针对慢性肾脏疾病（CKD）的进展，有针对性的全身性炎症调节剂表现出许多潜力，但特定炎症因子与CKD之间的因果关系仍然不确定。我们使用了对8,293个芬兰个体进行的41个血清细胞因子的全基因组关联研究，并进行了双向的两样本Mendelian随机化（MR）分析。此外，我们还通过遗传学预测分析评估了炎症因子与CKD，估计的肾小球滤过率（eGFR），透析，CKD快速进展和eGFR快速下降等5种表型之间的因果关系。其中，倒权方差估计（IVW）作为主要的MR方法，MR-Egger、加权中位数和MR-多基因效应残差和异常值（MR-PRESSO）用于敏感性分析。Cochrane的Q检验用于异质性测试。我们使用留一法来确保MR结果的稳定性，并使用Bonferroni校正来评估因果关系的强度。共有17种细胞因子与不同的肾脏结果相关联。在经过Bonferroni校正测试后，更高的肿瘤坏死因子α水平与eGFR快速下降相关（OR = 1.064，95% CI 1.028 - 1.103，P = 0.001），更高的白细胞介素-4水平与eGFR增加相关（β = 0.003，95% CI 0.001 - 0.005，P = 0.002），更高的生长调节性肿瘤基因α（GROα）水平与CKD风险增加相关（OR=1.035，95% CI 1.012 - 1.058，P = 0.003）。相反，对CKD的遗传易感性与GROα的增加以及eGFR的降低可能导致干细胞因子的增加。我们没有发现在分析过程中的水平性多基因效应。我们在遗传学预测水平发现了与引发和进展CKD有关的炎症因子的因果关系。Copyright © 2023 Li, Li, Liu, He, Dong, Dong and Zhang.

While targeted systemic inflammatory modulators show promise in preventing chronic kidney disease (CKD) progression, the causal link between specific inflammatory factors and CKD remains uncertain.Using a genome-wide association study of 41 serum cytokines from 8,293 Finnish individuals, we conducted a bidirectional two-sample Mendelian randomization (MR) analysis. In addition, we genetically predicted causal associations between inflammatory factors and 5 phenotypes, including CKD, estimated glomerular filtration rate (eGFR), dialysis, rapid progression of CKD, and rapid decline in eGFR. Inverse variance weighting (IVW) served as the primary MR method, while MR-Egger, weighted median, and MR-pleiotropy residual sum and outlier (MR-PRESSO) were utilized for sensitivity analysis. Cochrane's Q test for heterogeneity. Leave-one-out method ensured stability of MR results, and Bonferroni correction assessed causal relationship strength.Seventeen cytokines were associated with diverse renal outcomes. Among them, after Bonferroni correction test, higher tumor necrosis factor alpha levels were associated with a rapid decrease in eGFR (OR = 1.064, 95% CI 1.028 - 1.103, P = 0.001), higher interleukin-4 levels were associated with an increase in eGFR (β = 0.003, 95% CI 0.001 - 0.005, P = 0.002), and higher growth regulated oncogene alpha (GROα) levels were associated with an increased risk of CKD (OR=1.035, 95% CI 1.012 - 1.058, P = 0.003). In contrast, genetic susceptibility to CKD was associated with an increase in GROa, and a decrease in eGFR may lead to an increase in stem cell factor. We did not find the presence of horizontal pleiotropy during the analysis.We discovered causally related inflammatory factors that contribute to the initiation and progression of CKD at the genetic prediction level.Copyright © 2023 Li, Li, Liu, He, Dong, Dong and Zhang.