Work

Causal genetics prioritizes therapeutic targets and blood signatures in primary biliary cholangitis

Year: 2026

Type: article

Abstract: Primary biliary cholangitis is an autoimmune cholestatic liver disease, but upstream immune programs linking inherited risk to hepatic remodeling and therapeutic targets remain incompletely defined. We developed a cross-tissue causal multi-omics framework integrating PBC GWAS, 731 GWAS-derived immune traits, peripheral blood transcriptomes, and liver bulk and single-cell RNA-seq. Two-sample Mendelian randomization with reverse-causation testing and independent replication identified genetically predicted CD27⁺ unswitched memory B cells as a risk-increasing immune trait for PBC. Liver transcriptomic analyses showed immune and stromal remodeling, while functional mapping prioritized 18 immune-inflammatory genes and supported an 11-gene LASSO blood signature that distinguished PBC from controls. Single-cell analyses localized the causal signal to an expanded hepatic CD27⁺ IgM memory-like B-cell state characterized by terminal, non-proliferative features, adaptive immune activation, T-cell activation programs, and chemokine-centered intercellular communication. Transcription factor activity inference highlighted a CREB1/AP-1-centered regulatory module and nominated pathway inhibitors as hypothesis-generating candidates. Together, these findings provide convergent, but inferential, evidence linking CD27-related genetic susceptibility, a PBC-associated blood transcriptional signature.

Source: npj Systems Biology and Applications

DOI: 10.1038/s41540-026-00817-w

Authors: Qianwen Wang, Honglin Yan, Na Wang, Jingping Yuan

Institution: Renmin Hospital of Wuhan University

Language: English

Topic: Liver Diseases and Immunity

Subfield: Hepatology

Field: Medicine

Domain: Health Sciences

SDG: Good health and well-being

Open Access status: gold

Estimated APC paid: $3,490