Genetic Alterations in Intervertebral Disc Disease

Abstract

Background: Intervertebral disc degeneration (IVDD) is considered a multifactorial disease that is influenced by both environmental and genetic factors. The last two decades of research strongly demonstrate that genetic factors contribute about 75% of the IVDD etiology. Recent total genome sequencing studies have shed light on the various single-nucleotide polymorphisms (SNPs) that are associated with IVDD.

Aim: This review presents comprehensive and updated information about the diversity of genetic factors in the inflammatory, degradative, homeostatic, and structural systems involved in the IVDD. An organized collection of information is provided regarding genetic polymorphisms that have been identified to influence the risk of developing IVDD. Understanding the proteins and signaling systems involved in IVDD can lead to improved understanding and targeting of therapeutics.

Materials and methods: An electronic literature search was performed using the National Library of Medicine for publications using the keywords genetics of IVDD, lumbar disc degeneration, degenerative disc disease, polymorphisms, SNPs, and disc disease. The articles were then screened based on inclusion criteria that included topics that covered the correlation of SNPs with developing IVDD. Sixty-five articles were identified as containing relevant information. Articles were excluded if they investigated lower back pain or just disc herniation without an analysis of disc degeneration. This study focuses on the chronic degeneration of IVDs.

Results: Various genes were identified to contain SNPs that influenced the risk of developing IVDD. Among these are genes contributing to structural proteins, such as COL1A1, COL9A3, COL9A3, COL11A1, and COL11A2, ACAN, and CHST3. Furthermore, various SNPs found in the vitamin-D receptor gene are also associated with IVDD. SNPs related to inflammatory cytokine imbalance are associated with IVDD, although some effects are limited by sex and certain populations. SNPs in genes that code for extracellular matrix-degrading enzymes, such as MMP-1, MMP-2, MMP-3, MMP-9, MMP-14, ADAMTS-4, and ADAMTS-5 are also associated with IVDD. Apoptosis-mediating genes, such as caspase 9 gene (CASP9), TRAIL, and death receptor 4 (DR4), as well as those for growth factors, such as growth differentiation factor 5 and VEGF, are identified to have polymorphisms that influence the risk of developing IVDD.

Conclusion: Within the last 10 years, countless new SNPs have been identified in genes previously unknown to be associated with IVDD. Furthermore, the last decade has also revealed new SNPs identified in genes already known to be involved with increased risk of developing IVDD. Improved understanding of the numerous genetic variants behind various pathophysiological elements of IVDD could help advance personalized care and pharmacotherapeutic strategies for patients suffering from IVDD in the future.

Keywords: back pain; biomarker; degeneration; disc; gene expression; herniation; personalized care; single-nucleotide polymorphism.

Figure 1

(A) Normal intervertebral disc (IVD) from the sagittal view. (B) Normal IVD from the axial view. (C) Magnified illustration of an IVD. Used with permission from Barrow Neurological Institute, Phoenix, AZ, USA.

Figure 2

MRIs of intervertebral disc disease in patients with total Pfirrmann scores of (A) 24, (B) 18, and (C) 13 and the assessed score for each lumbar disc. The Pfirrmann grading scale for disc degeneration classifies discs into 5 grades according to the amount of degeneration. Grade 1 corresponds to a hyperintense healthy disc, while grade 5 corresponds to a hypointense severely degenerated disc. The figure contains a point system corresponding to each intervertebral disc from L1 to S1. Five points were given for a grade 1 score, four points for a grade 2, three for a grade 3, two for a grade 4, and one for a grade 5. The highest possible total score is 25; the lowest possible score is 5. Used with permission from Toktas et al. (20).

Figure 3

Illustration outlining the vitamin D receptor (VDR) signaling pathway. VDR/retinoid X receptor (RXR) interaction with vitamin D response element (VDRE) stimulates gene transcription. Used with permission from Barrow Neurological Institute, Phoenix, AZ, USA.