Exploring the Causal Relationship Between the Plasma Levels of MMP1 (Matrix Metalloproteinase-1), MMP3, MMP7, MMP10, and MMP12 and Intervertebral Disc Degeneration: Mendelian Randomization

Background: Several matrix metalloproteinases (MMPs) have been reported to be associated with intervertebral disc degeneration (IDD) in several previous studies. However, the causal relationship between MMPs and IDD remains unclear. In this study, Mendelian randomization (MR) was used to analyze the causal relationship between the plasma levels of multiple MMPs and the risk of IDD.

Methods: The GWAS data of the plasma levels of MMP1, MMP3, MMP7, MMP10, and MMP12 were derived from the genome-wide variation associations of 21 758 European individuals. The genetic associations of the variants with IDD were investigated in the largest genome-wide association study from GWAS pipeline using Phesant derived variables from UKBiobank (1045 cases; 461 965 controls). We used a two-sample MR method to evaluate the causal relationship between these five MMPs and IDD. The causal effects were examined by inverse variance weighted (IVW) test. And sensitivity analysis was performed using Q test of IVW and MR-Egger, MR-Egger-intercept and MR-PRESSO.

Results: We found a significant correlation between increased the plasma level of MMP3 and an increased risk of IDD (IVW: OR 1.000564, 95% CI 1.0000304-1.00110; p = 0.0383). The heterogeneity test (MR-Egger Q test: p = 0.346 and IVW Q test: p = 0.460) indicated that there was no heterogeneity in this instrumental variable on the surface. Also, no directional horizontal pleiotropy was observed in the MR analysis (MR-Egger, p = 0.708 and MR-PRESSO, p = 0.609). There was no significant correlation between the plasma levels of MMP1, MMP7, MMP10, and MMP12 and an increased risk of IDD.

Conclusion: Our MR analysis found that there is a potential causal relationship between increased the plasma level of MMP3 and the risk of IDD in the European population. There is no potential causal relationship between the plasma levels of MMP1, MMP7, MMP10, and MMP12 and an increased risk of IDD.