基于双向孟德尔随机化的不同BMI分型非酒精性脂肪性肝病与2型糖尿病的遗传关联分析

段浩鑫; 江宇泳; 吴亭彧; 熊飞翔; 姜艳丹; 张琴; 赵赛赛; 于浩

doi:10.12449/JCH241011

基于双向孟德尔随机化的不同BMI分型非酒精性脂肪性肝病与2型糖尿病的遗传关联分析

DOI: 10.12449/JCH241011

段浩鑫^{1, 2},
江宇泳²,
吴亭彧¹,
熊飞翔¹,
姜艳丹¹,
张琴¹,
赵赛赛¹,
于浩^2, , ,

1.
北京中医药大学东直门医院研究生院，北京 100700
2.
首都医科大学附属北京地坛医院中西医结合中心，北京 100015

基金项目:

北京市高层次公共卫生技术人才建设项目培养计划 (Discipline Leader-03-04);

首都卫生科研发展专项基金 (2020-2-2172)

利益冲突声明：本文不存在任何利益冲突。

作者贡献声明：段浩鑫负责文章设计，数据处理与分析，论文撰写；江宇泳、于浩负责思路指正，写作指导和文章修改；吴亭彧、熊飞翔负责数据处理与分析；姜艳丹、张琴、赵赛赛负责文献检索，数据搜集。

详细信息

通信作者:
于浩， yuhaodtyy@126.com （ORCID： 0000-0002-2213-0725）

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出版历程
- 收稿日期: 2024-06-04
- 录用日期: 2024-07-25
- 出版日期: 2024-10-25

The genetic association between nonalcoholic fatty liver disease and type 2 diabetes mellitus in different body mass index categories： A bidirectional Mendelian randomization study

1.
Graduate School，Dongzhimen Hospital，Beijing University of Chinese Medicine，Beijing 100700，China
2.
Department of Integrative Medicine，Beijing Ditan Hospital，Capital Medical University，Beijing 100015，China

Research funding:

Beijing Municipal High Rank Public Health Researcher Training Program (Discipline Leader-03-04);

Capital Health Research and Development Project (2020-2-2172)

More Information

Corresponding author: YU Hao， yuhaodtyy@126.com （ORCID： 0000-0002-2213-0725）

摘要

摘要: 目的运用双向双样本孟德尔随机化（MR）评估非酒精性脂肪性肝病（NAFLD）与2型糖尿病（T2DM）的遗传关联，并进一步探讨不同BMI的NAFLD人群与T2DM的因果关系。方法数据来源于以欧洲人群为研究对象的全基因组关联研究，其中NAFLD的样本量为32 941例，T2DM为312 646例，BMI为681 275例。运用单变量、多变量MR方法评估NAFLD总人群及各BMI亚型与T2DM之间的双向因果关系。采用逆方差加权法、MR-Egger回归、约束最大似然与模型平均法、加权中位数法进行MR分析，采用MR多效性残差和与离群值、径向MR、MR-Egger截距法、Cochran Q检验进行敏感性分析。结果单变量MR分析显示NAFLD总人群与T2DM之间存在双向因果关系（正向OR=9.75，95%CI：2.57～37.00，P<0.001；反向OR=1.01，95%CI：1.00～1.01，P<0.01）。多变量MR分析显示经BMI校正后，NAFLD总人群与T2DM的因果关系仍然保持显著（OR=33.12，95%CI：7.57～144.95，P<0.000 1）。亚组分析显示，NAFLD各亚组均与T2DM存在因果关系（瘦型OR=12.19，95%CI：3.35～44.40，P<0.001；超重型OR=4.30，95%CI：1.69～10.92，P<0.01；肥胖型OR=1.67，95%CI：1.14～2.44，P<0.01）。结论本研究从遗传学层面揭示了NAFLD总人群及各BMI亚型与T2DM之间的因果关系。
- 非酒精性脂肪性肝病 /
- 糖尿病， 2型 /
- 身体质量指数 /
- 孟德尔随机化分析
Abstract: Objective To investigate the genetic association between nonalcoholic fatty liver disease （NAFLD） and type 2 diabetes mellitus （T2DM） using bidirectional two-sample Mendelian randomization （MR）， as well as the causal relationship between NAFLD and T2DM across different body mass index （BMI） categories. Methods The data were derived from genome-wide association studies conducted in European populations， with a sample size of 32 941 cases for NAFLD， 312 646 cases for T2DM， and 681 275 cases for BMI. The univariate and multivariate MR methods were used to assess the bidirectional causal relationship between NAFLD and T2DM in the general population and across different BMI subtypes. The methods of inverse-variance weighting， MR-Egger regression， constrained maximum likelihood and model averaging， and weighted median were used to conduct the MR analysis， and MR-Pleiotropy Residual Sum and Outlier， radial MR， the MR-Egger intercept method， and the Cochrane Q test were used for sensitivity analysis. Results The univariate MR analysis revealed a bidirectional causal relationship between NAFLD and T2DM in the general population （forward analysis： odds ratio ［OR］=9.75， 95% confidence interval ［CI］： 2.57‍ ‍—‍ ‍37.00， P<0.001； reverse analysis： OR=1.01， 95%CI： 1.00‍ ‍—‍ ‍1.01， P<0.01）. After adjustment for BMI， the multivariate MR analysis showed that the causal relationship between NAFLD and T2DM remained significant in the general population （OR=33.12， 95%CI： 7.57‍ ‍—‍ ‍144.95， P<0.000 1）. The subgroup analysis showed a causal relationship between NAFLD and T2DM across all BMI subtypes （lean subgroup： OR=12.19， 95%CI： 3.35‍ ‍—‍ ‍44.40， P<0.001； overweight subgroup： OR=4.30， 95%CI： 1.69‍ ‍—‍ ‍10.92， P<0.01； obese subgroup： OR=1.67， 95%CI： 1.14‍ ‍—‍ ‍2.44， P<0.01）. Conclusion This study reveals the causal relationship between NAFLD and T2DM in the general population of NAFLD and across different BMI subtypes from a genetic perspective.
- Non-alcoholic Fatty Liver Disease /
- Diabetes Mellitus， Type 2 /
- Body Mass Index /
- Mendelian Randomization Analysis

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图 1 研究流程图

注： IVW，逆方差加权法；cML-MA，约束最大似然与模型平均法；WM，加权中位数法；MR-PRESSO，MR多效性残差和与离群值检验。

Figure 1. Study flowchart

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图 2 NAFLD总人群与T2DM的双向单变量MR结果

Figure 2. Bidirectional univariate MR results of NAFLD and T2DM in the overall population

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图 3 经BMI调整后的多变量MR分析结果

Figure 3. Multivariate MR analysis results adjusted for BMI

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图 4 NAFLD亚组与T2DM的双向单变量MR结果

Figure 4. Bidirectional univariate MR results of NAFLD subgroups and T2DM

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图 5 Leave-one-out检验结果

Figure 5. Leave-one-out test results

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表 1 各表型GWAS数据汇总信息

Table 1. Summary information of GWAS data for each phenotype

表型	数据来源	PMID	样本量（例）	种族
NAFLD（总人群）	UKB	37235137	32 941	欧洲
瘦型NAFLD	UKB	37235137	13 614	欧洲
超重型NAFLD	UKB	37235137	13 710	欧洲
肥胖型NAFLD	UKB	37235137	5 617	欧洲
T2DM	CMDKP	34862199	312 646	欧洲
BMI	GIANT	30124842	681 275	欧洲
注：PMID，PubMed唯一标识码。

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表 2 NAFLD各组与T2DM的敏感性分析

Table 2. Sensitivity analysis of NAFLD subgroups and T2DM

暴露	结局	正向				反向
		异质性（P值）	水平多效性			异质性（P值）	水平多效性
		异质性（P值）	MR-Egger截距法P值	MR-PRESSO P值	MR-PRESSO 剔除SNP	异质性（P值）	MR-Egger截距法P值	MR-PRESSO P值	MR-PRESSO 剔除SNP
NAFLD总人群	T2DM	0.02	0.69	0.32	无	0.41	0.91	0.38	无
瘦型NAFLD	T2DM	0.98	0.05	0.71	rs17547923， rs58489806^1）	0.99	0.30	0.99	无
超重型NAFLD	T2DM	0.04	0.39	0.21	无	0.61	0.40	0.58	无
肥胖型NAFLD	T2DM	0.74	0.32	0.60	无	1.00	0.87	1.00	无
注：1）第一次MR-Egger截距法P=0.002，进一步采用径向MR剔除的SNP离群值。

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