血管内皮生长因子与静脉血栓栓塞风险：一项遗传相关性和两样本孟德尔随机化研究
Vascular endothelial growth factor and the risk of venous thromboembolism: a genetic correlation and two-sample Mendelian randomization study.
作者信息
Zhang Qiaoyun, Zhang Xiaoyu, Zhang Jie, Wang Biyan, Tian Qiuyue, Meng Xiaoni, Zhang Jinxia, Jiang Mengyang, Zhang Yiqiang, Zheng Deqiang, Wu Lijuan, Wang Wei, Wang Baoguo, Wang Youxin
机构信息
School of Public Health, Capital Medical University, No. 10 Xitoutiao, Youanmenwai Street, Fengtai District, 100069, Beijing, China.
Department of Anesthesiology, Beijing Sanbo Brain Hospital, Capital Medical University, 50 Yikesong Road, Haidian District, 100093, Beijing, China.
出版信息
Thromb J. 2022 Nov 8;20(1):67. doi: 10.1186/s12959-022-00427-6.
BACKGROUND
The relationship between vascular endothelial growth factor (VEGF) and the risk of venous thromboembolism (VTE) has always been one of the concerns in the medical field. However, the causal inferences from published observational studies on this issue may be affected by confounders or reverse causality. We performed a two-sample bidirectional Mendelian randomization (MR) to infer the associations between VEGF and VTE.
METHODS
Summary statistics from genome-wide association studies (GWAS) for VEGF and VTE were obtained from published meta-analysis studies and the FinnGen consortium, respectively. Independent genetic variables significantly associated with exposure were selected as instrumental variables. Linkage disequilibrium score regression (LDSC) and five robust MR analytical approaches were conducted to estimate the genetic correlations and causal inference. The MR-Egger intercept, Cochran's Q, and MR pleiotropy residual sum and outlier (MR-PRESSO) were performed to evaluate the horizontal pleiotropy, heterogeneities, and stability of these genetic variants on outcomes. Notably, replication analyses were performed using different subgroups of VTE.
RESULTS
LDSC failed to identify genetic correlations between VEGF and VTE. Based on 9 SNPs, the circulating VEGF level was positively related to the risk of VTE using inverse variance weighting (IVW) method (odds ratio (OR) = 1.064, 95% confidence interval (CI), 1.009-1.122). Reverse MR analyses showed that genetic liability for VTE was not associated with increased VEGF level (β = -0.021, 95% CI, -0.087-0.045). Pleiotropy-robust methods indicated no bias in any estimates.
CONCLUSIONS
Our findings failed to detect coheritability between VEGF and VTE. The suggestive positive effect of the higher VEGF level on the VTE risk may have clinical implications, suggesting that VEGF as a possible predictor and therapeutic target for VTE prevention need to be further warranted.
背景
血管内皮生长因子（VEGF）与静脉血栓栓塞症（VTE）风险之间的关系一直是医学领域关注的问题之一。然而，已发表的关于该问题的观察性研究的因果推断可能受到混杂因素或反向因果关系的影响。我们进行了一项两样本双向孟德尔随机化（MR）研究，以推断VEGF与VTE之间的关联。
方法
分别从已发表的荟萃分析研究和芬兰基因联盟获得VEGF和VTE的全基因组关联研究（GWAS）汇总统计数据。选择与暴露显著相关的独立遗传变量作为工具变量。进行连锁不平衡评分回归（LDSC）和五种稳健的MR分析方法来估计遗传相关性和因果推断。采用MR-Egger截距、 Cochr an's Q和MR多效性残差和异常值（MR-PRESSO）来评估这些遗传变异对结局的水平多效性、异质性和稳定性。值得注意的是，使用不同的VTE亚组进行了重复分析。
结果
LDSC未能识别出VEGF与VTE之间的遗传相关性。基于9个单核苷酸多态性（SNP），使用逆方差加权（IVW）方法，循环VEGF水平与VTE风险呈正相关（比值比（OR）=1.064，95%置信区间（CI），1.009 - 1.122）。反向MR分析表明，VTE的遗传易感性与VEGF水平升高无关（β = -0.021，95% CI，-0.087 - 0.045）。多效性稳健方法表明任何估计均无偏差。
结论
我们的研究结果未能检测到VEGF与VTE之间的共同遗传性。较高的VEGF水平对VTE风险的提示性积极作用可能具有临床意义，表明VEGF作为VTE预防的可能预测指标和治疗靶点需要进一步证实。
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