Association of Polymorphisms (, , and ) with Susceptibility to Lumbar Disc Herniation: Systematic Review, Meta-Analysis, Trial Sequential Analysis, and Transcriptional Prediction.

: Lumbar disc herniation (LDH) is influenced by genetic, mechanical, and behavioral factors, with genetic predisposition playing a key role. () polymorphisms have been implicated in LDH susceptibility, warranting further investigation. This study aimed to assess the association between polymorphisms (, , and ) and LDH risk through a systematic review, meta-analysis, and trial sequential analysis (TSA). : A systematic literature search was conducted across PubMed, Web of Science, Scopus, Cochrane Library, and CNKI, up until 30 January 2025. A meta-analysis was performed using Review Manager 5.3, with odds ratios (ORs) and 95% confidence intervals (CIs), and heterogeneity assessed via the I statistic. The publication bias and TSA were evaluated using CMA 3.0 and TSA software to ensure the reliability of the results. The FATHMM-XF method was applied to predict the functional effect of coding and non-coding polymorphisms. : From 79 records, 10 studies were entered into the meta-analysis. The meta-analysis results showed no significant association of and polymorphisms with LDH, while exhibited a protective effect, particularly in Asian populations and larger studies. The subgroup analysis revealed significant ethnicity-specific associations for , with stronger effects observed in Asian compared to Caucasian individuals. The trial sequential analysis indicated that additional studies are required to confirm the findings for , while the recessive model of polymorphism showed a near-sufficient sample size for reliable conclusions. : The polymorphism, particularly the tt genotype, appears to have a protective effect against LDH, especially in Asian populations and larger studies. However, further large-scale, multi-ethnic research is needed to confirm these findings and explore underlying biological mechanisms.