Mendelian randomization study for the roles of IL-18 and IL-1 receptor antagonist in the development of inflammatory bowel disease

Mi, Jiarui; Liu, Zhengye; Pei, Shengduo; Wu, Xia; Zhao, Nan; Jiang, Lingjuan; Zhang, Zhenjie; Bai, Xiaoyin

doi:10.1016/j.intimp.2022.109020

Cited by 10 publications

(13 citation statements)

References 49 publications

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“…In this study, we suggested that the upregulation of IL‐18 might indicate increased risks of IBD and its subtypes. A comprehensive MR study (involving 2‐sample and 3‐sample MR design) about IL‐18 recently done by our group showed a positive correlation of IL‐18 and the susceptibility of IBD with MR meta‐analyses 54 . However, we should also admit that the MR study design is unable to recognize a potential U‐shape correlation between the IL‐18 level and the disease risk.…”

Section: Discussionmentioning

confidence: 90%

“…A comprehensive MR study (involving 2‐sample and 3‐sample MR design) about IL‐18 recently done by our group showed a positive correlation of IL‐18 and the susceptibility of IBD with MR meta‐analyses. 54 However, we should also admit that the MR study design is unable to recognize a potential U‐shape correlation between the IL‐18 level and the disease risk. Gain‐ and loss‐of‐function studies in mouse models as well as multi‐omics analyses in a mouse colitis model and human samples are highly needed to further elucidate the IL‐18 function in the initiation, progression, and healing stages of intestinal inflammation.…”

Section: Discussionmentioning

confidence: 99%

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ST2 and CSF‐1 as potential druggable targets of inflammatory bowel diseases: Results from two‐sample Mendelian randomization study

Bai

et al. 2022

Clinical Translational Sci

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Novel druggable targets are warranted for inflammatory bowel disease (IBD) treatment. We aimed to identify novel circulating proteins with causal associations with the risk of IBDs and provide potential therapeutic targets for IBD treatment. We performed a two-sample Mendelian randomization (MR) study to explore the associations of 55 circulating biomarkers on the risk of IBD, Crohn's disease (CD), and ulcerative colitis (UC) by leveraging the summary statistics from large genomewide association studies and protein quantitative trait loci studies.The individual estimate was pooled together by meta-analyses to estimate the causal effects of each outcome. In univariable MR, we identified several circulating proteins showed potential correlation with IBD, UC, and CD. Of note, we observed that a genetically proxied increased level of suppression of tumorigenicity 2 (ST2) was associated with an elevated risk of IBD (odds ratios [ORs] 1.133, 95% confidence interval [CI] 1.091-1.176, p < 0.0001), CD (ORs 1.188, 95% CI 1.103-1.281, p < 0.0001), and UC cohorts (ORs 1.087, 95% CI 1.050-1.125, p < 0.0001).Additionally, we observed a consistent positive correlation between the level of CSF-1 and the increased risk of IBD in individual MR, with statistically significant causal associations in the meta-analyses with ORs equal to 1.217 (IBD, 95% CI 1.115-1.328, p < 0.0001), 1.223 (CD, 95% CI 1.082-1.382, p = 0.0013), and 1.179 (UC, 95% CI 1.055-1.317, p = 0.0037). This study provided evidence for potential casual associations between circulating ST2 and CSF-1 levels, and increased risks of IBD, UC, and CD, implicating potential treatment targets for IBD and subtypes.

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Section: Discussionmentioning

confidence: 90%

Section: Discussionmentioning

confidence: 99%

ST2 and CSF‐1 as potential druggable targets of inflammatory bowel diseases: Results from two‐sample Mendelian randomization study

Bai

et al. 2022

Clinical Translational Sci

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“…5 Previous researchers have used the MR method and found that genetically predicted circulating IL-18 levels are causally associated with the risk of IBD and rheumatoid arthritis (RA). 6,7 This study of IBD chose six single nucleotide polymorphisms (SNPs) as genetic proxies to represent IL-18 levels based on a large IL-18 pQTL dataset. 6,8 Validation through two-sample Mendelian randomization (TSMR) revealed consistent positive associations between circulating IL-18 and the risk of IBD and its subtypes, with pooled odds ratios (ORs) ranging from 1.20 to 1.27.…”

Section: Introductionmentioning

confidence: 99%

“…6,7 This study of IBD chose six single nucleotide polymorphisms (SNPs) as genetic proxies to represent IL-18 levels based on a large IL-18 pQTL dataset. 6,8 Validation through two-sample Mendelian randomization (TSMR) revealed consistent positive associations between circulating IL-18 and the risk of IBD and its subtypes, with pooled odds ratios (ORs) ranging from 1.20 to 1.27. 6 Compared to the more definitive causal association with IBD, the identification of eight less stringent SNPs from the same data source indicated suggestive associations between genetically predicted IL-18 levels and RA risk, with an OR of 1.07 and a p value of .043.…”

Section: Introductionmentioning

confidence: 99%

“…6,8 Validation through two-sample Mendelian randomization (TSMR) revealed consistent positive associations between circulating IL-18 and the risk of IBD and its subtypes, with pooled odds ratios (ORs) ranging from 1.20 to 1.27. 6 Compared to the more definitive causal association with IBD, the identification of eight less stringent SNPs from the same data source indicated suggestive associations between genetically predicted IL-18 levels and RA risk, with an OR of 1.07 and a p value of .043. 7,8 However, the causal relationship between circulating IL-18 and the risk of other inflammatory and autoimmune diseases remains largely unclear.…”

Section: Introductionmentioning

confidence: 99%

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Genetically predicted circulating interleukin-18 levels are associated with risk of systemic lupus erythematosus and type 1 diabetes

Qin,

Wang,

Leng

et al. 2024

Lupus

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Objective Interleukin-18 (IL-18) is a proinflammatory cytokine. This study aims to determine whether there is a causal relationship between circulating IL-18 concentrations and the risk of inflammatory and autoimmune diseases. Methods We collected significant single nucleotide polymorphisms (SNPs) associated with circulating IL-18 levels ( p < 5 × 10−8) as instrumental variables (IVs) from a genome-wide association study (GWAS) involving 21,758 individuals of European descent. We mainly employed the inverse-variance weighed (IVW) method of two-sample Mendelian randomization (TSMR) analysis to estimate the causality of circulating IL-18 levels on inflammatory and autoimmune diseases. Results The IVW method results showed evidence of a causal relationship between IL-18 and the risk of systemic lupus erythematosus (SLE) (OR = 1.32; 95% CI 1.15, 1.50; p < .001) and type 1 diabetes (T1D) (OR = 1.22; 95% CI 1.06, 1.42; p = .007) in individuals of European ancestry. No significant heterogeneity or horizontal pleiotropy for SLE and T1D was detected. The sensitivity analysis, which involved removing confounding SNP, produced similar results for SLE and T1D. The results of sensitivity analysis using leave-one-out method indicated no single SNP significantly influenced the analysis results. However, we did not find any significant findings for multiple sclerosis, psoriasis, asthma, and osteoarthritis. Conclusions Our analyses suggest that circulating IL-18 is significantly related to SLE and T1D and may serve as a potential target for the treatment of these diseases.

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Synthesis and Anti‐Inflammatory Bowel Disease Activity of Pterostilbene Derivatives

Zhang,

Li,

Liu

et al. 2024

Chemistry & Biodiversity

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The aberrant activation of NLRP3 inflammasomes is intricately linked to various inflammatory diseases. In this study, we present the discovery and optimization of a series of NLRP3 inflammasome inhibitors based on the pterostilbene skeleton. All compounds underwent screening to evaluate their inhibitory effects on LPS/Nigericin‐induced IL‐1β secretion and anti‐cellular pyroptosis. Most compounds exhibit good biological activity and cellular safety, with compound D20 showing the most prominent activity. Preliminary mechanism studies suggest that compound D20 may affect the assembly of NLRP3 inflammasomes by targeting the NLRP3 protein, thereby inhibiting the activation of NLRP3 inflammasomes. The in vivo anti‐inflammatory activity demonstrated significant therapeutic effect of compound D20 on DSS‐induced acute colitis model in mice. This work has important reference significance for the development of drugs targeting NLRP3 inflammasomes.

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Mendelian randomization study for the roles of IL-18 and IL-1 receptor antagonist in the development of inflammatory bowel disease

Cited by 10 publications

References 49 publications

ST2 and CSF‐1 as potential druggable targets of inflammatory bowel diseases: Results from two‐sample Mendelian randomization study

ST2 and CSF‐1 as potential druggable targets of inflammatory bowel diseases: Results from two‐sample Mendelian randomization study

Genetically predicted circulating interleukin-18 levels are associated with risk of systemic lupus erythematosus and type 1 diabetes

Synthesis and Anti‐Inflammatory Bowel Disease Activity of Pterostilbene Derivatives

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