Causal effects between gut microbiota and IgA nephropathy: a bidirectional Mendelian randomization study.
Therapeutic approaches that target the gut microbiota (GM) may be helpful in the potential prevention and treatment of IgA nephropathy (IgAN). Meanwhile, relevant studies demonstrated a correlation between GM and IgAN, however, these confounding evidence cannot prove a causal relationship between GM and IgAN.
Based on the data from the GM genome-wide association study (GWAS) of MiBioGen and the IgAN GWAS data from the FinnGen research. A bi-directional Mendelian randomization (MR) study was performed to explore the causal relationship between GM and IgAN. We used inverse variance weighted (IVW) method as the primary method to determine the causal relationship between exposure and outcome in our MR study. Besides, we used additional analysis (MR-Egger, weighted median) and sensitivity analysis (Cochrane's Q test, MR-Egger and MR-PRESSO) to select significant results, followed by Bayesian model averaging (MR-BMA) to test the results of MR study. Finally, a reverse MR analysis was conducted to estimate the probability of reverse causality.
At the locus-wide significance level, the results of IVW method and additional analysis showed that Genus Enterorhabdus was a protective factor for IgAN [OR: 0.456, 95% CI: 0.238-0.875, p=0.023], while Genus butyricicoccus was a risk factor for IgAN [OR: 3.471, 95% CI: 1.671-7.209, p=0.0008]. In the sensitivity analysis, no significant pleiotropy or heterogeneity of the results was found.
Our study revealed the causal relationship between GM and IgAN, and expanded the variety of bacterial taxa causally related to IgAN. These bacterial taxa could become novel biomarkers to facilitate the development of targeted therapies for IgAN, developing our understanding of the "gut-kidney axis".
Ren F
，Jin Q
，Liu T
，Ren X
，Zhan Y
... -
《Frontiers in Cellular and Infection Microbiology》
A Mendelian randomization study investigating the causal relationships between inflammation and immunoglobulin A nephropathy.
Immunoglobulin A nephropathy (IgAN) is an autoimmune disease characterized by the production of galactose‑deficient IgA1 (Gd‑IgA1) and the deposition of immune complexes in the kidney. Exploring the landscape of immune dysregulation in IgAN is valuable for pathogenesis and disease treatment. We conducted Mendelian randomization (MR) to assess the causal correlations between inflammation and IgAN.
Based on available genetic datasets, we investigated potential causal links between inflammation and the risk of IgAN using two-sample MR. We used genome-wide association study (GWAS) summary statistics of 5 typical inflammation markers, 41 inflammatory cytokines, and 731 immune cell signatures, accessed from the public GWAS Catalog. The primary method employed for MR analysis was Inverse Variance Weighted (IVW). To confirm consistency across results, four supplementary MR methods were also conducted: MR-Egger, Weighted Median, Weighted Mode, and Simple Mode. To assess pleiotropy, we used the MR-Egger regression intercept test and Mendelian Randomization Pleiotropy RESidual Sum and Outlier (MR-PRESSO) test. Cochrane's Q statistic was applied to evaluate heterogeneity. Additionally, the stability of the MR findings was verified through the leave-one-out sensitivity analysis.
This study revealed that interleukin-7 (IL-7) and stem cell growth factor beta (SCGF-β) were possibly associated with the risk of IgAN according to the IVW approach, with estimated odds ratios (OR) of 1.059 (95 % confidence interval [CI] 1.015 to 1.104, P = 0.008) and 1.043 (95 % CI 1.002 to 1.085, P = 0.037). Five immune traits were identified that might be linked to IgAN risk, each with P-values below 0.01, including natural killer T %T cell (OR = 1.058, 95 % CI: 1.020 to 1.097, P = 0.002), natural killer T %lymphocyte (OR = 1.055, 95 % CI: 1.016 to 1.096, P = 0.006), CD25++ CD8+ T cell %T cell (OR = 1.057, 95 % CI: 1.016 to 1.099, P = 0.006), CD3 on effector memory CD4+ T cell (OR = 1.045, 95 % CI: 1.019 to 1.071, P = 0.001), and CD3 on CD28+ CD45RA+ CD8+ T cell (OR = 1.042, 95 % CI: 1.016 to 1.068, P = 0.001). CD4 on central memory CD4+ T cell might be a protective factor for IgAN (OR = 0.922, 95 % CI: 0.875 to 0.971, P = 0.002). Moreover, IgAN may be implicated in a high risk of elevated granulocyte colony-stimulating factor (G-CSF) (OR = 1.114, 95 % CI 1.002 to 1.239, P = 0.046).
Our study revealed exposures among typical inflammation markers, inflammatory cytokines, and immune cell signatures that may potentially linked to IgAN risk by MR analysis. This insight may advance our understanding of the etiology of IgAN and support the development of targeted therapeutic strategies.
Ren Y
，Zhang H
《-》
Causal Effects of Gut Microbiota and Metabolites on Chronic Obstructive Pulmonary Disease: A Bidirectional Two Sample Mendelian Randomization Study.
Recent evidence suggests that the gut microbiome and metabolites are intricately involved in Chronic Obstructive Pulmonary Disease (COPD) pathogenesis, yet the precise causal relationships remain unclear due to confounding factors and reverse causation. This study employs bidirectional two-sample Mendelian Randomization (MR) to clarify these connections.
Summary data from publicly available Genome-Wide Association Studies (GWAS) concerning the gut microbiome, metabolites, and COPD were compiled. The selection of genetic instrumental variables (Single Nucleotide Polymorphisms, or SNPs) for MR analysis was conducted meticulously, primarily utilizing the Inverse Variance Weighting (IVW) method, supplemented by MR-Egger regression and the Weighted Median (WM) approach. The evaluation of heterogeneity and horizontal pleiotropy was performed using Cochran's Q test, the MR-Egger intercept test, and the MR-PRESSO global test. Sensitivity analyses, including leave-one-out tests, were conducted to verify the robustness of our results. And the mediation effect of gut microbiota-mediated changes in metabolites on the causal relationship with COPD was analyzed.
Our study identified nine significant gut microbiota taxa and thirteen known metabolites implicated in COPD pathogenesis. Moreover, associations between the onset of COPD and the abundance of five bacterial taxa, as well as the concentration of three known metabolites, were established. These findings consistently withstood sensitivity analyses, reinforcing their credibility. Additionally, our results revealed that gut microbiota contribute to the development of COPD by mediating changes in metabolites.
Our bidirectional Two-Sample Mendelian Randomization analysis has revealed reciprocal causal relationships between the abundance of gut microbiota and metabolite concentrations in the context of COPD. This research holds promise for identifying biomarkers for early COPD diagnosis and monitoring disease progression, thereby opening new pathways for prevention and treatment. Further investigation into the underlying mechanisms is essential to improve our understanding of COPD onset.
Du Y
，Wang S
，Zhou T
，Zhao Z
... -
《International Journal of Chronic Obstructive Pulmonary Disease》
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