Causal association between inflammatory bowel disease and IgA nephropathy: A bidirectional two-sample Mendelian randomization study

Abstract

Background: An association between inflammatory bowel disease (IBD) [which includes ulcerative colitis (UC) and Crohn’s disease (CD)] and IgA nephropathy (IgAN) has been discovered in observational studies, but the causal relationship is still unknown. The aim of this study was to clarify the causal link between IBD (which includes UC and CD) and IgAN via a two-sample Mendelian randomization (MR) analysis.Methods: Eligible single-nucleotide polymorphisms (SNPs) were selected as instrumental variables (IVs) for analyses and were obtained from the publicly available genome-wide association study (GWAS) summary statistics. Inverse-variance weighting (IVW), Mendelian randomization–Egger (MR-Egger) regression, the Mendelian randomization pleiotropy residual sum and outlier (MR-PRESSO) test, and the weighted median were utilized to obtain the results. The MR-PRESSO test and MR-Egger regression were also performed to detect and correct horizontal pleiotropy. The Cochran’s Q test and “leave-one-out” analysis were also conducted to assess the stability and reliability of the MR results.Results: This study found that IBD, UC, and CD all had significant positive causal effects on IgAN risk (IBD: OR = 1.58, 95% CI 1.15–2.16, p = 4.53 × 10–3; UC: OR = 1.55, 95% CI 1.14–2.11, p = 4.88 × 10–3; CD: OR = 1.57, 95% CI 1.21–2.03, p = 5.97 × 10–4). No significant horizontal pleiotropic effect was found for the causal association between IBD, UC, CD, and the risk of IgAN. Cochran’s Q test identified no evidence of heterogeneity for the IV estimates. The “leave-one-out” sensitivity analysis also revealed that the MR results were robust.Conclusion: The results of this two-sample MR analysis supported that IBD, UC, and CD were causally associated with the risk of IgAN, while there was no sufficient evidence for the causal effect of IgAN on IBD, UC, or CD. Our findings provide theoretical support and a new perspective for the diagnosis and treatment of these two diseases.

Kidney Diseases Associated With Inflammatory Bowel Disease: Impact of Chronic Histologic Damage, Treatments, and Outcomes

“…Although the association between IgAN and IBD may be coincidental, emerging evidence suggests a potential common underlying mechanism in disease pathogenesis. 21 , 22 Recent studies have identified risk loci in genes involved in intestinal mucosal integrity, and common risk alleles for both IgAN and IBD. 23 , 24 The gut-kidney axis hypothesis supports a key role for imbalances between immunity and microbiota in the development or exacerbation of IgAN.…”

Advancements in understanding the role of intestinal dysbacteriosis mediated mucosal immunity in IgA nephropathy

“…These inhibitors effectively reduce the production of inflammatory mediators and the recruitment of inflammatory cells, thereby controlling inflammation driven by overactive Th17 cells. Despite increasing research indicating that IL-17 and Th17 cells play a central role in IgAN and other immune-mediated glomerular diseases, particularly through mechanisms related to the gut microbiome environment [82,193,194], the inhibition of IL-17 A has not consistently produced positive outcomes in some conditions, such as Crohn's disease and IgAN treatment. Moreover, its effectiveness has shown limitations in certain renal disease models [195][196][197].…”

Sequential administration of paricalcitol followed by IL-17 blockade for progressive refractory IgA nephropathy patients

“…Interestingly, a genome-wide association showed that most IgAN loci are directly associated with inflammatory bowel disease, suggesting that IgAN pathogenesis is likely linked to the intestine 16 . Similarly, a Mendelian randomized study indicated causality between inflammatory bowel disease and the development of IgAN 17 . Th17 expression in the gut is induced by intestinal microbiota.…”