孟德尔随机化分析克罗恩病与非酒精性脂肪性肝病之间因果关系

doi:10.3877/cma.j.issn.2095-3232.2025.04.016

目的

基于两样本孟德尔随机化（MR）方法探索克罗恩病（CD）与非酒精性脂肪性肝病（NAFLD）之间可能存在的风险因果关系。

方法

从IEU Open GWAS数据库获取CD与NAFLD的数据集。运用逆方差加权法（IVW）、MR-Egger回归、加权中位数法（WME）、简单模式和加权模式5种方法探讨CD与NAFLD的因果关系，并运用Cochran’s Q检验、MR-Egger回归、MR-PRESSO、留一法、漏斗图和森林图法等评价研究结果的稳定性和可靠性。

结果

5种方法得到的因果效应方向一致，IVW法分析显示CD与NAFLD存在因果关系（OR=1.034，95%CI：1.007~1.061，P=0.013）。异质性分析结果显示，IVW检验（Q=29.041，P=0.969）和MR-Egger检验（Q=29.021，P=0.960）未发现明显异质性。MR-PRESSO分析未检测到离群单核苷酸多态性（SNPs），排除了水平多效性（P=0.888）。MR-Egger回归结果（P=0.209）也未发现水平多效性证据。留一法分析表明，无单个SNPs明显影响总体效应。

结论

从遗传学的角度初步揭示CD可能与NAFLD风险的增加有因果关系，CD和NAFLD之间存在正相关关系，CD是增加NAFLD发生的危险因素。

关键词: 克罗恩病, 非酒精性脂肪性肝病, 孟德尔随机化, 遗传学, 危险因素

Objective

To explore the potential causal relationship between Crohn’s disease (CD) and nonalcoholic fatty liver disease (NAFLD) based on two-sample Mendelian randomization (MR) method.

Methods

The datasets of CD and NAFLD were obtained from IEU Open GWAS database. The causality between CD and NAFLD was analyzed by using five methods: inverse variance weighted (IVW) method, MR-Egger regression, weighted median estimator (WME), simple mode and weighted mode. The stability and reliability of the research results were evaluated by Cochran’s Q test, MR-Egger regression, MR-PRESSO, Leave-one-out, funnel diagram and forest plot.

Results

The causal effects obtained by these five methods were in the same direction. IVW analysis showed that there was causal relationship between CD and NAFLD (OR=1.034, 95%CI: 1.007-1.061, P=0.013). Heterogeneity analysis revealed no significant heterogeneity between IVW test (Q=29.041, P=0.969) and MR-Egger test (Q=29.021, P=0.960). No outlier single nucleotide polymorphisms (SNPs) were detected by MR-PRESSO analysis, and horizontal pleiotropy was excluded (P=0.888). MR-Egger regression analysis (P=0.209) also detected no evidence of horizontal pleiotropy. Leave-one-out analysis showed that no single SNPs significantly affected the overall effect.

Conclusions

From the perspective of heredity, this study preliminarily reveals that CD may have causal relationship with the increase of NAFLD risk. Positive correlation between CD and NAFLD is a risk factor for increasing the risk of NAFLD.

Key words: Crohn’s disease, Nonalcoholic fatty liver disease, Mendelian randomization, Genetics, Risk factors

表1 MR研究中暴露和结局GWAS信息简表

变量	GWAS ID	样本量	SNPs	人群	年份	PMID
CD(暴露)	ieu-a-30	20 883	12 276 506	欧洲	2015	26192919
NAFLD(结局)	ebi-a-GCST90091033	778 614	6 784 388	欧洲	2021	34841290

表1 MR研究中暴露和结局GWAS信息简表

变量	GWAS ID	样本量	SNPs	人群	年份	PMID
CD(暴露)	ieu-a-30	20 883	12 276 506	欧洲	2015	26192919
NAFLD(结局)	ebi-a-GCST90091033	778 614	6 784 388	欧洲	2021	34841290

图1 MR研究三个假设示意图注：MR为孟德尔随机化，CD为克罗恩病，NAFLD为非酒精性脂肪性肝病，SNPs为单核苷酸多态性

图2 纳入的46个SNPs的曼哈顿图注：SNPs为单核苷酸多态性

图3 CD与NAFLD因果关系的MR分析散点图注：CD为克罗恩病，NAFLD为非酒精性脂肪性肝病，MR为孟德尔随机化，SNPs为单核苷酸多态性，WME为加权中位数法，simple mode为简单模式，weighted mode为加权模式，IVW为逆方差加权法

表2 CD与NAFLD因果关系的MR分析结果

方法	SNPs	β	SE	P值	OR(95%CI)
MR-Egger	46	0.037	0.032	0.243	1.038(0.976~1.104)
WME	46	0.031	0.019	0.107	1.032(0.993~1.071)
IVW	46	0.033	0.013	0.013	1.034(1.007~1.061)
简单模式	46	0.050	0.037	0.180	1.052(0.978~1.130)
加权模式	46	0.035	0.026	0.199	1.035(0.983~1.090)

表2 CD与NAFLD因果关系的MR分析结果

方法	SNPs	β	SE	P值	OR(95%CI)
MR-Egger	46	0.037	0.032	0.243	1.038(0.976~1.104)
WME	46	0.031	0.019	0.107	1.032(0.993~1.071)
IVW	46	0.033	0.013	0.013	1.034(1.007~1.061)
简单模式	46	0.050	0.037	0.180	1.052(0.978~1.130)
加权模式	46	0.035	0.026	0.199	1.035(0.983~1.090)

图4 CD与NAFLD因果关系的MR分析漏斗图注：CD为克罗恩病，NAFLD为非酒精性脂肪性肝病，MR为孟德尔随机化，IVW为逆方差加权法

图5 CD与NAFLD之间风险因果关系的MR分析森林图注：CD为克罗恩病，NAFLD为非酒精性脂肪性肝病，MR为孟德尔随机化

图6 CD与NAFLD关联的MR分析留一法敏感性分析注：CD为克罗恩病，NAFLD为非酒精性脂肪性肝病，MR为孟德尔随机化

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Mendelian randomization analysis of causality between Crohn’s disease and nonalcoholic fatty liver disease

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Mendelian randomization analysis of causality between Crohn’s disease and nonalcoholic fatty liver disease