网络孟德尔随机化分析揭示了连接2型糖尿病和胃肠道疾病的蛋白质通路。

Network Mendelian randomisation analysis deciphers protein pathways linking type 2 diabetes and gastrointestinal disease.

作者信息

Geng Jiawei, Ruan Xixian, Wu Xing, Chen Xuejie, Fu Tian, Gill Dipender, Burgess Stephen, Chen Jie, Ludvigsson Jonas F, Larsson Susanna C, Li Xue, Du Zhongyan, Yuan Shuai

机构信息

Zhejiang Key Laboratory of Blood-Stasis-Toxin Syndrome, Zhejiang Chinese Medical University, Hangzhou, China.

Department of Big Data in Health Science School of Public Health, Center of Clinical Big Data and Analytics of The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China.

出版信息

Diabetes Obes Metab. 2025 Feb;27(2):866-875. doi: 10.1111/dom.16087. Epub 2024 Nov 26.

DOI:10.1111/dom.16087

PMID:39592890

原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC7617254/

Abstract

AIMS

The molecular mechanisms underlying the association between type 2 diabetes (T2D) and gastrointestinal (GI) disease are unclear. To identify protein pathways, we conducted a two-stage network Mendelian randomisation (MR) study.

MATERIALS AND METHODS

Genetic instruments for T2D were obtained from a large-scale summary-level genome-wide meta-analysis. Genetic associations with blood protein levels were obtained from three genome-wide association studies on plasma proteins (i.e. the deCODE study as the discovery and the UKB-PPP and Fenland studies as the replication). Summary-level data on 10 GI diseases were derived from genome-wide meta-analysis of the UK Biobank and FinnGen. MR and colocalisation analyses were performed. Pathways were constructed according to the directionality of total and indirect effects, and corresponding proportional mediation was estimated. Druggability assessments were conducted across four databases to prioritise protein mediators.

RESULTS

Genetic liability to T2D was associated with 69 proteins in the discovery protein dataset after multiple testing corrections. All associations were replicated at the nominal significance level. Among T2D-associated proteins, genetically predicted levels of nine proteins were associated with at least one of the GI diseases. Genetically predicted levels of SULT2A1 (odds ratio = 1.98, 95% CI 1.80-2.18), and ADH1B (odds ratio = 2.05, 95% CI 1.43-2.94) were associated with cholelithiasis and cirrhosis respectively. SULT2A1 and cholelithiasis (PH4 = 0.996) and ADH1B and cirrhosis (PH4 = 0.931) have strong colocalisation support, accounting for the mediation proportion of 72.8% (95% CI 45.7-99.9) and 42.9% (95% CI 15.5-70.4) respectively.

CONCLUSIONS

The study identified some proteins mediating T2D-GI disease associations, which provided biological insights into the underlying pathways.

摘要

目的

2型糖尿病（T2D）与胃肠道（GI）疾病之间关联的分子机制尚不清楚。为了确定蛋白质通路，我们进行了一项两阶段的网络孟德尔随机化（MR）研究。

材料与方法

T2D的遗传工具来自大规模汇总水平的全基因组荟萃分析。与血液蛋白质水平的遗传关联来自三项关于血浆蛋白质的全基因组关联研究（即作为发现阶段的deCODE研究以及作为复制阶段的UKB-PPP和芬兰研究）。关于10种GI疾病的汇总水平数据来自英国生物银行和芬兰基因库的全基因组荟萃分析。进行了MR和共定位分析。根据总效应和间接效应的方向性构建通路，并估计相应的比例中介作用。在四个数据库中进行了药物可及性评估，以对蛋白质介导物进行优先级排序。

结果

经过多重检验校正后，T2D的遗传易感性与发现蛋白质数据集中的69种蛋白质相关。所有关联均在名义显著性水平上得到复制。在与T2D相关的蛋白质中，9种蛋白质的遗传预测水平与至少一种GI疾病相关。SULT2A1的遗传预测水平（优势比=1.98，95%可信区间1.80-2.18）和ADH1B的遗传预测水平（优势比=2.05，95%可信区间1.43-2.94）分别与胆结石和肝硬化相关。SULT2A1与胆结石（PH4=0.996）以及ADH1B与肝硬化（PH4=0.931）具有很强的共定位支持，分别占中介比例的72.8%（95%可信区间45.7-99.9）和42.9%（95%可信区间15.5-70.4）。