Atopic Dermatitis Linked to Increased Risk of IgA Nephropathy

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New research has identified a strong positive causal association between atopic dermatitis and IgA nephropathy (IgAN), suggesting atopic dermatitis may increase the risk of IgAN through a decrease in GALNT12 and C1GALT1C1 expression and an increase of aberrant IgA1 production.¹

The bidirectional 2-sample Mendelian randomization study explored the causality between atopic dermatitis, acne, and psoriasis with IgAN and found only atopic dermatitis was causally associated with IgAN, providing new insights into the pathogenesis of IgAN and potential strategies for its prevention and treatment.¹

“The link between inflammatory skin diseases and chronic kidney disease has been demonstrated in studies,” Jing Xiong, of the department of nephrology at Tongji Medical College and Huazhong University of Science and Technology, and colleagues wrote.¹ “At present, studies on the relationship between inflammatory skin diseases and IgAN are so limited that only one cohort study has found a higher risk of IgAN in psoriasis patients.”

A leading cause of glomerulonephritis and renal failure, an estimated 20%-50% of patients with IgAN develop end-stage renal disease within 20 years of diagnosis. A multi-hit model has been proposed suggesting abnormal immune regulation is the core of IgAN pathogenesis, with susceptibility influenced by various genetic and environmental factors. However, the exact cause of IgAN and factors increasing one’s risk for IgAN are not completely understood.²

To investigate the causal associations and potential mechanisms between inflammatory skin diseases and IgAN, investigators conducted a bi-directional 2-sample Mendelian randomization study, selecting instrumental variables for inflammatory skin diseases and IgAN based on genome-wide association studies. Following heterogeneity and pleiotropy tests, the bidirectional causality was evaluated by inverse variance weighted model of random effect along with four other approaches: simple mode, weighted mode, weighted median, and MR-Egger.¹

Investigators obtained 3 atopic dermatitis-related microarray datasets from the GEO database, including GSE16161, GSE32924, and GSE6012. In the combined dataset, the expression of galactose-deficient IgA1-associated genes, including GALNT2, GALNT12, C1GALT1, C1GALT1C, and ST6GALNAC2, was compared between patients with atopic dermatitis and healthy controls.¹

Upon analysis, atopic dermatitis was associated with an increased risk of IgAN (Odds ratio [OR], 1.054; 95% CI, 1.014–1.095; P = .0069). Of note, no single single nucleotide polymorphism was found to drive the entire effect in leave-one–out analysis and no obvious outliers were found on the funnel plot. However, investigators pointed out acne (OR, 0.988; 95% CI, 0.948–1.031; P = .583) and psoriasis (OR, 0.996; 95% CI, 0.966–1.028; P = .821) showed no significant causal relationship with IgAN.¹

In the combined microarray dataset, investigators noted the expression levels of C1GALT1C1 (P = .0025) and GALNT12 (P = 2.3e−9) were significantly decreased in patients with atopic dermatitis compared with controls, while C1GALT1 increased significantly (P = .00067). Although decreased GALNT2 expression (P = .18) and increased ST6GALNAC2 expression (P = .13) were also observed in these patients, there was no statistical significance.¹

Investigators outlined multiple limitations to these findings, including the European population sample included in the GWAS dataset and the lack of validation in an Asian population; the inability to completely exclude pleiotropy; and the use of bioinformatics methods.¹

“In summary, among inflammatory skin diseases, only atopic dermatitis was found to be a risk factor for IgAN. Potential mechanism may be linked to the aberrant expression of Gd-IgA1-related genes,” investigators concluded.¹ “Our findings may provide new insights into the pathogenesis of IgAN and innovative strategies for the prevention and treatment of IgAN.”

References

1. ^{Cao W, Xiong J. Causal associations and potential mechanisms between inflammatory skin diseases and IgA nephropathy: a bi-directional Mendelian randomization study. Front Genet. doi:10.3389/fgene.2024.1402302}
2. ^{Rout P, Limaiem F, Hashmi MF. IgA Nephropathy (Berger Disease). StatPearls. April 22, 2024. Accessed August 16, 2024.https://www.ncbi.nlm.nih.gov/books/NBK538214/}