Causal effects of systemic inflammatory regulators on chronic kidney diseases and renal function: a bidirectional Mendelian randomization study

Frontiers in Immunology

Immunology

Mingxuan Li¹  Ao Dong²  Pengfei He²  Hongdian Li²  Cong Liu²  Mianzhi Zhang³  Shaoning Dong⁴ 

[1] Department of Cardiology, Beijing Hospital of Traditional Chinese Medicine, Capital Medical University, Beijing, China;Department of Nephrology, Dongfang Hospital, Beijing University of Chinese Medicine, Beijing, China;Department of Nephrology, Dongfang Hospital, Beijing University of Chinese Medicine, Beijing, China;Department of Nephrology, Tianjin Academy of Traditional Chinese Medicine Affiliated Hospital, Tianjin, China;Department of Nephrology, Tianjin Academy of Traditional Chinese Medicine Affiliated Hospital, Tianjin, China;

关键词: chronic kidney disease;    systemic inflammation;    inflammatory modulators;    Mendelian randomization;    genetic causal association;   

DOI  :  10.3389/fimmu.2023.1229636

 received in 2023-05-26, accepted in 2023-08-14,  发布年份 2023

来源: Frontiers

【 摘 要 】

BackgroundWhile targeted systemic inflammatory modulators show promise in preventing chronic kidney disease (CKD) progression, the causal link between specific inflammatory factors and CKD remains uncertain.MethodsUsing 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.ResultsSeventeen 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.ConclusionWe discovered causally related inflammatory factors that contribute to the initiation and progression of CKD at the genetic prediction level.

【 授权许可】

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Copyright © 2023 Li, Li, Liu, He, Dong, Dong and Zhang