基于 GWAS Catalog 数据库样本分析 39 种血浆凝血因子与慢性肾脏病的关系.

Causal relationship between 39 plasma coagulation factors and chronic kidney disease based on samples from the GWAS Catalog database.

BACKGROUND: Plasma coagulation factors have been shown to be strongly associated with chronic kidney disease in many observational studies. Nevertheless, the causal relationship between plasma coagulation factors and chronic kidney disease has not been fully revealed. OBJECTIVE: To assess and explore the association between plasma coagulation factors and chronic kidney disease risk using a two-sample Mendelian randomization approach. METHODS: Genome-wide association study data of 39 plasma coagulation factors with different ID numbers were obtained from the GWAS Catalog database and chronic kidney disease genome-wide association analysis data (ebi-a-GCST003374) were obtained from the Open Genome-Wide Association Study database (IEU Open GWAS), where the sample size of the chronic kidney disease dataset was 117 165 cases and the number of single nucleotide polymorphisms was 2 179 497. Inverse variance weighting, MR-Egger regression, weighted median, weighted mode, and simple mode were used to explore causality. Meanwhile, Cochran Q test was used to assess the variability of single nucleotide polymorphism loci. Horizontal pleiotropy of single nucleotide polymorphisms was verified by MR-Egger intercept test. Sensitivity analyses were performed using the “leave-one-out” method to determine whether the Mendelian randomization results would be confounded by a single single nucleotide polymorphism site. RESULTS AND CONCLUSION: (1) A total of four plasma coagulation factors were associated with chronic kidney disease by Mendelian randomization analysis of 39 plasma coagulation factors and chronic kidney disease. Plasma coagulation factor V (FV) level (odds ratio [OR]=0.922, 95% confidence interval [CI]: 0.875-0.971, P=0.002), plasma FVII level (OR=0.719, 95% CI: 0.521-0.991, P=0.044), plasma FXa level (OR=1.113, 95% CI: 1.009-1.227, P=0.032 ), plasma antithrombin- level (OR=0.849, 95% CI: 0.739-0.975, P=0.020) were significantly associated with chronic kidney disease (all P < 0.05). Horizontal pleiotropy and heterogeneity were not detected. (2) Based on the two-sample Mendelian randomization in the genetic epidemiologic method, plasma FVII level, plasma antithrombin- level, and plasma FV level of coagulation factors were protective factors for the risk of chronic kidney disease, and plasma FXa level was a risk factor of chronic kidney disease. (3) The above results confirm that there is a significant potential causal relationship between plasma coagulation factors and chronic kidney disease. Although we analyzed the data of European populations from international databases, these data analyses have a reference value for the study of chronic kidney disease and coagulation factors in China, and they also provide innovative insights into the study of the genetic epidemiology of chronic kidney disease, and they also provide a certain reference value for the in-depth study of the related databases in China, including the China Health and Retirement Longitudinal Study database. Future studies can focus on the assessment of hypocoagulability or hypercoagulability of related coagulation factors in patients with chronic kidney disease. [ABSTRACT FROM AUTHOR]

背景: 在许多观察性研究中表明, 血浆凝血因子与慢性肾脏病密切相关。尽管如此, 血浆凝血因子与慢性肾脏病之间的因果关系仍尚未完 全揭示清楚。 目的: 采用双样本孟德尔随机化方法评估和探讨血浆凝血因子与慢性肾脏病风险之间的关联。 方法: 从GWAS Catalog数据库中获取不同ID号的39种血浆凝血因子的全基因组关联研究数据, 从开放全基因组关联研究数据库(IEU Open GWAS)中获取慢性肾脏病全基因组关联分析数据(ebi-a-GCST003374), 其中慢性肾脏病数据集的样本量为117 165例, 单核苷酸多态性位 点数量为2 179 497个。使用逆方差加权法, MR-Egger回归法, 加权中位数法, 加权模式法和简单模式法来探讨因果关系；同时, 使用 Cochran Q检验来评估单核苷酸多态性位点的差异性。通过孟德尔随机化-Egger截距测试来验证单核苷酸多态性位点的水平多效性。利用 “留一法”进行敏感性分析, 以确定孟德尔随机化结果是否会受到单一单核苷酸多态性位点的干扰。 结果与结论: ①通过对 39 种血浆凝血因子和慢性肾脏病的孟德尔随机化分析, 总共发现 4 种血浆凝血因子与慢性肾脏病相关。血浆凝血 因子 (F Ⅴ ) 水平 (OR=0.922, 95%CI: 0.875-0.971, P=0.002), 血浆 F Ⅶ水平 (OR=0.719, 95%CI: 0.521-0.991, P=0.044), 血浆 F Ⅹ a 水平 (OR=1.113, 95%CI: 1.009-1.227, P=0.032), 血浆抗凝血Ⅲ水平 (OR=0.849, 95%CI: 0.739-0.975, P=0.020) 与慢性肾脏病之间均有显 著性意义, P 均 < 0.05；未检测到水平多效性和异质性。②基于遗传流行病学方法中双样本孟德尔随机化分析, 凝血因子中血浆 F Ⅶ水平, 血浆抗凝血酶Ⅲ水平, 血浆 F Ⅴ水平是慢性肾脏病发生风险的保护因素, 凝血因子中血浆 F Ⅹ a 水平是慢性肾脏病发生风险的危险因素。 ③上述结果证实, 血浆凝血因子与慢性肾脏病之间存在显著的潜在因果关系, 虽然文章的数据分析研究的是国际数据库的欧洲人群, 但这 些数据分析对中国慢性肾脏病与凝血因子的研究有参考价值, 对慢性肾脏病的遗传流行病学研究提供了创新的见解, 也可为中国相关数据 库的深入研究提供一定的参考价值, 包括中国健康与养老追踪调查数据库等；未来研究可以重点关注相关凝血因子对慢性肾脏病患者体内 低凝或高凝状态的评估。 [ABSTRACT FROM AUTHOR]