一项大规模血浆蛋白质组学孟德尔随机化研究鉴定出与原发性胆汁性胆管炎相关的新型因果性血浆蛋白。

A large-scale plasma proteome Mendelian randomization study identifies novel causal plasma proteins related to primary biliary cholangitis.

机构信息

Hepatobiliary and Pancreatic Surgery Department, General Surgery Center, First Hospital of Jilin University, Changchun, Jilin, China.

出版信息

Front Immunol. 2023 Feb 7;14:1052616. doi: 10.3389/fimmu.2023.1052616. eCollection 2023.

DOI:10.3389/fimmu.2023.1052616

PMID:36825008

原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC9941641/

Abstract

BACKGROUND AND AIMS

Primary biliary cholangitis (PBC) is a progressive chronic autoimmune cholestatic liver disease characterized by the destruction of small intrahepatic bile ducts leading to biliary cirrhosis. Liver biopsy is required in the diagnosis of Antimitochondrial antibody-negative patients. Therefore, novel biomarkers are needed for the non-invasive diagnosis of PBC. To identify novel biomarkers for PBC, we conducted large-scale plasma proteome Mendelian randomization (MR).

METHODS

A total of 21,593 protein quantitative trait loci (pQTLs) for 2297 circulating proteins were used and classified into four different groups. MR analyses were conducted in the four groups separately. Furthermore, the results were discovered and replicated in two different cohorts of PBC. Colocalization analysis and enrichment analysis were also conducted.

RESULTS

Three plasma proteins (ficolin-1, CD40 and protein FAM177A1) were identified and replicated as being associated with PBC. All of them showed significant protective effects against PBC. An increase in ficolin-1 (OR=0.890 [0.843-0.941], p=3.50×10), CD40 (OR=0.814 [0.741-0.895], p=1.96×10) and protein FAM177A1 (OR=0.822 [0.754-0.897], p=9.75×10) reduced the incidence of PBC. Ficolin-1 (PP4 = 0.994) and protein FAM177A1 (PP4 = 0.995) colocalized with the expression of the genes FCN1 and FAM177A1 in whole blood, respectively. Furthermore, CD40 (PP4 = 0.977) and protein FAM177A1 (PP4 = 0.897) strongly colocalized with PBC.

CONCLUSIONS

We expand the current biomarkers for PBC. In total, three (ficolin-1, CD40, and protein FAM177A1) plasma proteins were identified and replicated as being associated with PBC in MR analysis. All of them showed significant protective effects against PBC. These proteins can be potential biomarkers or drug targets for PBC.

摘要

背景和目的

原发性胆汁性胆管炎（PBC）是一种进行性慢性自身免疫性胆汁淤积性肝病，其特征为小肝内胆管破坏导致胆汁性肝硬化。在诊断抗线粒体抗体阴性患者时需要进行肝活检。因此，需要新的生物标志物来进行 PBC 的非侵入性诊断。为了确定 PBC 的新生物标志物，我们进行了大规模血浆蛋白质组 Mendelian 随机化（MR）研究。

方法

共使用了 21593 个蛋白质定量性状基因座（pQTL），用于 2297 种循环蛋白，并将其分为四个不同的组。分别对四个组进行了 MR 分析。此外，在两个不同的 PBC 队列中进行了结果的发现和复制。还进行了共定位分析和富集分析。

结果

鉴定并复制了三种血浆蛋白（ficolin-1、CD40 和蛋白 FAM177A1）与 PBC 相关。它们都显示出对 PBC 的显著保护作用。ficolin-1（OR=0.890[0.843-0.941]，p=3.50×10）、CD40（OR=0.814[0.741-0.895]，p=1.96×10）和蛋白 FAM177A1（OR=0.822[0.754-0.897]，p=9.75×10）的增加降低了 PBC 的发生率。ficolin-1（PP4=0.994）和蛋白 FAM177A1（PP4=0.995）与全血中 FCN1 和 FAM177A1 基因的表达发生共定位。此外，CD40（PP4=0.977）和蛋白 FAM177A1（PP4=0.897）与 PBC 强烈共定位。