Lv Xin, Wu Pengfei, Xiao Shipeng, Zhang Wan, Li Yawei, Ren Bolin, Li Zhihong, Xia Kun, Wang Bing
Department of Spine Surgery, The Second Xiangya Hospital, Central South University, Changsha, China.
Center for Medical Genetics and Hunan Key Laboratory of Medical Genetics, School of Life Sciences, Central South University, Changsha, China.
Front Genet. 2021 Nov 18;12:754795. doi: 10.3389/fgene.2021.754795. eCollection 2021.
We aimed at investigating causal associations between matrix metalloproteinases (MMPs) and bone mineral density (BMD) by the Mendelian randomization (MR) analysis. From genome-wide association studies of European ancestry, we selected instrumental variables for MMP-1, MMP-3, MMP-7, MMP-8, MMP-10, and MMP-12. Accordingly, we retrieved summary statistics of three site-specific BMD, namely, forearm, femoral neck, and lumbar spine. We conducted an inverse variance weighted MR as the primary method to compute overall effects from multiple instruments, while additional MR approaches and sensitivity analyses were implemented. Bonferroni-adjusted significance threshold was set at p < 0.05/18 = 0.003. Totally, there was no evidence for causal effects of genetically-predicted levels of MMPs on BMD measurement at three common sites. MR results indicated that there were no causal associations of circulating MMPs with forearm BMD (all p ≥ 0.023) by the inverse variance weighted method. Similarly, there were no causal effects of MMPs on femoral neck BMD (all p ≥ 0.120) and MR results did not support causal relationships between MMPs and lumbar spine BMD (all p ≥ 0.017). Multiple sensitivity analyses suggested the robustness of MR results, which were less likely to be biased by unbalanced pleiotropy or evident heterogeneity. We found no evidence for the causal relationship between MMPs and BMD in the European population.
我们旨在通过孟德尔随机化（MR）分析研究基质金属蛋白酶（MMPs）与骨密度（BMD）之间的因果关联。从欧洲血统的全基因组关联研究中，我们为MMP-1、MMP-3、MMP-7、MMP-8、MMP-10和MMP-12选择了工具变量。相应地，我们检索了三个特定部位骨密度的汇总统计数据，即前臂、股骨颈和腰椎。我们采用逆方差加权MR作为主要方法来计算多个工具变量的总体效应，同时实施了额外的MR方法和敏感性分析。Bonferroni校正的显著性阈值设定为p < 0.05/18 = 0.003。总体而言，没有证据表明基因预测的MMPs水平对三个常见部位的骨密度测量有因果效应。MR结果表明，通过逆方差加权法，循环MMPs与前臂骨密度之间没有因果关联（所有p≥0.023）。同样，MMPs对股骨颈骨密度没有因果效应（所有p≥0.120），MR结果也不支持MMPs与腰椎骨密度之间的因果关系（所有p≥0.017）。多项敏感性分析表明MR结果具有稳健性，不太可能因不平衡的多效性或明显的异质性而产生偏差。我们在欧洲人群中未发现MMPs与骨密度之间存在因果关系的证据。
