Causal association between cathepsins and bone mineral density : univariate and multivariate Mendelian randomization analyses

Abstract

Background: Bone mineral density (BMD) is one of the criteria for assessing osteoporosis, and the mechanisms of its change are complex. However, cathepsins can intervene in the onset and progression of osteoporosis. Previous researchers have found an association between cathepsin K and BMD in middle-aged and older people. However, the association between the cathepsin family and other lifecycle BMD remains uncertain. Method: We first performed univariateMendelian randomisation (MR) analysis to explore potential the association between eight cathepsins and five lifecycle BMD. Next, reverse MR was used to analyze the causality between five lifecycle BMD and each cathepsin. Finally, we used multivariate MR to analyze potential associationbetween multiple cathepsins and five lifecycle BMD. Analysis method uses inverse variance weighting (IVW) to assess causal associations. The weighted median method (WME) and MR-Egger regression were taken as the supplementary note. In addition, sensitivity analyses were performed to assess the reliability of this result. Result: The results of IVW by univariate MR analysis showed that histone enzyme Z was a unfavourable protein for BMD in people aged 60 over years of age (IVW: OR=0.95, 95%Cl=0.92-0.99, P=0.03). In people aged 45-60 years, cathepsin H was a risk protein for BMD (IVW: OR =0.97, 95%Cl =0.94-0.99, P=0.04). The remaining cathepsins showed no associations associated with BMD at different life stages. The IVW results of multivariate MR analysis showed that after adjusting for other cathepsins, cathepsin Z was still negatively correlated with BMD in people aged 60 over years (IVW: OR=0.96, 95%Cl=0.92-1.00, P=0.01). Cathepsin H had no correlated with BMD in people aged 45-60 years (IVW: OR=0.97, 95%Cl=0.93-1.00, P=0.06). The results of IVW in the reverse MR analysis showed no association between cathepsins and BMD at different life stages. The results of the sensitivity analyses of the three analytical methods described above indicate the existence of a robust causal relationship. Conclusions: High content of histone enzyme Z may increase the risk of osteoporosis and fractures in people over the age of 60. This finding may not only improve the accuracy of BMD and cathepsin K in predicting and screening for osteoporosis, but may also provide a potential new avenue for effective treatment of osteoporosis.