GWAS-Informed Candidate Genetic Variants and Gene–Gene/Gene–Environment Interaction Patterns Associated with Intervertebral Disc Degeneration: A Chinese Han Case–Control Study

Background/Objectives: Intervertebral disc degeneration (IDD) is a multifactorial spinal degenerative condition influenced by inherited susceptibility and environmental exposures. Genetic evidence from Chinese Han populations remains limited. This study aimed to evaluate GWAS-informed and previously reported candidate single-nucleotide polymorphisms (SNPs) associated with IDD and to explore potential gene–gene and gene–environment interaction patterns. Methods: A hospital-based case–control study was conducted in 1951 unrelated Chinese Han participants, including 929 patients with magnetic resonance imaging-confirmed IDD and 1022 control subjects without evident IDD. Candidate SNPs were genotyped using the MassARRAY platform. Multivariable logistic regression was used to assess genetic associations under different genetic models, and linkage disequilibrium, haplotype associations, additive and multiplicative interactions, and generalized multifactor dimensionality reduction (GMDR) were further evaluated. Results: Of the 60 initially selected candidate SNPs, 49 passed quality control and were retained for association analyses. Several variants showed nominal associations with IDD susceptibility. Representative associations included MMP3 rs591058 under the recessive model (OR = 1.37, 95% CI: 1.06–1.79, p = 0.019) and VDR rs2228570 under the dominant model (OR = 1.52, 95% CI: 1.10–2.11, p = 0.012), whereas the CCDC26 rs6651255–rs7816342 AC haplotype showed a protective association (OR = 0.87, 95% CI: 0.76–0.99, p = 0.046). Exploratory interaction analyses suggested possible gene–gene interactions involving ACAN, IL1B, VDR, CASP3, and CEP162/RIPPLY2, as well as gene–environment interactions involving smoking, weight-bearing workload, and duration of bending work. Conclusions: This study provides preliminary genetic epidemiological evidence that GWAS-informed candidate variants and exploratory interaction patterns may be associated with IDD susceptibility in the Chinese Han population. These findings require further replication and functional validation.