目的:已经报道了一种崩解素和金属蛋白酶(ADAM)和一种崩解素和金属蛋白酶与血小板反应素基序(ADAMTS)可能参与骨代谢并与骨矿物质密度有关。进行该孟德尔随机化(MR)分析以确定血清ADAM/ADAMTS与BMD是否存在因果关联,以消除混杂因素。
方法:四个特定位点BMD测量的全基因组汇总统计是从欧洲血统个体的研究中获得的,包括前臂(n=8,143),股骨颈(n=32,735),腰椎(n=28,498)和脚跟(n=426,824)。从最新的欧洲血统全基因组关联研究(n=5336〜5367)中检索了ADAM12,ADAM19,ADAM23,ADAMTS5和ADAMTS6循环水平的遗传工具变量。估计的因果效应由每个变体的Wald比率给出,逆方差加权模型被用作组合来自多个工具的估计的主要方法,并进行了敏感性分析,以评估MR结果的稳健性.Bonferroni校正的显著性设置为P<0.0025,以说明多重检验,宽松的阈值P<0.05被认为是因果关系。
结果:遗传预测的血清ADAM/ADAMTS水平对前臂BMD测量的因果影响,股骨颈和腰椎的MR分析没有统计学支持.尽管主要MR分析给出的ADAMTS5对脚跟BMD的因果效应(β=-0.006,-0.010至0.002,P=0.004)未能达到Bonferroni校正的显著性,额外的MR方法和敏感性分析表明存在稳健的因果关系.
结论:我们的研究为ADAMTS5血清水平升高对足跟BMD降低的因果效应提供了暗示性证据。虽然ADAM12、ADAM19、ADAM23和ADAMTS6与前臂BMD的相关性没有支持性证据,欧洲人的股骨颈和腰椎。
OBJECTIVE: A Disintegrin and Metalloproteinase (ADAM) and A Disintegrin and Metalloproteinase with Thrombospondin Motif (ADAMTS) have been reported potentially involved in bone metabolism and related to bone mineral density. This Mendelian Randomization (MR) analysis was performed to determine whether there are causal associations of serum ADAM/ADAMTS with BMD in rid of confounders.
METHODS: The genome-wide summary statistics of four site-specific BMD measurements were obtained from studies in individuals of European ancestry, including forearm (n = 8,143), femoral neck (n = 32,735), lumbar spine (n = 28,498) and heel (n = 426,824). The genetic instrumental variables for circulating levels of ADAM12, ADAM19, ADAM23, ADAMTS5 and ADAMTS6 were retrieved from the latest genome-wide association study of European ancestry (n = 5336 ~ 5367). The estimated causal effect was given by the Wald ratio for each variant, the inverse-variance weighted model was used as the primary approach to combine estimates from multiple instruments, and sensitivity analyses were conducted to assess the robustness of MR results. The Bonferroni-corrected significance was set at P < 0.0025 to account for multiple testing, and a lenient threshold P < 0.05 was considered to suggest a causal relationship.
RESULTS: The causal effects of genetically predicted serum ADAM/ADAMTS levels on BMD measurements at forearm, femoral neck and lumbar spine were not statistically supported by MR analyses. Although causal effect of ADAMTS5 on heel BMD given by the primary MR analysis (β = -0.006, -0.010 to 0.002, P = 0.004) failed to reach Bonferroni-corrected significance, additional MR approaches and sensitivity analyses indicated a robust causal relationship.
CONCLUSIONS: Our study provided suggestive evidence for the causal effect of higher serum levels of ADAMTS5 on decreased heel BMD, while there was no supportive evidence for the associations of ADAM12, ADAM19, ADAM23, and ADAMTS6 with BMD at forearm, femoral neck and lumbar spine in Europeans.