Application of GBD 2021 and multiple omics to reveal the association and potential mechanism between glycated hemoglobin and intervertebral disc degeneration.

This study aimed to comprehensively characterize the relationship between glycated hemoglobin (HbA1c) and intervertebral disc degeneration (IVDD) by integrating population-level epidemiological profiling, Mendelian randomization (MR) analysis, multi-omics data, and single-cell transcriptomics. The objectives included clarifying the causal effect of HbA1c on IVDD, identifying key HbA1c-related genes, elucidating their cellular and molecular roles in disc degeneration, and exploring potential therapeutic targets. Global Burden of Disease (GBD) 2021 database was used to evaluate the incidence rate of diabetes mellitus (DM) and low back pain (LBP) across the entire global population. To assess the causal effect of HbA1c on IVDD, MR approache was conducted using summary statistics from large genome-wide association studies. Subsequently, integrating cis-eQTL information, bulk RNA sequencing, and single-cell RNA sequencing were performed to identify HbA1c-related genes involved in disc degeneration, and explore their roles along pseudotime differentiation trajectories. Potential associations between hub genes and IVDD, as well as candidate therapeutic compounds targeting these genes, were further evaluated through database screening and molecular docking. The findings from GBD indicated a correlation between diabetes and low back pain in both 1990 and 2021. The results of MR analysis revealed a causal relationship between HbA1c levels and IVDD. After integrated analysis of the eQTLGen database and RNA-seq data, we identified five hub HRGs, including STAT5A, CDKN1C, TRPS1, NME4, and OASL, which have been implicated in multiple biological processes and pathways associated with IVDD. Moreover, the scRNA-seq analysis showed that hub HRGs were associated with specific cell subpopulations in human nucleus pulposus (NP) tissues, such as inflamed chondrocytes, fibrochondrocytes, chondrocytes, and calcifying chondrocytes. Additionally, hub HbA1c related genes (HRGs) have been found to be associated with several DDDs such as back pain, osteoporosis, and spinal stenosis. Meanwhile, 12 drugs, including resveratrol, dexamethasone, and simvastatin, were identified that have the potential to target hub HRGs. This study revealed a causal effect of HbA1c on IVDD and identified five key HbA1c-related genes (STAT5A, CDKN1C, TRPS1, NME4, and OASL) involved in disc degeneration, providing potential targets for future research.