Mendelian randomization analysis identifies HLA‐A and AP2M1 as genetic biomarkers linked to immune–endocytic crosstalk in intervertebral disc degeneration

TL;DR

This study identifies HLA-A and AP2M1 as genetic biomarkers linking immune and endocytic processes in intervertebral disc degeneration.

Contribution

The novel contribution is the identification of HLA-A and AP2M1 as causal genes in immune-endocytic crosstalk in IVDD through Mendelian randomization.

Findings

HLA-A and AP2M1 show significant causal associations with IVDD risk confirmed via Mendelian randomization.

Overexpression of HLA-A or AP2M1 promotes nucleus pulposus cell proliferation and reduces apoptosis.

Immune infiltration analysis links macrophages and T cells to HLA-A and AP2M1 expression in IVDD tissues.

Abstract

Intervertebral disc degeneration (IVDD) is a major contributor to chronic spinal disorders, yet the role of endocytosis in its pathogenesis remains incompletely understood. In this study, we systematically investigated endocytosis‐related genes associated with IVDD by integrating bulk transcriptome data, single‐cell RNA sequencing datasets, and Mendelian randomization (MR) analysis. Differential expression analyses identified six ERGs consistently dysregulated in IVDD, among which HLA‐A and AP2M1 exhibited significant causal associations with disease risk in MR analysis and were further validated in independent datasets. Functional enrichment and gene set enrichment analyses indicated that these genes were closely involved in immune‐related pathways, including natural killer cell‐mediated cytotoxicity and mammalian target of rapamycin signaling. Immune infiltration analysis revealed marked alterations in macrophages, activated CD4+ T cells, and eosinophils in IVDD tissues, with strong correlations between immune cell proportions and the expression of HLA‐A and AP2M1. In vitro experiments demonstrated that overexpression of HLA‐A or AP2M1 promoted nucleus pulposus cell proliferation, suppressed apoptosis, and enhanced endocytic activity, whereas in vivo overexpression alleviated disc degeneration in a rat model. Collectively, these findings identify HLA‐A and AP2M1 as potential biomarkers linking immune dysregulation and endocytic dysfunction in IVDD and provide new insights into the molecular mechanisms underlying disc degeneration.

HLA‐A and AP2M1 are identified as key endocytosis‐related biomarkers that modulate immune–endocytic crosstalk via mTOR signaling to regulate cell survival, immune infiltration, and the progression of intervertebral disc degeneration.

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