Genetics of Smoking and Risk of Spinal Degenerative Diseases: A Two-Sample Mendelian Randomization Study

Abstract

Abstract Background: The causal association of smoking in spinal degenerative diseases (SDD) remains uncertain. The main objective of this study was to investigate the causal association between genetic susceptibility of smoking and degenerative spinal disorders by using Mendelian randomization (MR). Materials and methods: Summary statistics for SDD were obtained from the Genome-Wide Association Study (GWAS), including 20,001 intervertebral disc degenerative disease (IVDD) cases, 8,915 sciatica cases, 13,178 low back pain (LBP) cases, and 164,682 controls. Instrumental variables (IVs) and genetic association estimates for smoking initiation were obtained from the Consortium for the Sequencing to Alcohol and Nicotine Use's (GSCAN) GWAS study that included 607,291 individuals of European ancestry. MR analyses were performed using the inverse variance weighting (IVW) method, supplemented with a weighted median method. Potential pleiotropy was assessed using MR-Egger regression. A further sensitivity analysis was performed to test the robustness of the association. Results: In inverse-variance–weighted MR analysis, the genetic susceptibility to smoking initiation was associated with increased risk of IVDD (OR, 1.22; 95% CI, 1.07-1.39; P = 3.6 × 10−16), sciatica (OR, 1.22; 95% CI, 1.03-1.46; P = 0.02), and LBP (OR, 1.34; 95% CI, 1.15-1.56; P = 0.04). The results of the multivariate MR analysis showed that the point estimates of the association between smoking and SDD were not attenuated after accounting for the risk factors associated with SDD (IVDD: OR, 1.24 [95% CI, 1.03-1.45]; P < 0.05; LBP: OR, 1.33 [95% CI, 1.08-1.58]; P < 0.01). However, a significant causal association between smoking and sciatica was not identified in multivariate MR (Sciatica: OR, 1.06 [95% CI, 0.84-1.28]; P = 0.599). Conclusion: These results support a causal association between smoking and increased risk of SDD. Further studies are needed to explain the potential mechanisms of smoking in the development of SDD.