整合多组学方法鉴定AIF1为IgA肾病的保护因子

文献信息

中文摘要

背景： IgA肾病（IgAN）是全球最常见的原发性肾小球疾病，其诊断仍依赖有创性肾活检。方法：为鉴定无创生物标志物和治疗靶点，我们采用多祖先孟德尔随机化（MR）框架，使用冰岛人群的全蛋白质组关联数据，并在独立的Fenland和英国队列中验证，随后进行转录组学、单细胞RNA测序（scRNA-seq）和细胞间通讯分析。结果：共鉴定出19个候选蛋白，贝叶斯共定位支持其中8个（包括AIF1）共享基因组区域。转录组分析显示IgAN患者外周血单核细胞中AIF1下调，scRNA-seq将该缺失定位至树突状细胞（DCs），扁桃体切除术后150天部分恢复。临床表型MR显示AIF1与血尿和蛋白尿呈负相关，酶联免疫吸附试验（ELISA）显示患者循环AIF1降低。结论：AIF1可能通过DC介导的抗原提呈对IgAN发挥保护作用，是候选的无创生物标志物和治疗靶点。

英文摘要

IgA nephropathy (IgAN) is the most prevalent primary glomerular disease worldwide, and its diagnosis still relies on invasive kidney biopsy. To identify noninvasive biomarkers and therapeutic targets, we applied a multi-ancestry Mendelian randomization (MR) framework using proteome-wide association data from an Icelandic population, with validation in independent Fenland and United Kingdom cohorts, followed by transcriptomic, single-cell RNA sequencing (scRNA-seq), and cell-cell communication analyses. Nineteen candidate proteins were identified, and Bayesian colocalization supported a shared genomic region for eight, including AIF1. Transcriptomic analysis revealed downregulation of AIF1 in peripheral blood mononuclear cells from patients with IgAN, and scRNA-seq localized this depletion to dendritic cells (DCs), with partial restoration 150 days after tonsillectomy. Clinical phenotype MR showed inverse associations between AIF1 and hematuria and albuminuria, and enzyme-linked immunosorbent assay (ELISA) showed reduced circulating AIF1 in patients. AIF1 may protect against IgAN through DC-mediated antigen presentation, representing a candidate noninvasive biomarker and therapeutic target.