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

Hongdian Li; Mingxuan Li; Cong Liu; Pengfei He; Ao Dong; Shaoning Dong; Mianzhi Zhang

doi:10.3389/fimmu.2023.1229636

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

Front Immunol. 2023 Aug 30:14:1229636. doi: 10.3389/fimmu.2023.1229636. eCollection 2023.

Authors

Hongdian Li¹, Mingxuan Li², Cong Liu¹, Pengfei He¹, Ao Dong¹, Shaoning Dong³, Mianzhi Zhang^{1

3}

Affiliations

¹ Department of Nephrology, Dongfang Hospital, Beijing University of Chinese Medicine, Beijing, China.
² Department of Cardiology, Beijing Hospital of Traditional Chinese Medicine, Capital Medical University, Beijing, China.
³ Department of Nephrology, Tianjin Academy of Traditional Chinese Medicine Affiliated Hospital, Tianjin, China.

Abstract

Background: 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.

Methods: 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.

Results: 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.

Conclusion: We discovered causally related inflammatory factors that contribute to the initiation and progression of CKD at the genetic prediction level.

Keywords: Mendelian randomization; chronic kidney disease; genetic causal association; inflammatory modulators; systemic inflammation.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Cytokines / genetics
Genome-Wide Association Study*
Humans
Kidney / physiology
Mendelian Randomization Analysis
Renal Insufficiency, Chronic* / genetics

Substances

Cytokines

Grants and funding

This work was supported by National Natural Science Foundation of China (No. 82074242) and Research Project of Tianjin Academy of Traditional Chinese Medicine Affiliated Hospital (No. 2022008).