DataSheet_1_Causal Effect of Blood Pressure on Bone Mineral Density and Fracture: A Mendelian Randomization Study.docx

BackgroundHypertension may have some association with osteoporosis. This Mendelian randomization (MR) study aimed to explore the causal effect of blood pressure (BP) on bone mineral density (BMD), fall, and fracture.MethodsWe used the genome-wide association study (GWAS) summary data among 330,956 European-descent individuals to identify 107 single-nucleotide polymorphisms (SNPs) as the instrumental variables of BP. MR analyses of these instruments were performed on 53,236 European individuals for the association with forearm BMD (FA-BMD), femoral neck BMD (FN-BMD), and lumbar spine BMD (LS-BMD); 451,179 European individuals for fall susceptibility; and up to 1.2 million individuals from European descent for fracture. Conventional inverse variance weighted (IVW) method was adopted to obtain the causal estimates of BP on different outcomes, while weighted median, MR-egger, and MR pleiotropy residual sum and outlier (MR-PRESSO) test were used for sensitivity analyses.ResultsGenetically high pulse pressure (PP) could significantly improve FA-BMD (beta-estimate: 0.038, 95% confidence interval [CI]: 0.013 to 0.063, SE:0.013, P-value=0.0032 (95% CI: 0.013 to 0.063). This positive finding was also confirmed by weighted-median analysis (beta-estimate: 0.034, 95% CI: 0.000 to 0.067, SE:0.017, P-value=0.046) and MR-Egger analysis (beta-estimate: 0.117, 95% CI: 0.026 to 0.208, SE:0.046, P-value=0.011). However, there was no remarkable MR association between BP and other outcomes (i.e., FN-BMD, LS-BMD, fall, and fracture).ConclusionsOur findings reveal a potentially causal relationship between high PP and improved FA-BMD, which may provide new sights for the treatment of osteoporosis.

背景：高血压可能与骨质疏松症存在一定的关联。本研究旨在通过孟德尔随机化（MR）方法，探讨血压（BP）对骨矿物质密度（BMD）、跌倒和骨折的因果效应。方法：本研究利用来自330,956名欧洲裔个体的全基因组关联研究（GWAS）汇总数据，识别出107个单核苷酸多态性（SNPs）作为血压的 instrumental variables。在53,236名欧洲裔个体中，对这些工具变量进行了MR分析，以探讨其与尺骨骨密度（FA-BMD）、股骨颈骨密度（FN-BMD）和腰椎骨密度（LS-BMD）的相关性；在451,179名欧洲裔个体中，分析了跌倒的易感性；在至120万欧洲裔个体中，分析了骨折的发生。采用传统的逆方差加权（IVW）方法获得血压对不同结局的因果估计，同时使用加权中位数、MR-Egger和MR-pleiotropy残差和异常值（MR-PRESSO）测试进行敏感性分析。结果：遗传高脉压（PP）与FA-BMD显著相关（β估计值：0.038，95%置信区间[CI]：0.013至0.063，标准误：0.013，P值=0.0032（95% CI：0.013至0.063））。这一积极发现也得到加权中位数分析（β估计值：0.034，95% CI：0.000至0.067，标准误：0.017，P值=0.046）和MR-Egger分析（β估计值：0.117，95% CI：0.026至0.208，标准误：0.046，P值=0.011）的证实。然而，血压与其它结局（即FN-BMD、LS-BMD、跌倒和骨折）之间不存在显著的MR关联。结论：本研究揭示了高PP与FA-BMD改善之间的潜在因果关系，这或许为骨质疏松症的治疗提供了新的视角。