Vascular endothelial growth factor (VEGF) is important for bone formation and has been associated with osteoporosis in humans. Therefore, we conducted a two-sample Mendelian randomization study to test whether genetically decreased circulating VEGF was associated with decreased bone mineral density (BMD) and increased risk of fracture. Summary statistics from a genomewide association study (GWAS) meta-analysis of circulating VEGF level (n = 16,112) were used to identify 10 genetic variants explaining up to 52% of the variance in circulating VEGF levels. GWAS meta-analyses on dual-energy X-ray absorptiometry (DXA)-derived BMD of forearm, lumbar spine, and femoral neck (n = up to 32,735) and BMD estimated from heel calcaneus ultrasound (eBMD) (n = 426,824) were used to assess the effect of genetically lowered circulating VEGF levels on BMD. A GWAS meta-analysis including a total of 76,549 cases and 470,164 controls was used to assess the effect of genetically lowered circulating VEGF levels on risk of fracture. A natural log-transformed pg/mL decrease in circulating VEGF levels was not associated with a decrease in forearm BMD (0.02 standard deviation [SD], 95% confidence interval [CI] -0.024 to 0.064, p = 0.38), lumbar spine BMD (-0.005 SD, 95% CI -0.03 to 0.019, p = 0.67), femoral neck BMD (0.004 SD, 95% CI -0.017 to 0.026, p = 0.68), eBMD (-0.006 SD, 95% CI -0.012 to -0.001, p = 0.031) or risk of fracture (odds ratio = 0.99, 95% CI 0.98 to 1.0, p = 0.37) in inverse-variance-weighted Mendelian randomization analyses. Sensitivity analyses did not provide evidence that our results were influenced by pleiotropy. Genetically lowered circulating VEGF was not associated with a decrease in BMD or increased risk of fracture, suggesting that efforts to influence circulating VEGF level are unlikely to have beneficial effects on osteoporosis outcomes and that previous observational associations of circulating VEGF with BMD were influenced by confounding or reverse causation. © 2019 American Society for Bone and Mineral Research.

中文翻译：

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遗传性降低的循环血管内皮生长因子和骨质疏松症结果：孟德尔随机研究。

血管内皮生长因子 (VEGF) 对骨形成很重要，并且与人类的骨质疏松症有关。因此，我们进行了一项两样本孟德尔随机化研究，以测试遗传性循环 VEGF 降低是否与骨矿物质密度 (BMD) 降低和骨折风险增加相关。来自循环 VEGF 水平 (n = 16,112) 的全基因组关联研究 (GWAS) 荟萃分析的汇总统计数据用于鉴定 10 种遗传变异，解释高达 52% 的循环 VEGF 水平差异。GWAS 荟萃分析对双能 X 射线骨密度仪 (DXA) 衍生的前臂、腰椎和股骨颈的 BMD（n = 高达 32,735）和从跟骨超声 (eBMD) 估计的 BMD (n = 426,824)用于评估遗传降低的循环 VEGF 水平对 BMD 的影响。一项包括 76,549 例病例和 470,164 例对照的 GWAS 荟萃分析用于评估遗传降低的循环 VEGF 水平对骨折风险的影响。循环 VEGF 水平的自然对数转换 pg/mL 降低与前臂 BMD 降低无关（0.02 标准偏差 [SD]，95% 置信区间 [CI] -0.024 至 0.064，p = 0.38），腰椎 BMD (-0.005 SD, 95% CI -0.03 to 0.019, p = 0.67), 股骨颈 BMD (0.004 SD, 95% CI -0.017 to 0.026, p = 0.68), eBMD (-0.006 SD, 95% CI -0.012 to -0.001，p = 0.031）或骨折风险（优势比 = 0.99，95% CI 0.98 至 1.0，p = 0.37）在逆方差加权孟德尔随机化分析中。敏感性分析没有提供证据表明我们的结果受到多效性的影响。遗传性降低的循环 VEGF 与 BMD 降低或骨折风险增加无关，这表明影响循环 VEGF 水平的努力不太可能对骨质疏松症结果产生有益影响，并且先前观察到的循环 VEGF 与 BMD 的关联受到混杂或反向因果。© 2019 美国骨与矿物研究学会。