Introduction
Intervertebral disc degeneration (IDD) is a common age-related degenerative disease recognized as one of the leading causes of low back pain and disability in the working-age population. It is the first step in the process leading to degenerative spinal changes, including spondylosis, spondylolisthesis, and spinal stenosis. However, the aetiology of IDD has not yet been fully elucidated. Several single nucleotide polymorphisms (SNPs) have been significantly associated with IDD, although none have been confirmed in subsequent studies. Cross-sectional analyses of the intervertebral disc brightness changes in whole spine MRI of the general population cohort (Wakayama Spine Study: WSS) revealed an association between THBS2 and IDD. An important issue in genetic studies of IDD is that the effects of environmental factors involved in the progression of disc degeneration (DD) differ at each intervertebral disc level. Since IDD prevalence differs at each intervertebral disc level, we separately analysed IDD for each intervertebral disc level. Therefore, we selected eight SNPs of genes with biological evidence from published studies to reveal IDD progression in a 7-year longitudinal study of the general population in Japan.
Materials and Methods
We included 512 participants (age 21-85, average 60) from WSS, who underwent whole spine MRI and blood genome extraction for a 7-year longitudinal study. DD was evaluated using the Pfirrmann classification (Grade 1-5). We selected 8 SNPs [rs2073711 (CILP), rs1676486 (COL11A1), rs9406328 (THBS2), rs17576 (MMP9), rs16924573 (SKT), rs143383 (GDF5), rs4148941 (CHST3), and rs731236 (MMP3)] with a biological basis and a reported significant correlation with DD for reproducibility examination. A multivariate regression analysis was performed, incorporating age and the number of risk alleles as interaction terms. We categorized the degeneration phases based on the amount of change with age: “progressive” if increasing and “terminal” if decreasing.
RESULTS
Across all spinal levels, the transition of degeneration and the 7-year prevalence progression revealed a characteristic low prevalence at the cervicothoracic (C7-T1) and thoracolumbar (T12-L1) junctions, maintaining the same characteristic while increasing prevalence. In the age group of 50 to 80 years, when analyzing the amount of change in DD by disc level, the high-risk groups for THBS2 showed terminal phasewas significant in the thoracolumbar junction (p<0.00625) whereas nominal association of and MMP3 with progressive changes in DD in the thoracic and lumbar regions respectively (p<0.05), CILP with terminal phase at the cervicothoracic junction (C7-T1, T1-2), CHST3with progressive phase in the mid-thoracic region (T5-6, T6-7), GDF5 with progressive phase in the cervical region (C5-6), and terminal phase in the lumbar region (L3-4).
DISCUSSION
We revealed that the genomic factor in IDD progression differed with age by disc levels. The differences in prevalence by disc levels may be attributed to differences in the genetic contribution to DD progression. Utilizing the timing of the effects of susceptibility genes may be useful for predicting DD progression. This study is the first to mention the timing of the action of susceptibility genes and may provide new insights into IDD pathogenesis and potential targets for novel therapy.