Causal associations between modifiable risk factors and intervertebral disc degeneration

Intervertebral disc degeneration (IVDD) is a common degenerative condition, which is thought to be a major cause of lower back pain (LBP). However, the etiology and pathophysiology of IVDD are not yet completely clear.

To examine potential causal effects of modifiable risk factors on IVDD.

Bidirectional Mendelian randomization (MR) study.

Genome-wide association studies (GWAS) with sample sizes between 54,358 and 766,345 participants.

Outcomes included (1) modifiable risk factors associated with IVDD use in the forward MR; and (2) modifiable risk factors that were determined to have a causal association with IVDD in the reverse MR, including smoking, alcohol intake, standing height, education level, household income, sleeplessness, hypertension, hip osteoarthritis, HDL, triglycerides, apolipoprotein A-I, type 2 diabetes, fasting glucose, HbA1c, BMI and obesity trait.

We obtained genetic variants associated with 33 exposure factors from genome-wide association studies. Summary statistics for IVDD were obtained from the FinnGen consortium. The risk factors of IVDD were analyzed by inverse variance weighting method, MR-Egger method, weighted median method, MR-PRESSO method and multivariate MR Method. Reverse Mendelian randomization analysis was performed on risk factors found to be caustically associated with IVDD in the forward Mendelian randomization analysis. The heterogeneity of instrumental variables was quantified using Cochran's Q statistic.

Genetic predisposition to smoking (OR=1.221, 95% CI: 1.068-1.396), alcohol intake (OR=1.208, 95% CI: 1.056-1.328) and standing height (OR=1.149, 95% CI: 1.072-1.231) were associated with increased risk of IVDD. In addition, education level (OR=0.573, 95%CI: 0.502-0.654)and household income (OR=0.614, 95%CI: 0.445-0.847) had a protective effect on IVDD. Sleeplessness (OR=1.799, 95%CI: 1.162-2.783), hypertension (OR=2.113, 95%CI: 1.132-3.944) and type 2 diabetes (OR=1.069, 95%CI: 1.024-1.115) are three important risk factors causally associated with the IVDD. In addition, we demonstrated that increased levels of triglycerides (OR=1.080, 95%CI:1.013-1.151), fasting glucose (OR=1.189, 95%CI:1.007-1.405), and HbA1c (OR=1.308, 95%CI:1.017-1.683) could significantly increase the odds of IVDD. Hip osteoarthritis, HDL, apolipoprotein A-I, BMI and obesity trait factors showed bidirectional causal associations with IVDD, therefore we considered the causal associations between these risk factors and IVDD to be uncertain.

This MR study provides evidence of complex causal associations between modifiable risk factors and IVDD. It is noteworthy that metabolic disturbances appear to have a more significant effect on IVDD than biomechanical alterations, as individuals with type 2 diabetes, elevated triglycerides, fasting glucose, and elevated HbA1c are at higher risk for IVDD, and the causal association of obesity-related characteristics with IVDD incidence is unclear. These findings provide new insights into potential therapeutic and prevention strategies. Further research is needed to clarify the mechanisms of these risk factors on IVDD.