Causal Effects of Plasma Metabolites on Intervertebral Disc Degeneration and Low Back Pain: A Mendelian Randomization Study
Abstract
Background: Metabolic disturbances have been implicated in intervertebral disc degeneration (IVDD) and low back pain, but the contribution of circulating metabolites remains uncertain.
Objectives: We examined associations of genetically proxied plasma metabolites and metabolite ratios with IVDD outcomes defined at different anatomical locations and with a related pain phenotype.
Methods: Summary statistics for metabolite exposures were obtained from the Canadian Longitudinal Study on Ageing (CLSA) plasma metabolome genome-wide association study (GWAS). The outcomes were Intervertebral Disc Degeneration of Cervical Spine (IVDD_Cervical), Intervertebral Disc Degeneration of Thoracic, Thoracolumbar, and Lumbosacral Spine (IVDD_TTL), and Low Back Pain (Pain_Lowback). IVDD_Cervical and IVDD_TTL represented IVDD outcomes defined at different anatomical locations of the spine, whereas Pain_Lowback was analysed separately as an IVDD-related pain phenotype. One genome-wide significant sentinel single-nucleotide variant (SNV) was used for each exposure, and Mendelian randomization (MR) estimates were calculated with the Wald ratio. The within-outcome Bonferroni threshold was 6.25 × 10-4.
Results: Eighty metabolites and metabolite ratios were evaluated. Two associations were significant, both for IVDD_TTL. Higher genetically proxied dimethylarginine (SDMA + ADMA), mapped to DDAH1, was associated with lower IVDD_TTL risk (odds ratio [OR] = 0.80; 95% confidence interval [CI]: 0.72-0.90;…
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