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

doi:10.12307/2025.733

Abstract

Abstract: 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.

中国组织工程研究杂志出版内容重点：组织构建；骨细胞；软骨细胞；细胞培养；成纤维细胞；血管内皮细胞；骨质疏松；组织工程

Key words: plasma coagulation factors, chronic kidney disease, Mendelian randomization, causality, genetic variation, genetic epidemiology, instrumental variables, single nucleotide polymorphisms, genome-wide association analysis, sensitivity analysis

CLC Number:

Peng Zehong, Zhu Xi, Wen Jianglong, Zhu Wenzhuo, Liu Chao, Tang Jianwei, Cao Ziyue, Zhu Lili. Causal relationship between 39 plasma coagulation factors and chronic kidney disease based on samples from the GWAS Catalog database[J]. Chinese Journal of Tissue Engineering Research, 2025, 29(24): 5272-5280.

Figures/Tables 6

2.1 工具变量的筛选及弱工具变量偏倚的判断根据GWAS Catalog数据库中ID号的不同，总共发现39种凝血因子表型，并在进行这39种凝血因子对慢性肾脏病影响的孟德尔随机化分析时，根据工具变量筛选条件，筛选出4种凝血因子表型对慢性肾脏病的影响，分别为血浆FⅤ水平、血浆FⅦ水平、血浆FⅩa水平、血浆抗凝血酶Ⅲ水平，并且每种表型分别最终筛选出5，2，4，3个与凝血因子强相关的SNP作为工具变量，见表2。 2.2 凝血因子与慢性肾脏病之间的因果关系在进行GWAS Catalog数据库中的39种凝血因子表型对慢性肾脏病影响的孟德尔随机化分析中发现，在5种孟德尔随机化分析方法中，ivW作为主要分析方法的结果显示，有4种凝血因子：血浆FⅤ水平(OR=0.922，95%CI：0.875-0.971，P=0.002)、血浆FⅦ水平(OR=0.719，95%CI：0.521-0.991，P=0.044)、血浆FⅩa水平(OR=1.113，95%CI：1.009-1.227，P=0.032)、血浆抗凝血酶Ⅲ水平(OR=0.849，95%CI：0.739-0.975，P=0.020)与慢性肾脏病之间有显著性意义，发现其中凝血因子中血浆FⅩa水平是慢性肾脏病发生风险的危险因素，而血浆FⅤ水平、血浆FⅦ水平、血浆抗凝血酶Ⅲ水平是慢性肾脏病发生风险的保护因素，见图2，3。根据双样本孟德尔随机化分析结果所示，在进行MR-Egger回归、WM、简单模型、加权模型分析时，由于血浆FⅦ水平强相关的SNP只有2个，强相关的SNP不足以进行MR-Egger回归、加权中位数、简单模型、加权模型分析，而血浆FⅤ水平、血浆FⅩa水平、血浆抗凝血酶Ⅲ水平进行MR-Egger回归、加权中位数、简单模型及加权模型分析的结果与ivW分析结果总的效应值方向是一致的，见表3，图4。 2.3 凝血因子对慢性肾脏病影响的敏感性分析 2.3.1 异质性和水平多效性分析在进行GWAS Catalog数据库中的39种凝血因子对慢性肾脏病影响的孟德尔随机化分析中，通过使用ivW方法进行异质性检测分析，Cochran′s Q检验结果表明，有4种凝血因子表型：血浆FⅤ水平、血浆FⅦ水平、血浆FⅩa水平、血浆抗凝血酶Ⅲ水平，对慢性肾脏病的工具变量中均不存在异质性(P > 0.05)。在进行MR-Egger回归的截距项来分析SNP的水平多效性时，血浆FⅤ水平、血浆FⅩa水平、血浆抗凝血酶Ⅲ水平分别对慢性肾脏病的工具变量中均不存在水平多效性(P > 0.05)，但是由于血浆FⅦ水平与慢性肾脏病之间强相关的SNP只有2个，强相关的SNP太少，所以无法进行水平多效性检验，Egger-intercep值、SE值、P值显示结果为无，见表3。 2.3.2 留一法敏感性分析结果通过leave-one-out敏感性分析法对结果进行评估，逐一剔除所选SNP，并对其是否影响总体因果关系进行分析，血浆FⅤ水平、血浆FⅩa水平、血浆抗凝血酶Ⅲ水平与慢性肾脏病之间的留一法分析结果显示，均未出现影响总体因果关系显著变化的SNP位点，但是由于血浆FⅦ水平与慢性肾脏病之间强相关的SNP太少，所以无法进行留一法敏感性分析，另外，分别从血浆FⅤ水平、血浆FⅩa水平、血浆抗凝血酶Ⅲ水平与慢性肾脏病之间的漏"

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