Mendelian randomization uncovers a protective effect of interleukin-1 receptor antagonist on kidney function

Cho, Jeong Min; Koh, Jung Hun; Kim, Seong Geun; Lee, Soojin; Kim, Yaerim; Cho, Semin; Kim, Kwangsoo; Kim, Yong Chul; Han, Seung Seok; Lee, Hajeong; Lee, Jung Pyo; Joo, Kwon Wook; Lim, Chun Soo; Kim, Yon Su; Park, Sehoon

doi:10.1038/s42003-023-05091-8

Cited by 3 publications

(4 citation statements)

References 63 publications

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“…Increasing blood pressure, diabetes, and inflammatory pathways, for example, all have evidence supporting causal relationships with both renal impairment and AS. 6 , 7 , 15 , 16 , 17 The present study is additionally strengthened by its ability to evaluate the hypothesis of reverse causality. There are several mechanisms through which AS may have been hypothesized to increase the risk of renal impairment.…”

Section: Discussionmentioning

confidence: 82%

Aortic Stenosis and Renal Function: A Bidirectional Mendelian Randomization Analysis

Ciofani,

Han,

Allahwala

et al. 2024

JAHA

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Background Large observational studies have demonstrated a clear inverse association between renal function and risk of aortic stenosis (AS). Whether this represents a causal, reverse causal or correlative relationship remains unclear. We investigated this using a bidirectional 2‐sample Mendelian randomization approach. Methods and Results We collected summary statistics for the primary analysis of chronic kidney disease (CKD) and AS from genome‐wide association study meta‐analyses including 480 698 and 653 867 participants, respectively. We collected further genome‐wide association study summary statistics from up to 1 004 040 participants for sensitivity analyses involving estimated glomerular filtration rate (eGFR) derived from creatinine, eGFR derived from cystatin C, and serum urea nitrogen. Inverse‐variance weighted was the primary analysis method, with weighted‐median, weighted‐mode, Mendelian randomization‐Egger, and Mendelian randomization‐Pleiotropy Residual Sum and Outlier as sensitivity analyses. We did not find evidence of a causal relationship between genetically predicted CKD liability as the exposure and AS as the outcome (odds ratio [OR], 0.94 per unit increase in log odds of genetic liability to CKD [95% CI, 0.85–1.04], P =0.26) nor robust evidence of AS liability as the exposure and CKD as the outcome (OR, 1.04 per unit increase in log odds of genetic liability to AS [95% CI, 0.97–1.12], P =0.30). The sensitivity analyses were neutral overall, as were the analyses using eGFR derived from creatinine, eGFR derived from cystatin C, and serum urea nitrogen. All positive controls demonstrated strong significant associations. Conclusions The present study did not find evidence of a substantial effect of genetically predicted renal impairment on risk of AS. This has important implications for research efforts that attempt to identify prevention and treatment targets for both CKD and AS.

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Section: Discussionmentioning

confidence: 82%

Aortic Stenosis and Renal Function: A Bidirectional Mendelian Randomization Analysis

Ciofani,

Han,

Allahwala

et al. 2024

JAHA

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“…Further support for the deleterious role of IL-1R signaling in kidney disease was recently provided by Cho et al [40]. Using Mendelian randomization analyses to examine the causality between serum interleukin levels and kidney function in the CKDGen and UK Biobank databases, Cho et al found that higher serum levels of the naturally occurring IL-1R antagonist (IL-1ra) were significantly associated with higher eGFR values [40]. IL-1ra is a 16-18-kDa member of the IL-1 family that binds to IL-1 receptors without activating signaling [41,42].…”

Section: Deleterious Effects Of Interleukins In Ns: Il-1r Superfamilymentioning

confidence: 81%

“…Interleukin 1 inhibitors have also been shown to reduce proteinuria and preserve glomerular function in a cohort of patients with Familial Mediterranean Fever [38,39], demonstrating the utility of IL-1/IL-1R antagonists for the treatment of certain forms of podocytopathy. Further support for the deleterious role of IL-1R signaling in kidney disease was recently provided by Cho et al [40]. Using Mendelian randomization analyses to examine the causality between serum interleukin levels and kidney function in the CKDGen and UK Biobank databases, Cho et al found that higher serum levels of the naturally occurring IL-1R antagonist (IL-1ra) were significantly associated with higher eGFR values [40].…”

Section: Deleterious Effects Of Interleukins In Ns: Il-1r Superfamilymentioning

confidence: 99%

Swollen Feet: Considering the Paradoxical Roles of Interleukins in Nephrotic Syndrome

Kovalik,

Dacanay,

Crowley

et al. 2024

Biomedicines

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Interleukins are a family of 40 bioactive peptides that act through cell surface receptors to induce a variety of intracellular responses. While interleukins are most commonly associated with destructive, pro-inflammatory signaling in cells, some also play a role in promoting cellular resilience and survival. This review will highlight recent evidence of the cytoprotective actions of the interleukin 1 receptor (IL-1R)- and common gamma chain receptor (IL-Rγc)-signaling cytokines in nephrotic syndrome (NS). NS results from the injury or loss of glomerular visceral epithelial cells (i.e., podocytes). Although the causes of podocyte dysfunction vary, it is clear that pro-inflammatory cytokines play a significant role in regulating the propagation, duration and severity of disease. Pro-inflammatory cytokines signaling through IL-1R and IL-Rγc have been shown to exert anti-apoptotic effects in podocytes through the phosphoinositol-3-kinase (PI-3K)/AKT pathway, highlighting the potential utility of IL-1R- and IL-Rγc-signaling interleukins for the treatment of podocytopathy in NS. The paradoxical role of interleukins as drivers and mitigators of podocyte injury is complex and ill-defined. Emerging evidence of the cytoprotective role of some interleukins in NS highlights the urgent need for a nuanced understanding of their pro-survival benefits and reveals their potential as podocyte-sparing therapeutics for NS.

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“…It is often characterized by decreased glomerular filtration rate (GFR) which can be estimated from the serum creatinine or cystatin-C level. Various factors play a role in renal function, including cytokines, metabolites, vascular regulation and renal innervation ( 2 ). Although many underlying causes such as hypertension, diabetes and drugs with renal toxicity are known, CKD etiology still remains at least partially unclear, which deserves further investigations.…”

Section: Introductionmentioning

confidence: 99%

Metabolome-wide Mendelian randomization reveals causal effects of betaine and N-acetylornithine on impairment of renal function

Liu,

Ling,

Shen

et al. 2024

Front. Nutr.

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BackgroundChronic kidney disease (CKD) is a common public health problem, which is characterized as impairment of renal function. The associations between blood metabolites and renal function remained unclear. This study aimed to assess the causal effect of various circulation metabolites on renal function based on metabolomics.MethodsWe performed a two-sample Mendelian randomization (MR) analysis to estimate the causality of genetically determined metabolites on renal function. A genome-wide association study (GWAS) of 486 metabolites was used as the exposure, while summary-level data for creatinine-based estimated glomerular filtration rate (eGFR) or CKD occurrence were set the outcomes. Inverse variance weighted (IVW) was used for primary causality analysis and other methods including weight median, MR-egger, and MR-PRESSO were applied as complementary analysis. Cochran Q test, MR-Egger intercept test, MR-PRESSO global test and leave-one-out analysis were used for sensitivity analysis. For the identified metabolites, reverse MR analysis, linkage disequilibrium score (LDSC) regression and multivariable MR (MVMR) analysis were performed for further evaluation. The causality of the identified metabolites on renal function was further validated using GWAS data for cystatin-C-based eGFR. All statistical analyses were performed in R software.ResultsIn this MR analysis, a total of 44 suggestive associations corresponding to 34 known metabolites were observed. After complementary analysis and sensitivity analysis, robust causative associations between two metabolites (betaine and N-acetylornithine) and renal function were identified. Reverse MR analysis showed no causal effects of renal function on betaine and N-acetylornithine. MVMR analysis revealed that genetically predicted betaine and N-acetylornithine could directly influence independently of each other. The causal effects of betaine and N-acetylornithine were also found on cystatin-C-based eGFR.ConclusionOur study provided evidence to support the causal effects of betaine and N-acetylornithine on renal function. These findings required further investigations to conduct mechanism exploration and drug target selection of these identified metabolites.

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Mendelian randomization uncovers a protective effect of interleukin-1 receptor antagonist on kidney function

Cited by 3 publications

References 63 publications

Aortic Stenosis and Renal Function: A Bidirectional Mendelian Randomization Analysis

Aortic Stenosis and Renal Function: A Bidirectional Mendelian Randomization Analysis

Swollen Feet: Considering the Paradoxical Roles of Interleukins in Nephrotic Syndrome

Metabolome-wide Mendelian randomization reveals causal effects of betaine and N-acetylornithine on impairment of renal function

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