiotropy analysis of GM related with hyperthyroidism

肠道菌属	方法	异质性检验		多效性检验
肠道菌属	方法	Q	P值	RSS	P值	Egger_截距	P值
Dialister	Inverse variance weighted	10.546	0.482
	MR Egger	7.680	0.660			0.000	0.121
	MR-PRESSO			12.580	0.515
Escherichia. Shigella	Inverse variance weighted	18.673	0.178
	MR Egger	18.524	0.137			0.000	0.751
	MR-PRESSO			21.445	0.197
RuminococcaceaeUCG014	Inverse variance weighted	25.318	0.088
	MR Egger	21.615	0.156			0.000	0.117
	MR-PRESSO			28.091	0.120

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